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Extracellular Matrix and Tissue Specificity

00:00:00.29 Hello.
00:00:02.00 I'm Mina Bissell.
00:00:03.11 I work at Lawrence Berkeley National Laboratory.
00:00:06.08 It is one of the first national laboratories
00:00:09.08 in the US,
00:00:10.22 but it is part of the UC campus,
00:00:12.10 so we are a campus of the University of California.
00:00:14.24 I'm delighted to be giving this talk to you
00:00:17.20 because, as you will see,
00:00:21.02 a lot of what I'm going to tell you
00:00:22.26 is still not in your textbooks,
00:00:24.22 so I'm delighted to be able to talk to you
00:00:27.13 and explain why I got so excited about it
00:00:31.05 and why it's so important.
00:00:33.18 So, the title of the talk is
00:00:35.09 "The Importance of Extracellular Matrix (ECM)
00:00:37.21 and Microenvironment
00:00:39.21 in Tissue-Specificity and Breast Cancer."
00:00:43.04 So, the Part I,
00:00:45.16 which is more general, for a more general
00:00:48.03 and less experienced audience,
00:00:50.09 is that half the secret of the cell
00:00:52.13 is outside the cell,
00:00:54.26 and so the talk is going to say that
00:00:57.25 the genes and the microenvironment
00:01:00.07 actually talk to each other.
00:01:02.13 So, to try and start this,
00:01:04.28 I work in a national lab,
00:01:06.22 and very often I have physicists in my talks,
00:01:11.24 so I try to tell them what I do
00:01:13.28 and I give them the lesson 1
00:01:15.24 in developmental biology,
00:01:18.00 and what's in lesson 1 is,
00:01:19.27 when your mom and dad met,
00:01:21.28 there is an egg
00:01:24.04 and there is a sperm on top, that little blip.
00:01:29.06 A single cell gets fertilized.
00:01:34.14 It does this
00:01:36.06 - it becomes double, quadruple, moves on...
00:01:39.22 it then becomes an embryo,
00:01:43.05 and before you know it,
00:01:44.18 look what it does, it makes this.
00:01:48.01 So, the question is,
00:01:50.19 how do these cells,
00:01:53.13 that all started from that single one,
00:01:56.04 all of them read the same genetic material,
00:01:59.26 how do they make her the way she is?
00:02:02.06 Of course, not the lipstick,
00:02:04.02 but all the rest.
00:02:06.02 Now, have a guess.
00:02:08.06 How many cells do you think are in her body?
00:02:11.01 So, the opinions vary...
00:02:14.08 some people say 10 trillion,
00:02:16.13 some people say 70 trillion.
00:02:18.06 I don't know who counted them, really,
00:02:20.19 but the point is that it is more
00:02:23.08 than the national debt of the US.
00:02:25.22 Now, every one of these cells
00:02:27.23 have the same genetic material,
00:02:30.11 so the question is
00:02:32.07 not only how your nose becomes your nose
00:02:33.29 and your finger your finger,
00:02:35.24 but how do they remember
00:02:37.19 to be a nose and a finger?
00:02:39.24 How do they do that?
00:02:41.21 It's a very important question.
00:02:44.09 So... and all these cells
00:02:46.28 have to coordinate in a way
00:02:48.29 to make you who you are
00:02:50.28 and to tell them to remember
00:02:52.25 what they do.
00:02:54.08 Now, many years ago when I used to say that,
00:02:56.12 people would say,
00:02:57.25 there is such a thing as terminal differentiation.
00:03:00.16 Well, one morning you got up
00:03:02.22 and what you saw in the front page of the New York Times
00:03:05.09 or your local paper
00:03:07.08 was that somebody took a cell from a mammary gland...
00:03:10.16 now remember, it's the mammary gland...
00:03:14.13 a single cell from a frozen mammary gland,
00:03:16.27 and what did they make?
00:03:18.19 A Dolly.
00:03:20.06 So, it says that that particular cell
00:03:22.09 has all the information to make a whole sheep,
00:03:27.00 so why don't we get up one morning
00:03:30.08 and have our nose turn into your elbow?
00:03:33.19 It doesn't, right?
00:03:35.12 Okay, so I came from a background of
00:03:40.01 chemistry and bacterial genetics,
00:03:43.02 and I really had not taken any biology
00:03:46.10 during my career.
00:03:47.27 Some biochemistry,
00:03:49.20 but not very much biology.
00:03:51.09 So, I came to do my postdoc,
00:03:53.12 working with what is known as Rous sarcoma virus.
00:03:59.02 This was discovered
00:04:01.15 by Rous is 1911,
00:04:03.24 and I'm going to be referring to it as RSV.
00:04:07.16 It is a chicken virus
00:04:09.16 and forms ugly tumors like this
00:04:12.02 in the chickens.
00:04:13.13 I mean, look at it.
00:04:15.17 Rous discovered this
00:04:17.19 and then he made the Koch's postulate
00:04:20.17 to come true.
00:04:22.13 In other words, what he did was he took the tumor,
00:04:24.23 he made a filtrate,
00:04:27.03 and then he injected the filtrate into the chicken
00:04:29.17 and, when he did that,
00:04:31.21 he got another tumor.
00:04:33.14 So, everybody got so excited about this,
00:04:36.05 and when people defined what was the cancer gene,
00:04:39.21 then they could even just inject the cancer gene
00:04:42.09 and still get a tumor,
00:04:44.08 so the whole wonderful,
00:04:47.16 exciting field of oncogenes and tumor suppressors
00:04:52.01 got created because of this discovery
00:04:54.10 and because of the later discoveries,
00:04:57.00 but in all honesty, it didn't make any sense to me.
00:05:01.05 We have 10-70 trillion cells in our body.
00:05:04.19 The chicken has quite a few too.
00:05:07.09 So, you inject a single virus into the chicken wing
00:05:10.17 and you get this huge tumor,
00:05:12.04 and you kill the chicken?
00:05:14.02 This doesn't make sense.
00:05:15.21 Every time you breathe,
00:05:17.04 every time you go out in the sun,
00:05:18.24 every time you get depressed,
00:05:20.07 every time... whatever, you get wounded,
00:05:23.15 you have mutations,
00:05:26.18 and some of these mutations are quite deleterious.
00:05:29.27 So, if every time you had some oncogene activated
00:05:33.17 you ended up with a tumor,
00:05:35.13 you would be tumor, tumor, tumor... all over.
00:05:37.11 And you're not.
00:05:39.11 So, what is going on
00:05:41.07 and why does this appear as if it's a single step,
00:05:45.20 single oncogene.
00:05:47.07 So, I did an experiment when I had my own lab
00:05:50.10 at Lawrence Berkeley Lab,
00:05:52.09 and what we did was that we injected this virus
00:05:55.18 into the wing of a chicken embryo,
00:05:59.07 so we could visualize the embryo inside the egg
00:06:03.01 and we could inject the virus into the embryo,
00:06:05.22 and we did it for a reason
00:06:07.13 that I don't have time to tell you
00:06:09.10 but you can read the original papers,
00:06:11.08 and we showed that the virus
00:06:14.23 didn't cause tumors in the embryo.
00:06:18.10 And we showed that, in fact,
00:06:20.09 the oncogene was active.
00:06:23.15 We published this in a fancy journal,
00:06:25.08 like Nature in 1984,
00:06:28.24 and not a ripple, because,
00:06:30.22 and I don't blame people,
00:06:32.19 the burden of proof was on us to go and actually show this,
00:06:35.28 but as you see here,
00:06:38.18 we took the oncogene and we made it blue
00:06:41.01 by attaching it to a reporter gene,
00:06:43.18 and then in order to make people to really believe
00:06:46.05 that the oncogene is active,
00:06:48.08 every one of these beautiful cells,
00:06:52.29 blue cells in that wing of the chicken,
00:06:56.27 in that feather,
00:06:58.24 could in fact be a tumor,
00:07:00.24 and they are not.
00:07:02.17 Now, if we dissociate the wing
00:07:05.00 and we put it in a dish,
00:07:06.23 we get mass transformation overnight.
00:07:10.20 So, what on Earth is going on?
00:07:12.19 In the chicken you get a tumor,
00:07:14.21 in the embryo you don't,
00:07:16.24 you put it in a dish and you get mass transformation...
00:07:20.00 what does that tell you?
00:07:21.23 And as you see, we published this in many different journals
00:07:24.25 and they were well known journals,
00:07:27.11 but again nobody would pay attention,
00:07:29.24 but this told me something very important,
00:07:32.18 and that was that the context,
00:07:35.09 i.e. the microenvironment,
00:07:38.03 determines what even a potent oncogene can do.
00:07:43.24 But, what is context made of?
00:07:46.10 And, does it signal?
00:07:48.19 And besides, people were really not interested
00:07:51.18 in chickens and chicken viruses.
00:07:54.12 They wanted to really talk about our genes
00:07:56.27 and they wanted to talk about mammals,
00:07:59.06 so I decided that I'm going to really
00:08:02.05 be spending a lot of my time, and life,
00:08:06.04 answering the following questions.
00:08:08.14 How is tissue specificity maintained?
00:08:11.12 ...i.e. nose-ness, finger-ness,
00:08:14.05 elbow-ness, prostate-ness,
00:08:16.09 mammary-ness...
00:08:18.10 how is it maintained?
00:08:20.12 How does one study the problem in mammals?
00:08:22.29 Oh, the number of times I wished
00:08:25.16 Drosophila would have mammary glands
00:08:27.20 so one could do genetics,
00:08:29.14 but they don't.
00:08:31.07 And, how is the program lost in cancer and aging?
00:08:34.02 It is precisely when a cell
00:08:37.20 doesn't know that it's supposed to be a nose
00:08:39.23 or a finger
00:08:41.08 or a mammary gland
00:08:42.25 that it starts to pile up and go elsewhere,
00:08:45.10 and aging is the most important risk factor in cancer,
00:08:51.24 and these things are related
00:08:54.02 and they have something to do
00:08:56.04 with the title of my talk,
00:08:58.16 which is the microenvironment.
00:09:00.05 And finally, of course,
00:09:02.02 how can one use the information for therapy?
00:09:04.26 I'm not going to be able to answer all these questions
00:09:07.08 in my introductory lecture,
00:09:09.05 but I will answer some more of these
00:09:11.21 in my next lecture.
00:09:13.23 So, to model mammals,
00:09:15.29 we turned to using the mammary gland
00:09:18.10 as an experimental "organism".
00:09:21.04 It is one of the few tissues
00:09:23.08 that changes during the adult life of the organism,
00:09:26.24 and it moves again and again,
00:09:29.04 and it is an organism within an organism.
00:09:32.08 How?
00:09:34.12 Because it doesn't develop in the embryo.
00:09:36.23 It only happens when the young women
00:09:39.15 start getting their puberty hormones.
00:09:43.15 So, both men and women
00:09:46.08 start with the anlage,
00:09:48.13 of the mammary anlage.
00:09:50.25 Then, the hormones come
00:09:53.03 and the mammary gland grows,
00:09:54.23 and grows,
00:09:56.01 and grows,
00:09:57.10 and grows,
00:09:59.02 and ends puberty with those little pretty things at the end.
00:10:01.18 Then the animal starts getting pregnant
00:10:04.04 and then it buds,
00:10:05.14 and buds,
00:10:06.20 and buds,
00:10:07.09 just like the clusters of grapes,
00:10:08.27 and then when the animal is pregnant
00:10:10.19 it looks like that,
00:10:12.10 and when the babies are taken away
00:10:14.13 after they suckle,
00:10:16.26 the whole gland goes back to this
00:10:18.28 and travels all the way around.
00:10:21.14 So, it's a magnificent model system
00:10:24.02 to answer this question
00:10:26.13 that I have raised for you.
00:10:28.20 So, we decided that the mammary gland itself
00:10:31.21 is quite complex.
00:10:33.27 Here on the left,
00:10:36.08 here, you have this one single lobe
00:10:39.24 of the human mammary gland,
00:10:42.06 but the mammary gland, as you see,
00:10:44.06 has a nipple, has ducts,
00:10:45.22 has branches,
00:10:47.12 has all of this other stuff,
00:10:49.04 and then when the animal gets pregnant,
00:10:51.03 at the tip of that thing,
00:10:52.28 of the branch,
00:10:54.21 there is what is referred to as an acinus,
00:10:58.27 here.
00:11:00.15 It's a very lovely organization...
00:11:02.22 has a lovely organization.
00:11:04.10 It has a basement membrane
00:11:06.16 which is made of extracellular matrix molecules,
00:11:11.12 large molecules
00:11:13.20 that are outside the side,
00:11:15.03 like collagen, like laminin,
00:11:16.28 all these things that keep you together.
00:11:18.24 If you took the collagen out of your body
00:11:21.01 you are going to be like JELL-O.
00:11:22.24 So, people always believed these things
00:11:25.29 had no information
00:11:27.23 and they were just structural elements.
00:11:30.28 Now, you have that lovely basement membrane around,
00:11:34.28 then you have one layer of epithelial cells
00:11:38.02 that are beautiful and polar,
00:11:40.15 and they secrete the milk inside,
00:11:43.03 but between the basement membrane
00:11:45.07 and the epithelial cells,
00:11:47.00 the luminal epithelial cells,
00:11:49.01 there are those blue cells
00:11:51.17 that are called myoepithelial cells,
00:11:53.27 and these cells squeeze the gland
00:11:57.08 and when they squeeze the milk comes out.
00:12:00.07 Okay, so we said,
00:12:02.06 wonderful, we are going to model this
00:12:04.07 and we are going to say,
00:12:06.05 how does the mammary gland do it?
00:12:08.07 Now, no sooner than we had done this
00:12:11.25 than we looked at a single cell
00:12:17.28 of the mammary gland
00:12:19.15 and we could see that it was beautiful and polar.
00:12:22.08 It had secretory activity.
00:12:24.17 It had a beautiful basement membrane.
00:12:26.24 It had a nicely organized nucleus right there,
00:12:30.22 and it was secreting gobs and gobs of milk.
00:12:34.08 So, we take these cells,
00:12:36.00 we put them in a dish,
00:12:37.25 we give them all the lactogenic hormones,
00:12:39.24 we give them everything they need,
00:12:41.29 growth factors, whatever... no serum...
00:12:43.29 trying to keep them functional...
00:12:46.15 in no time at all they looked like this.
00:12:50.06 As you see on the right,
00:12:51.29 the cells lose shape,
00:12:53.27 they lose polarity,
00:12:55.26 and they completely forget to make milk.
00:12:57.28 And you say, "You silly cells,
00:12:59.13 two days ago you were in the mouse,
00:13:01.15 you were making all this milk,
00:13:03.03 what happened to you??"
00:13:04.27 So, it says that the function is not permanent.
00:13:07.05 If you change the context,
00:13:09.13 the function changes, right?
00:13:11.20 So we said, "What is missing?"
00:13:13.29 So, we a section of the mammary gland
00:13:16.01 and, as you see,
00:13:17.24 here is a section of the mouse mammary gland.
00:13:19.24 There are all those beautiful acini
00:13:21.24 surrounded by the red,
00:13:23.16 which is marking the basement membrane,
00:13:26.10 in this case laminin, laminin 111,
00:13:29.17 a very important extracellular matrix molecule
00:13:32.18 that is part of the basement membrane,
00:13:34.28 and you see that the center i
00:13:37.00 s where the milk is
00:13:38.23 and you see these big globule things in here
00:13:41.20 that have fat in them.
00:13:44.16 So, I began to think,
00:13:46.02 and this was late '70s, early '80s,
00:13:48.28 maybe this material has information,
00:13:51.22 and maybe it's telling the cells what to do.
00:13:54.17 And, just around those times,
00:13:56.20 we didn't even know that extracellular matrix molecules
00:14:01.03 either had receptors or they could actually signal.
00:14:04.12 So, we said,
00:14:05.26 "Maybe this material is important,"
00:14:07.19 and to make a very long story short,
00:14:09.19 we made a gelatinous basement membrane
00:14:13.06 that we isolated from a tumor,
00:14:15.16 and there is a woman called Hynda Kleinman
00:14:18.00 who had done initial purification at NIH,
00:14:21.28 and we took these tumors
00:14:23.27 that we used to make in my lab
00:14:25.16 and now they can sell it under the name Matrigel
00:14:28.15 and they can make a lot of money...
00:14:30.24 they have made a lot of money
00:14:32.12 and I wish we could have patented it,
00:14:33.28 we would have made a lot of money.
00:14:36.13 But we didn't, but nevertheless,
00:14:38.21 we put this stuff on a dish,
00:14:40.09 we put the cells on top of it
00:14:42.00 and, as you see,
00:14:43.28 in no time at all they go from this clump,
00:14:46.14 they pull this material over them,
00:14:48.28 they reorganize,
00:14:51.06 and they make that beautiful acini...
00:14:54.08 this is in culture,
00:14:56.09 and this thing is actually in vivo...
00:14:58.26 and even the sizes are similar.
00:15:01.08 So we then said,
00:15:02.29 "It is only looking lovely?
00:15:04.29 Is it also looking polar?
00:15:06.14 It puts the milk inside
00:15:08.09 and it puts the other stuff outside.
00:15:09.27 Does it actually look beautiful like this,
00:15:12.03 as you see how gorgeous they look,
00:15:14.18 or do they also make milk?"
00:15:16.17 They make gobs and gobs of milk.
00:15:19.05 Now, on the left is what they make on plastic.
00:15:22.17 On the right, the red is all the milk that is inside
00:15:27.03 and the blue are other things that go outside,
00:15:30.20 we actually labeled this and did this experiment.
00:15:34.04 Okay, now if you look inside these beautiful acini
00:15:38.05 that have come together,
00:15:40.00 you see that it's full of milk.
00:15:41.27 Now, I am getting up there,
00:15:44.16 because I told you that I was doing these experiments in the '70s, etc...
00:15:48.07 and people in my lab did a wonderful birthday celebration for me
00:15:52.03 for one of those big birthdays
00:15:53.26 and they did this.
00:15:55.12 Now, for those of you who don't read the American newspapers
00:15:58.28 and don't know the ad for milk,
00:16:01.10 this makes the American audiences crack up,
00:16:05.02 but I have a hard time doing this in Europe
00:16:07.24 because they don't understand it, but anyway...
00:16:10.27 So, we got milk and we have a lot of milk.
00:16:13.16 Now, given that normal cells
00:16:16.28 can remember how to look in 3-dimensions,
00:16:20.06 and they can make milk,
00:16:22.03 and they remember that they're mammary gland,
00:16:24.07 we said, "Could tissue structure
00:16:27.21 also be a message for the tumor cells?"
00:16:30.18 We didn't have any assays
00:16:33.23 for distinguishing normal and malignant cells
00:16:36.24 from each other, okay?
00:16:38.28 So, I thought,
00:16:40.25 "Gee, maybe we could do this,"
00:16:42.14 and I did this for humans
00:16:44.21 to also have a counterpart to the mouse
00:16:48.00 after a wonderful guy called Ole Peterson,
00:16:51.03 who is now is a huge professor in Denmark
00:16:53.25 and the head of the department, etc...
00:16:56.05 he came to my lab and he said,
00:16:58.05 "I really would like to do a sabbatical in your lab,
00:17:00.19 I want to work with you."
00:17:02.17 He was an MD/PhD, so I said,
00:17:04.19 "Okay, let's take cells from reduction mammoplasty,
00:17:09.01 this is when women have large breasts
00:17:11.02 and they do it to themselves,
00:17:12.21 they go and take a piece of it out
00:17:14.17 and usually they used to throw it in the garbage,
00:17:17.00 so we could take this material,
00:17:19.02 we could separate the cells and the material,
00:17:22.10 and we said, "Can they actually
00:17:25.13 make the same kind of the organization?"
00:17:29.00 And they do, and they look gorgeous.
00:17:31.19 And then, as you see in this movie on the top,
00:17:34.23 there are the normal cells
00:17:36.11 and in the bottom there are the malignant cells,
00:17:38.24 and Ole did with primary cells
00:17:41.11 as well as with cell lines,
00:17:43.22 and we could show that every one of them...
00:17:46.10 now, the ones on the top, remember,
00:17:48.26 they are not actually single cells,
00:17:52.09 they are like that lovely acini on the black part on the top,
00:17:57.18 but the ones on the bottom are the tumors
00:18:00.21 and every one of them
00:18:03.20 make an ugly tumor.
00:18:05.03 So, it's like having hundreds and thousands
00:18:08.12 of transgenic, normal breast acini
00:18:12.20 and thousands of tumors out there
00:18:15.22 and they're clonal, so it's a wonderful way
00:18:18.24 of being able to take them out,
00:18:20.27 do all sorts of things with it,
00:18:22.26 and if I would have had time for you,
00:18:24.27 I would have told you a fantastic screen we came up with doing
00:18:28.24 just using this concept,
00:18:30.26 which has now been sent out for review
00:18:33.09 but it is not yet published.
00:18:35.00 Okay, but, you know, I did not want
00:18:39.24 to be doing these experiments
00:18:42.12 comparing a normal cell to a malignant cell,
00:18:46.03 where they came from two different individuals,
00:18:48.14 they came 50 years ago,
00:18:50.04 they came at all those...
00:18:52.06 and there was no comparisons.
00:18:54.00 So, we took advantage of a very interesting experiment
00:18:58.10 that Ole Petersen and his professor had done.
00:19:03.03 They had taken cells from reduction mammoplasty,
00:19:06.20 as you see from this woman right there,
00:19:10.11 then they put these cells in a dish,
00:19:13.10 complete defined medium,
00:19:15.04 and they grew it, and grew it, and grew it,
00:19:17.19 only in the presence of epidermal growth factor.
00:19:20.23 Now, at some time around this time,
00:19:25.10 they took the epidermal growth factor away,
00:19:28.03 and I kind of came into the picture at that time,
00:19:32.02 and they started injecting the cells
00:19:35.05 that were grown in the absence of the growth factor,
00:19:39.17 and they started injecting
00:19:41.10 it into the animals,
00:19:43.10 and they eventually got a tumor,
00:19:45.19 and the tumor could go back.
00:19:47.09 So, what do we have?
00:19:49.09 We have the first model of human breast
00:19:52.20 outside humans.
00:19:55.10 We have every step of a cell
00:19:58.25 going from normal to malignant,
00:20:02.06 and we have so many passages
00:20:04.19 and we have them frozen,
00:20:06.16 so it's a wonderful progression model to tell us,
00:20:10.20 how do they do it?
00:20:13.09 Now, the non-malignant cells,
00:20:15.25 as you see, are called S1,
00:20:18.16 the pre-malignant cells are called S2,
00:20:20.16 the malignant cells are called T4-2,
00:20:23.10 and when I was looking at these on the microscope
00:20:26.03 they all looked the same on 2-D,
00:20:28.20 on plastic.
00:20:30.07 Now, if I take this progression
00:20:33.18 and put them in 3-dimensions,
00:20:35.25 that's what they do.
00:20:37.12 So, I'm going to take you through this, alright?
00:20:40.01 So, we start...
00:20:42.11 let's start with passage 50,
00:20:44.17 which is the passage that they actually use in culture.
00:20:47.11 As you see, they already have amplification and deletion,
00:20:50.17 I did these in collaboration with people
00:20:53.19 who do comparative genomic hybridization
00:20:55.27 and so I did it with Ole Petersen.
00:20:58.04 Now, on passage 110,
00:21:00.02 as you see MYC amplifies in passage 50,
00:21:04.01 already p53 got lost,
00:21:06.15 all sorts of things are happening,
00:21:09.02 but the cells still say,
00:21:10.15 "Hey, I'm normal.
00:21:12.14 I can make this beautiful structure."
00:21:14.16 Even in passage 175,
00:21:16.15 they get a little bit bigger
00:21:18.01 and they have a whole lot of other mutations,
00:21:20.06 but they still think they are normal.
00:21:22.04 Now, the exciting thing
00:21:24.14 are the pre-malignant cells.
00:21:26.04 We all of a sudden
00:21:28.09 have an assay for pre-malignancy,
00:21:30.11 as you see those are called S2,
00:21:32.10 and they already lost the structure.
00:21:34.16 That's very interesting.
00:21:36.08 It is before malignancy.
00:21:38.03 The structure is going before malignancy.
00:21:41.14 And, as you see, they have a lot of mutations,
00:21:43.25 but they are not yet malignant.
00:21:45.13 Once in a blue moon,
00:21:47.00 we got that tumor that I showed you,
00:21:48.25 the one at the end,
00:21:50.23 and that one is also a mess,
00:21:52.18 but something happens between S2 and T4
00:21:56.04 that makes them malignant,
00:21:58.00 but the structure goes first.
00:22:00.02 Now, if you think about it,
00:22:03.03 when I destroyed the structure of that chicken wing...
00:22:06.29 chicken embryo wing...
00:22:10.01 they became malignant.
00:22:11.18 When I had it in the beautiful feather
00:22:14.09 and the beautiful wing,
00:22:16.05 they thought they were normal.
00:22:18.04 So, here it's similar ideas.
00:22:20.16 So, we then said,
00:22:22.18 and we made this very crazy hypothesis,
00:22:25.21 we said, "If tissue structure is the message,
00:22:29.18 we can hypothesize that tumor cells,
00:22:33.02 even with abnormal genomes,
00:22:35.24 should be capable
00:22:37.25 of becoming phenotypically normal
00:22:41.01 if the structure is restored.
00:22:43.22 And, then the destruction of tissue structure,
00:22:46.24 by itself,
00:22:48.23 could be a carcinogenic event."
00:22:52.03 Now, this was crazy,
00:22:54.16 because I was saying we could make malignant cells
00:22:59.06 by making them remember their structure,
00:23:01.26 making them think they are normal.
00:23:03.19 Alternatively, we could take a perfectly normal mouse,
00:23:08.13 mess up the structure of the mammary gland,
00:23:10.27 without oncogenes, without suppressor genes,
00:23:13.22 and make them malignant.
00:23:14.29 Well, we have done both of these
00:23:16.26 and I'll now show you a little bit of data on this.
00:23:20.15 So, on the left are these beautiful acini
00:23:23.25 of the non-malignant or "normal" cell.
00:23:26.12 The reason "normal" is in quotations
00:23:28.27 is because we used cell lines from time to time,
00:23:30.21 but everything I'm telling you
00:23:32.19 has also been done with primary cells
00:23:35.05 from human breast from reduction mammoplasty.
00:23:38.05 And, on the right you see these ugly cells
00:23:41.02 that were derived from there.
00:23:43.12 They have something in common,
00:23:46.06 I mean the ancestry in common,
00:23:48.07 but one is completely messed up.
00:23:50.29 Okay, we said,
00:23:52.20 "How does the normal know
00:23:54.12 and the tumor doesn't?"
00:23:56.22 How does that happen?
00:23:58.07 So, they get the message
00:23:59.21 from the microenvironment, right?
00:24:02.09 So, Valerie Weaver,
00:24:03.21 who was a postdoc in my lab
00:24:04.25 and now has her own mini-empire at UCSF,
00:24:07.24 she basically started
00:24:10.24 taking these cells and measuring
00:24:12.28 what was on their surface,
00:24:14.27 because it's the surface
00:24:16.21 that is allowing things to go in and out
00:24:19.16 and messages be taken
00:24:21.25 from the extracellular matrix and microenvironment.
00:24:25.03 So, we showed that the tumor cells and normal cells
00:24:28.09 have a lot in common.
00:24:29.24 They have the same kind of integrins,
00:24:31.09 they have the same kind of epidermal growth factor receptor,
00:24:34.19 but the ratios are different.
00:24:36.28 The malignant cells had something like
00:24:39.16 six times the level of β1 integrin,
00:24:41.07 five times the level of EGFR,
00:24:42.24 etc, etc, etc...
00:24:45.21 So, for various reasons,
00:24:46.18 we decided to go back
00:24:48.29 and make the malignant cells
00:24:51.25 have the level of β1 integrin
00:24:54.21 on their surface
00:24:56.13 which is equivalent to the level in the normal,
00:24:59.12 okay?
00:25:01.00 Not to zero, but equivalent to the normal.
00:25:04.17 And we used an inhibitory antibody
00:25:07.04 against β1.
00:25:08.29 When we did this,
00:25:10.17 look what happened.
00:25:12.14 The cells stopped growing,
00:25:14.08 they reorganized...
00:25:16.18 they're not 100% normal
00:25:18.22 because they have all those mutations, right?
00:25:20.26 And, to just show you that we didn't select,
00:25:24.18 here they are.
00:25:26.12 Every one of those on the top, malignant...
00:25:28.15 every one of them on the bottom, reverted.
00:25:31.09 We call this reversion.
00:25:33.03 Now, if we take these cells on the bottom
00:25:35.27 and inject them like that into the mice
00:25:38.13 - zero tumors.
00:25:40.20 There are 100% tumors if we do these cells on the top, right?
00:25:44.17 So, I would show this to people
00:25:47.12 and people would still say,
00:25:48.20 "No, you must have selected.
00:25:50.06 You must have selected."
00:25:51.29 What selection means?
00:25:53.22 How did I select 10^7 cells or 10^6 cells
00:25:56.24 in 3 days.
00:25:58.16 So, we had to again do the darn experiment,
00:26:00.16 another experiment to make people to listen to us,
00:26:03.10 so we did this:
00:26:05.00 we said, "Reversion is reversible."
00:26:07.29 What did we do?
00:26:10.08 We took cells
00:26:13.08 that were taken from the monolayer,
00:26:15.10 and they...
00:26:17.14 on the top we put them without antibody,
00:26:19.12 you see that ugly picture,
00:26:21.18 and in the bottom you see that
00:26:24.07 we reverted every one of them.
00:26:26.16 Okay, we then took these cells...
00:26:29.16 these cells...
00:26:31.17 dissociated them,
00:26:33.11 put them in another monolayer,
00:26:35.18 and the one without the antibody
00:26:38.06 again did that, on top,
00:26:43.14 and the one with the antibody did this,
00:26:45.13 on the bottom.
00:26:46.24 So, we can do it again and again and again,
00:26:49.14 showing that this is not a selection,
00:26:52.06 and the conclusion of these studies
00:26:54.27 is profound.
00:26:56.22 It's again what I told you in the beginning,
00:26:58.29 and that is that phenotype
00:27:01.12 is dominant over genotype.
00:27:04.04 Now, this used to drive people up the wall,
00:27:06.28 but I will say to them,
00:27:08.09 "Look at yourself in the mirror"...
00:27:10.21 the same gene, the same gene,
00:27:12.08 the same gene, the same gene...
00:27:14.21 so why couldn't tumor cells
00:27:16.26 have the same gene
00:27:18.14 and an entirely different shape,
00:27:19.27 which is exactly the same thing?
00:27:21.28 Alright, that being the case,
00:27:24.14 our conclusion was that
00:27:27.04 growth and malignant behavior
00:27:29.06 are regulated at the level of tissue organization,
00:27:32.07 and that tissue organization
00:27:34.06 is dependent on the extracellular matrix.
00:27:37.19 And I wrote a theoretical paper,
00:27:40.03 long before this,
00:27:42.04 in Journal of Theoretical Biology
00:27:43.28 in 1982,
00:27:45.29 and I suggested that the outside
00:27:48.26 talks to the nucleus and chromatin.
00:27:51.27 Chromatin reorganizes,
00:27:54.11 talks through the cytoskeleton to the outside,
00:27:57.18 and the whole thing is dynamic
00:28:00.14 and reciprocal.
00:28:02.11 So, more than 200 publications
00:28:05.28 and reviews from our lab,
00:28:07.26 in different aspects of this statement I just gave you,
00:28:11.11 and please Google us
00:28:13.28 if you're still skeptical.
00:28:16.07 So, one other thing to tell you:
00:28:19.16 signaling in 2 dimensions and 3 dimensions
00:28:22.28 are entirely different.
00:28:25.05 And, I'm just showing you
00:28:27.13 one very interesting example.
00:28:29.14 Now, remember,
00:28:31.10 until very recently the drug companies
00:28:33.10 are trying to find cancer drugs
00:28:35.19 and they test them in 2 dimensions,
00:28:38.05 and we showed that the top blot over there
00:28:42.13 is coxsackie adenovirus receptor,
00:28:45.21 and as you see on the bottom,
00:28:48.10 the S1 and T4,
00:28:50.06 one non-malignant and one malignant...
00:28:52.16 in 2D they are identical.
00:28:54.25 αv-integrin, on the bottom,
00:28:57.01 is identical.
00:28:58.20 Now, you take the S1
00:29:01.21 and you put it in the 3D
00:29:05.22 and look at it,
00:29:07.16 it's like day and night,
00:29:09.22 it just goes down
00:29:11.23 and in the tumor cells it still remains high,
00:29:14.16 and then when we revert them,
00:29:16.17 which is the last thing on that side,
00:29:20.00 you see that it is reverted
00:29:22.05 and it is in 3D,
00:29:23.19 and so it says that
00:29:26.23 the cells are completely dependent
00:29:29.28 on the context
00:29:31.23 and they are plastic,
00:29:33.11 because if you look on the bottom,
00:29:35.26 αv-integrin, which is needed for the activity
00:29:38.17 of coxsackie adenovirus receptor,
00:29:41.05 is the same in 2D
00:29:42.21 in normal and malignant cells,
00:29:44.11 but when you put them in 3D,
00:29:46.02 even the tumor cells now upregulate it.
00:29:49.03 Now, this is very exciting,
00:29:51.15 and it says that regulation
00:29:54.21 in 2 dimensions and 3 dimensions
00:29:56.18 are not the same,
00:29:58.05 and nothing about you,
00:29:59.23 absolutely nothing about you,
00:30:01.08 in your body,
00:30:02.24 is 2 dimensional, right?
00:30:05.04 So, that's why they are able
00:30:07.05 to do the kind of things they do,
00:30:09.00 due to the shapes that they have,
00:30:11.00 and I'll come back to that later
00:30:13.06 in my next talk.
00:30:14.28 So, there was something
00:30:16.27 very interesting happening,
00:30:18.28 because what was happening
00:30:21.10 was that we were actually giving these cells
00:30:24.28 β1 inhibitory antibody.
00:30:27.16 Now, these cells
00:30:29.18 had six times the level of EGFR...
00:30:31.16 six times the level of EGFR...
00:30:33.22 how did they stop growing?
00:30:36.08 What happened to that?
00:30:37.23 So, we measured EGFR:
00:30:39.09 EGFR was down.
00:30:41.10 So, we then used inhibitors of EGFR,
00:30:43.24 that made β1 go down.
00:30:45.22 So, it said that these things
00:30:47.23 are talking to each other,
00:30:49.16 and when we looked at the same phenomenon
00:30:52.15 in 2 dimensions,
00:30:53.28 they weren't doing it.
00:30:55.29 Now we have done the experiment
00:30:57.21 with many, many different inhibitors, as you see.
00:31:00.20 β1 integrin is making the tumor cells
00:31:05.00 go down and revert.
00:31:07.20 You see that EGFR does the same thing,
00:31:10.25 you see that MAP Kinase does the same thing,
00:31:13.13 you see that the PI-3 Kinase does the same thing,
00:31:16.15 if I go off the screen you can see it,
00:31:18.08 and you see that if you put back
00:31:20.28 dystroglycan it does the same thing...
00:31:23.01 Notch, TACE, etc, etc.
00:31:25.22 What then is an oncogene?
00:31:29.17 All these pathways have to integrate,
00:31:32.27 and many of these pathways
00:31:35.01 have oncogenic activity if the balance of the signaling
00:31:41.01 becomes awry... it goes awry, right?
00:31:43.26 So, we can also take metastatic cells
00:31:46.01 and we can inhibit them with two different inhibitors.
00:31:49.23 That being the case,
00:31:51.22 I would argue that if you gave me
00:31:54.26 any of these breast cancer cells,
00:31:56.22 I'm going to be able to put it in this assay,
00:31:59.06 understand what was outside on the surface,
00:32:02.28 and I could revert them.
00:32:05.15 Alright, so form and function are related,
00:32:10.03 dynamically and reciprocally.
00:32:13.01 You mess up one,
00:32:14.17 you mess up the other.
00:32:16.10 This is really important to think about,
00:32:19.06 both at the level...
00:32:20.28 it's not just your mind and body,
00:32:23.06 it has to do with every atom
00:32:25.16 and every single cell
00:32:27.07 of your body,
00:32:29.07 that the form and function have to be integrated.
00:32:32.06 What gives the signal to the mammary gland in vivo
00:32:35.08 to tell it to be polar and functional?
00:32:38.06 And what substitutes for laminin-rich gels
00:32:40.18 in vivo?
00:32:42.07 Now, if you look at the structure of a mammary gland,
00:32:44.19 as you see I love this picture,
00:32:46.12 it's a section from a mouse mammary gland,
00:32:49.05 you see one of those beautiful acini in the middle,
00:32:51.28 and you see that there is that...
00:32:54.15 there are luminal and myoepithelial cells,
00:32:57.22 and around it is a basement membrane
00:32:59.23 and all those white stuff are the fat
00:33:02.03 in the mammary gland.
00:33:03.18 So, what surrounds the cells
00:33:05.15 that make the milk
00:33:06.29 are the myoepithelial cells.
00:33:10.08 So, together with Ole Petersen,
00:33:12.27 we began to think,
00:33:14.20 maybe it is myoepithelial cells
00:33:16.12 that gives the structural cues
00:33:18.09 to make that lovely structure.
00:33:20.00 They don't have Matrigel
00:33:21.12 in the mammary gland.
00:33:23.16 So, you see in situ,
00:33:25.07 if you look at it,
00:33:26.17 you see that that beautiful picture
00:33:29.19 of one layer of epithelial cells,
00:33:31.16 one layer of myoepithelial cells around them,
00:33:35.19 and they are actually shown...
00:33:37.11 they are highlighted in red.
00:33:39.09 Now, if we dissociate and separate the myoepithelial cells
00:33:42.20 and the epithelial cells
00:33:44.14 using magnetic beads and purify them,
00:33:47.10 before we can do that...
00:33:49.08 and we put them on the dish in culture...
00:33:51.12 you see that the myoepithelial cells
00:33:53.14 start looking like a muscle
00:33:55.14 and the epithelial cells are behind.
00:33:57.18 And so we then separate them
00:33:59.18 and then we do a classical experiment.
00:34:02.12 Now, we can't do the experiment
00:34:04.12 and test the action of myoepithelial cells
00:34:07.02 in actually laminin-rich basement membrane,
00:34:12.07 because as you have seen,
00:34:13.26 in laminin-rich basement membrane
00:34:15.22 you already get this.
00:34:17.14 So, we said...
00:34:19.15 because laminin-rich membrane
00:34:21.19 gives the signal, right?
00:34:23.15 So, we put them in Collagen-I,
00:34:25.23 which if you only looked at them
00:34:27.19 you see that they looked the same,
00:34:29.17 but if you sectioned through these two
00:34:33.09 very similarly-looking structures,
00:34:36.23 on the bottom you see
00:34:39.03 that this one has a lumen in the middle,
00:34:42.03 while that one doesn't,
00:34:44.09 the one on the right doesn't.
00:34:46.11 Okay, so,
00:34:49.06 we take the luminal epithelial cells
00:34:52.22 and put them in the basement membrane gel,
00:34:55.20 as I have shown you.
00:34:57.07 On the top you see luminal epithelial cells,
00:35:01.04 we are calling it LEP,
00:35:03.19 in the basement membrane.
00:35:05.13 They have epithelial-specific antigen
00:35:07.09 shown in green
00:35:08.21 and then sialomucin shown in red, on top,
00:35:11.14 and on the bottom you see the nuclei in red
00:35:14.21 and then you see that beautiful basement membrane
00:35:17.09 in green.
00:35:18.21 Now, you put the same cells in collagen...
00:35:21.07 for crying out loud, look at it.
00:35:23.13 The cells in collagen are inside-out.
00:35:26.26 Even though they look the same,
00:35:28.12 even though they both had to stop growing,
00:35:30.24 they are not getting the right signal from ECM.
00:35:33.26 Collagen is not laminin,
00:35:35.22 and ECM is not ECM.
00:35:38.26 They give different signals
00:35:40.26 at different parts of your body,
00:35:42.29 and so these same cells in collagen
00:35:45.15 are doing that funny thing, on the right,
00:35:48.03 as you see,
00:35:50.10 that they are pouring out
00:35:52.24 tremendous amounts of basement membrane molecules,
00:35:55.14 and when they do that
00:35:57.08 you think they should make a basement membrane.
00:35:59.06 They don't, because they are inside-out.
00:36:01.14 They don't have the right structure.
00:36:03.17 So now, we can test the function of the myoepithelial cells
00:36:07.09 if we add it to the collagen.
00:36:09.20 We can't add it again, remember,
00:36:11.05 to the basement membrane
00:36:13.01 because they already have that pretty structure.
00:36:14.28 We want to know what gives the signal in vivo, right?
00:36:18.03 So, we now add myoepithelial cells
00:36:19.27 and look at that.
00:36:21.22 On the left is in collagen without myoepithelial cells,
00:36:25.11 on the right we have the epithelial cells
00:36:27.12 and they're gorgeous.
00:36:28.26 They make the double layer of the mammary gland,
00:36:31.03 and now the make a lovely basement membrane,
00:36:34.09 in green on the bottom.
00:36:36.01 The one on the bottom
00:36:37.20 is called the double-layer tube.
00:36:39.27 Okay, we published this,
00:36:41.07 it was very exciting,
00:36:42.20 but then we wanted to know,
00:36:44.03 how did myoepithelial cells do this?
00:36:46.11 So, when we looked at that
00:36:48.06 we realized that LAMA-A1 chain,
00:36:50.26 and now I'm going to be giving a little bit more
00:36:53.25 science-specific detail,
00:36:56.25 just for those of you
00:36:58.29 who are just dying to see gels,
00:37:01.14 so here it is.
00:37:03.08 So, here are the luminal epithelial cells
00:37:05.16 in basement membrane, on the top.
00:37:07.28 They have no LAMA1, laminin-A1 change,
00:37:10.25 while they have the LAMA3 and LAMA5
00:37:14.29 and collagen-4A1, and even collagen 4A2,
00:37:17.09 although it's a little bit lower than normal,
00:37:19.12 and then the LEP in collagen,
00:37:21.18 they have all of those,
00:37:23.02 again they don't have LAMA1,
00:37:25.00 but the myoepithelial cells are the only ones
00:37:29.24 that have that lovely band,
00:37:33.22 on top,
00:37:35.13 so all of a sudden everything came together for me.
00:37:37.25 How exciting!
00:37:39.21 Myoepithelial cells, in vivo,
00:37:42.15 make laminin.
00:37:44.11 And that's why, in the laminin-rich gel,
00:37:47.04 we are able to substitute for myoepithelial cells
00:37:51.11 without having the myoepithelial cells.
00:37:53.20 So, this was quite exciting,
00:37:55.20 and then we could show that
00:37:58.12 in place of myoepithelial cells
00:38:00.05 we could add laminin-1,
00:38:01.18 and when we did that,
00:38:03.03 again they made these beautiful organizations
00:38:05.16 that I showed you, in these acini,
00:38:07.17 and if you use all other kinds of laminins,
00:38:10.29 all type 4 collagen,
00:38:12.12 all fibronectin,
00:38:13.29 all whatever, you won't get it.
00:38:15.25 Now, the exciting thing came
00:38:18.00 when we looked at tumor cell myoepithelial cells.
00:38:21.15 We realized that the tumor cells,
00:38:23.25 70% of them were not making the laminin-A1 chain,
00:38:27.16 they weren't making laminin,
00:38:29.06 and some of them were making a little bit
00:38:31.13 and that's shown here,
00:38:33.07 but you can read it in the paper,
00:38:34.28 it came out in Journal of Cell Science in 2002
00:38:38.12 from Ole Petersen and my laboratory,
00:38:41.00 and as you see here now,
00:38:43.03 on the left is one of the tumor cell myoepithelial cells
00:38:46.19 that could partially revert,
00:38:48.18 and on the right
00:38:50.16 you see that they look as if nothing...
00:38:52.22 no myoepithelial cells were added.
00:38:54.18 They look just like plain luminal cells inside.
00:38:57.03 70% of tumors cannot do this.
00:39:00.06 It's quite important.
00:39:02.12 And then we went to the human patients.
00:39:04.07 On the top you see the normal,
00:39:06.15 beautiful acini
00:39:08.05 with laminin around them,
00:39:10.04 and then you take the other five
00:39:12.14 are sections of the tumor,
00:39:14.00 laminin is basically gone.
00:39:16.15 So, that's one of the reasons
00:39:18.24 that the tumors don't do well.
00:39:21.16 They're not getting the right message
00:39:23.19 and, remember,
00:39:25.10 in breast cancer one of the things that happens
00:39:28.04 is that myoepithelial cells get lost
00:39:30.07 and nobody still knows why,
00:39:32.05 and it probably has a lot to do with the stem cells,
00:39:34.15 it has a lot to do with others,
00:39:36.16 but more of that later
00:39:38.10 and hopefully somebody else comes and lectures to you,
00:39:40.16 although we also have some data at that level.
00:39:44.06 Okay, so let's see now,
00:39:46.28 does this have what we found in culture...
00:39:49.17 is that reproducible in vivo?
00:39:51.27 And, the very well-known
00:39:54.03 and talented scientist at Harvard,
00:39:56.27 a good colleague of mine, Kornelia Polyak,
00:39:59.07 had a paper in Cancer Cell in 2008
00:40:01.20 and I'm one of the 17 authors
00:40:04.05 but it's really from her lab,
00:40:06.02 and what she did...
00:40:07.21 she made a model of a ductal carcinoma in situ,
00:40:10.23 and what she did...
00:40:12.09 she put luminal cells together
00:40:14.11 with either fibroblasts or with nothing,
00:40:17.20 or with tumor myoepithelial cells,
00:40:21.05 and then injected them into the mouse
00:40:24.29 and they always became malignant
00:40:27.03 and they became an invasive ductal carcinoma,
00:40:32.01 even if she gave them normal fibroblasts.
00:40:34.16 But, when we sent her
00:40:36.20 some of our normal myoepithelial cells,
00:40:38.27 the only thing that could prevent that arrow
00:40:42.18 from going to the left,
00:40:44.05 or to the right in this case,
00:40:45.22 depending on how you're looking at,
00:40:48.11 is normal myoepithelial cells.
00:40:50.09 So, that was very, very gratifying.
00:40:53.23 So, finally, does loss or aberration of ECM
00:40:58.02 have a functional significance and, if so,
00:41:01.09 can it lead to tumor formation?
00:41:04.05 And so, we did experiments with Zena Werb,
00:41:08.11 who is a professor at UCSF...
00:41:10.17 we made a mouse in my lab
00:41:12.26 where we took...
00:41:14.10 we made a conditional mouse where we took
00:41:16.16 a milk protein promoter,
00:41:18.17 attached it with a metalloprotease
00:41:20.25 that destroys the basement membrane and ECM,
00:41:23.24 called MMP-3,
00:41:25.19 that was occurring during involution,
00:41:28.03 and we showed that we could indeed
00:41:32.13 make an almost conditional mouse
00:41:35.28 that, when it got pregnant,
00:41:37.22 because it had the milk protein promoter,
00:41:39.23 it could now upregulate MMP-3
00:41:42.15 in the middle of pregnancy,
00:41:44.08 and these mice, as they aged,
00:41:46.01 got tumors.
00:41:47.17 Look at it.
00:41:48.28 They have tumors - now, remember,
00:41:50.25 no oncogene.
00:41:52.19 At least not in the beginning,
00:41:54.03 it doesn't mean that later they don't get it,
00:41:56.24 but at least at the moment
00:41:58.17 we started simply by messing up the structure.
00:42:01.18 This was quite exciting.
00:42:03.16 We published a lot of these data
00:42:06.10 in Cell in 1999
00:42:08.26 and tomorrow I'm going to talk
00:42:10.19 a little bit about the mechanism
00:42:12.19 that we uncovered,
00:42:14.17 and a lot more detail
00:42:16.21 about how this happens.
00:42:18.15 So, we have done both sides of that equation
00:42:20.16 that I started from.
00:42:22.24 You restore structure,
00:42:26.05 cells think they're normal.
00:42:28.20 You take a normal cell and destroy the structure,
00:42:30.26 they become malignant.
00:42:32.19 This can explain, actually,
00:42:34.13 what happens when you have asbestos
00:42:36.27 because, like a chronic wound,
00:42:39.07 it's constantly changing the structure.
00:42:41.22 When people have inflammation in their body,
00:42:44.12 they're constantly getting the wrong signals,
00:42:47.03 and we are now learning that
00:42:49.19 a lot of these things are important in cancer.
00:42:52.03 I was in France doing a sabbatical,
00:42:55.17 and it was Jacob and Monod
00:42:58.00 were two Nobel Prize winners,
00:43:00.02 and these Nobel Prize winners,
00:43:02.13 one of them, Jacob...
00:43:04.23 or was it Monod...
00:43:06.21 said, "What is true for E. coli"
00:43:09.15 ...and E. coli is this little bacteria...
00:43:11.05 "is also true for elephants,"
00:43:13.10 meaning that if we study E. coli
00:43:15.29 we'll get all the answers for the elephant.
00:43:18.14 That is actually true
00:43:20.17 80% of the time,
00:43:22.11 however it is not true all the time,
00:43:24.18 and this cartoon that somebody drew for me
00:43:27.25 shows E. coli on the top
00:43:30.13 and the elephant on the bottom,
00:43:32.08 and it gave me great pleasure
00:43:34.01 to show it to the French audiences.
00:43:35.27 I would say the E. coli is saying,
00:43:38.09 "Is it really true that what's true for me
00:43:41.11 is also true for the elephant?"
00:43:43.20 And what I like to say is that
00:43:46.07 what is true for E. coli may be true for elephant,
00:43:49.11 but what is true for elephant
00:43:51.25 is not true for E. coli,
00:43:54.01 because when two higher organism cells
00:43:57.04 come together
00:43:59.04 the results are logarithmically different.
00:44:03.27 The cells come together, form a junction,
00:44:06.12 have a bottom, have a top,
00:44:08.04 have secretory activity,
00:44:09.24 have different structure in their nuclei,
00:44:11.22 have a different dynamic reciprocity...
00:44:14.16 so we have to be cognizant of this
00:44:18.03 as we keep treating our cells in culture
00:44:21.01 as if they are E. coli.
00:44:22.26 They are not.
00:44:24.15 The question is,
00:44:26.18 how do we now model metastases?
00:44:28.20 A lot of people are using 3 dimensional models,
00:44:31.10 even companies are using 3 dimensional models,
00:44:34.21 they are using it for testing drugs,
00:44:38.21 which is wonderful,
00:44:40.02 and we thought that maybe we wanted to
00:44:42.01 make a model for metastasis,
00:44:44.22 and we again want to use this invasion
00:44:47.24 of the mammary gland into the fat pad
00:44:50.00 as a model,
00:44:51.20 and that I will discuss at the end of my next segment.
00:44:55.07 So, and that's shown here,
00:44:56.26 the mammary gland whole mount on the top
00:44:59.00 and the higher magnification on the bottom.
00:45:02.01 And, I want to finish with this
00:45:04.12 very favorite cartoon of mine,
00:45:06.29 where the guy is looking
00:45:10.01 in his very, very formal suit,
00:45:12.22 and telling the cat,
00:45:14.25 "Never, Ever think outside the box."
00:45:18.10 Now, I used to be the cat,
00:45:22.08 and those were the authorities.
00:45:25.10 Sadly, I have now become an authority,
00:45:28.21 so I don't want you to listen to me either,
00:45:31.14 but to always,
00:45:33.20 always think outside the box.
00:45:36.08 And now I will just make some general comments
00:45:39.01 about cancer.
00:45:40.23 The reason this is so important
00:45:42.28 is because, even though we know a lot,
00:45:45.08 we don't know enough.
00:45:46.27 There is so much we don't know
00:45:49.07 that it's not even funny
00:45:51.10 and, here, if you look at this article
00:45:53.16 that came out by Clifton Leaf,
00:45:56.19 in Fortune Magazine in 2004,
00:45:59.07 and I hate to tell you that even the current data
00:46:02.07 haven't changed that much,
00:46:04.01 we are making a lot of progress
00:46:06.01 on some aspects of breast cancer,
00:46:07.20 but many different kinds of cancers we are not.
00:46:10.11 Heart disease has gone down
00:46:13.07 between 1960, 1950 and now,
00:46:18.24 at that time, quite a bit,
00:46:21.02 and cancer mortality...
00:46:23.11 I mean deaths from heart disease
00:46:26.15 has gone down...
00:46:28.00 cancer mortality, if anything,
00:46:29.16 has remained completely steady.
00:46:32.13 So, we have a lot to do,
00:46:35.03 and this is why I encourage
00:46:37.26 all the students and others
00:46:39.21 to do a lot more.
00:46:41.21 I usually dedicate my talk
00:46:44.06 to this gorgeous woman
00:46:45.29 who was a friend of mine.
00:46:47.18 She modeled this dress
00:46:49.26 a few months after her breasts were removed,
00:46:53.12 and she struggled wonderfully,
00:46:56.10 but it was too late for Sonia.
00:46:59.07 I do not want it to be too late
00:47:01.10 for my granddaughter.
00:47:03.03 Here she is, Chloe,
00:47:05.01 when she was five,
00:47:06.27 and she's now eleven.
00:47:08.07 She always says,
00:47:09.22 "Grandma, why do you keep showing this same picture??"
00:47:11.27 And, in all honesty,
00:47:13.13 I haven't had time to change it.
00:47:15.04 Even now, even for this.
00:47:17.23 So, here is Lawrence Berkeley Lab,
00:47:20.02 and I usually,
00:47:21.13 when I lecture you know we have Lawrence Livermore
00:47:23.15 and Lawrence Berkeley,
00:47:24.18 this is...
00:47:25.25 and even the Secretaries of Energy
00:47:27.28 sometimes mix up Lawrence Berkeley Lab
00:47:30.02 and Lawrence Livermore...
00:47:31.21 it drives me absolutely crazy.
00:47:33.20 Anyway, so... here is Lawrence Berkeley Lab.
00:47:35.29 We are part of the University of California.
00:47:38.02 We have that beautiful Golden Gate Bridge.
00:47:40.10 We don't do defense-related stuff,
00:47:42.01 not that I have anything against doing defense,
00:47:44.16 but we don't do it.
00:47:46.06 We do multiple things, including biology,
00:47:48.27 as you have gathered.
00:47:50.23 And when Lawrence,
00:47:53.02 again I said it's the first national lab in the US,
00:47:56.08 when Lawrence smashed an atom,
00:47:58.29 he was using a building
00:48:01.04 that had the accelerator on the bottom.
00:48:03.22 Then, they kept the dome
00:48:05.18 and they put it on the top
00:48:07.21 of a very intense synchrotron radiation beam
00:48:12.13 called the Advanced Light Source,
00:48:14.04 and those of you who do structural biology come see us,
00:48:17.01 and so that you will never forget,
00:48:20.01 and not mix up Lawrence Berkeley Lab
00:48:22.03 and Lawrence Livermore,
00:48:23.23 what does this remind you of?
00:48:25.23 Does it look like a breast?
00:48:27.25 Now, only women get away with this,
00:48:30.12 and this is for you to, never...
00:48:33.17 when you come to Berkeley and you look up,
00:48:35.23 you will say, "Ahh, that's Lawrence Berkeley Lab."
00:48:38.05 And here is my lab,
00:48:40.21 a few years ago actually,
00:48:43.09 but tomorrow
00:48:45.22 I will talk about some other work of each one of these kids,
00:48:49.02 but the general picture that I have given you
00:48:53.24 has been done because of wonderful students and postdocs
00:48:56.04 over the years,
00:48:58.19 and I love many of them,
00:49:00.19 and in fact most of them, almost all of them,
00:49:03.01 they are all over the world
00:49:04.21 and, again, tomorrow I will talk specifically...
00:49:07.12 well, I keep calling it tomorrow, but in my next lecture
00:49:10.00 I'm going to be talking
00:49:11.24 about the specific work of some of them.
00:49:14.06 And I spent three months in France recently
00:49:16.00 and I came back and, as you see,
00:49:18.19 we actually take the mammary gland seriously.
00:49:20.28 Eight of my fellows,
00:49:23.04 either the guys with their wives,
00:49:24.18 or the wives who are my own fellows,
00:49:26.15 had a baby and they made me a human acini.
00:49:29.21 And, where do we go now, and that is Part II.
00:49:32.28 Thank you very much for your attention.

This Talk
Speaker: Mina Bissell
Audience:
  • Educators of Adv. Undergrad / Grad
  • Researcher
  • Educators
Recorded: September 2011
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Talk Overview

How can trillions of cells all with the same genetic information coordinate to form a complex organism? To address this question, Bissell uses the mammary gland as an experimental “organism”.

In early work, she found that cells isolated from mammary tissue and cultured on plastic rapidly lost all structural organization while those cultured in the presence of extracellular matrix molecules maintained their complex 3-dimensional structure; evidence for the importance of ECM in maintaining normal tissue structure. Bissell proceeded to demonstrate that ECM components are key in determining the development of a normal or malignant phenotype irrespective of genotype.

Speaker Bio

Mina Bissell

Mina Bissell

Mina Bissell completed her undergraduate degree in chemistry at Radcliffe College and her PhD in bacteriology at Harvard Medical School. She then moved to the University of California, Berkeley for post-doctoral studies. Bissell started her own lab at the Lawrence Berkeley National Laboratory and she has remained there for 30 years. Bissell is now a… Continue Reading

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Related Resources

Recommended Reading Of microenvironments and mammary stem cells. LaBarge MA, Petersen OW, Bissell MJ. Stem Cell Rev. 2007 Jun;3(2):137-46. Review.

Unraveling the microenvironmental influences on the normal mammary gland and breast cancer. Weigelt B, Bissell MJ. Semin Cancer Biol. 2008 Oct;18(5):311-21.Epub 2008 Mar 26. Review.

Why don’t we get more cancer? A proposed role of the microenvironment in restraining cancer progression. Bissell MJ, Hines WC. Nat Med. 2011 Mar;17(3):320-9. Review.

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