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Science Signaling Podcast: 11 September 2012

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Sci. Signal.  11 Sep 2012:
Vol. 5, Issue 241, pp. pc21
DOI: 10.1126/scisignal.2003541

Abstract

This Podcast features an interview with Alissa Weaver, author of a Research Article published in the 11 September 2012 issue of Science Signaling. Metastasis is the process by which cancer cells from a primary tumor spread to a new site where they establish secondary tumors and involves cells switching between adherent and invasive states. Cells adhere to substrates through structures called focal adhesions and invade tissues using structures called invadopodia, which allow the cells to break down the extracellular matrix and penetrate tissues. Weaver’s group has combined network analysis of invadopodia and focal adhesions with data from head and neck cancers to identify key signaling molecules that influence the formation of invadopodia in invasive cancer cells.

(Length: 13 min; file size: 7.2 MB; file format: mp3; location: http://podcasts.aaas.org/science_signaling/ScienceSignaling_120911.mp3)

Technical Details

Length: 13 min

File size: 7.2 MB

File Format: mp3

RSS Feed: http://stke.sciencemag.org/rss/podcast.xml

Listen to Podcast: http://podcasts.aaas.org/science_signaling/ScienceSignaling_120911.mp3

Educational Details

Learning Resource Type: Audio

Context: High school upper division 11-12, undergraduate lower division 13-14, undergraduate upper division 15-16, graduate, professional, general public and informal education

Intended Users: Teacher, learner

Intended Educational Use: Learn, teach

Discipline: Bioinformatics, genomics, and proteomics; cell biology; human biology

Keywords: Science Signaling, cancer, extracellular matrix, focal adhesion, invadopodia, invasion, metastasis, network analysis, phosphatidylinositol 3-kinase, PI3K, PI 3-kinase, PIP3, PKCα, protein kinase C

Transcript

Host – Annalisa VanHookWelcome to the Science Signaling podcast for September 11th, 2012. I’m Annalisa VanHook, and today I’ll be speaking with Alissa Weaver, senior author of a paper that appears in this week’s issue of Science Signaling about regulation of the formation of invadopodia in invasive cancer cells. (1)

Metastasis is the process by which cancer cells from a primary tumor spread to new sites to establish secondary tumors. In order to metastasize, cancer cells have to be able to do several things. First, they have to detach from the original tumor and make their way into the bloodstream or lymphatic system. In most normal tissues, cells stick very tightly to one another, but cancer cells are often not adherent, and so they can break free from the tumor and enter the bloodstream or lymphatic system, which transports them to a new site. The cells then have to stick to the new site and then penetrate the tissue to establish a secondary tumor. Cellular protrusions called invadopodia allow the cells to breakdown extracellular matrix to first enter the bloodstream, and then later to penetrate tissues to establish secondary tumors. So, metastasis involves cells switching between adherent and invasive states.

While invadopodia allow cells to invade tissues, focal adhesions are the structures that cells use to stick to substrates, and they contain many of the same proteins as invadopodia. In a new study published this week in Science Signaling, Alissa Weaver’s group has analyzed the network of proteins that make up invadopodia and focal adhesions and identified key regulatory hubs that allow cells to switch between making focal adhesions and making invadopodia. Weaver joined me by telephone from the Vanderbilt University School of Medicine in Nashville.

Interviewer – Annalisa VanHookWelcome, Dr. Weaver.

Interviewee – Alissa WeaverThank you very much. I’m delighted to talk with you.

Interviewer – Annalisa VanHookFocal adhesions allow cells to stick to a substrate, and invadopodia allow them to penetrate the substrate. Adhesions are associated with nonmetastatic cells, whereas invadopodia are associated with metastatic cancer cells. Is the production of invadopodia or the absence of focal adhesions sufficient to cause cells to become invasive?

Interviewee – Alissa WeaverSo, I would say no. It’s more of a transition that takes place, but production of invadopodia is an important component of it. So, in order for cells to become invasive, they need to degrade the matrix, and they need to move. So, invadopodia are critical for the degrading the matrix, and then the ability to both assemble and disassemble focal adhesions is important for sticking and, thus, moving. So both of those processes are involved.

Interviewer – Annalisa VanHookMorphologically, how do those two structures differ? How do focal adhesions look different from invadopodia?

Interviewee – Alissa WeaverSo, most of these are characterized in cell culture. And in cell culture, focal adhesions are these sort of linear streaklike structures. So, they’re flat and look like lines. Invadopodia tend to be characterized as protrusions—they’re very thin and cylindrical, and they protrude down into the matrix.

Interviewer – Annalisa VanHookFocal adhesions and invadopodia perform very different functions. Focal adhesions help cells stick and move, and invadopodia help them penetrate tissues. But they have many proteins in common. What sorts of proteins do those two structures share?

Interviewee – Alissa WeaverYeah, so this is a really interesting part. They do share proteins in common, and they have been shown to sort of transition from one structure to the other, specifically focal adhesions to invadopodia. So, they tend to share mainly adhesion and signaling proteins, then what invadopodia tend to have is they acquire branched actin-type proteins and membrane trafficking proteins so that they can get proteases secreted at those sites. Also, recent work—and actually this paper highlights that as well—has shown that PI 3-kinase–produced lipids are important for invadopodia formation. And so, you could imagine that proteins that bind to PIP3 would be important invadopodia proteins. So, that’s another way to sort of produce invadopodia, is to recruit these new proteins.

Interviewer – Annalisa VanHookPIP3 is a membrane lipid that’s produced by PI 3-kinase.

Interviewee – Alissa WeaverThat’s right. And so, we think we know a few PIP3 binding proteins that are important in invadopodia, but I suspect that there are a lot more that we don’t know about. But we do know that that’s an important signal to make in invadopodia. So, one thing that one could look for are, you know, a variety of PIP3 binding proteins.

Interviewer – Annalisa VanHookIn this current study, your group analyzed the networks of proteins that define each of those structures and then went looking for regulators that might influence cells to switch from making one type of structure to the other. How did you do that?

Interviewee – Alissa WeaverSo what we did is, we used graph theory actually to analyze the connectedness of proteins in the network. So, just like airport networks have hubs that people travel through, protein networks also have hubs. And those hubs tend to be signaling proteins because they’re very highly connected proteins, and so they can lead to large changes in cellular phenotypes just by interacting with their many different binding partners. So, what we did is we identified hubs for both the invadopodia and focal adhesion networks using graph theory, and then another critical thing that we did was we compared those results with signaling data from human tumors. And so, that final step was what really helped us prioritize targets to test.

Interviewer – Annalisa VanHookAnd what sort of targets did you get from that analysis?

Interviewee – Alissa WeaverWell, we did get many signaling proteins and also some cytoskeletal proteins. You get these long lists when you do analyses of networks because the networks start off very large, and then you end up with a long list of things. So, what we decided to follow up on is we had noticed that both PI 3-kinase and PKCα had clustered together in some signaling data from recurrent human head and neck cancers, and it seemed like there was a relationship between the two molecules that was interesting and unexpected. So, we manipulated both of those and followed up on the relationship between the two. By doing that, we ended up identifying the negative feedback loop from one of the molecules to the other. So, the tumor data really sort of pointed us in the right direction and suggested that the two molecules work together to control aggressive behavior.

Interviewer – Annalisa VanHookIs signaling through PI 3-kinase sufficient to induce invadopodia?

Interviewee – Alissa WeaverRight. So, we have not put an activated PI 3-kinase in noncancer cells to see if we can induce invadopodia. That would be the most strict test. However, when we put activating PI 3-kinase mutant molecules into cancer cells that are very poorly invasive, they all of a sudden make a lot of invadopodia. So it’s a pretty strong signal for formation of invadopodia. PKCα is interesting, and one of the major points of this paper, in fact, was that, depending on the status of PI 3-kinase, you get a completely different effect by changing PKCα. So, PKCα is, at least in this context, more of a modulator of PI 3-kinase activity. In systems that do not have aberration in PI 3-kinase activity, if you reduce PKCα, the cells make fewer invadopodia and are less invasive. But you get completely the opposite effect when cells have activating mutations in the PI 3-kinase pathway. And so, what this suggests is that it would make a big difference for tumors to manipulate PKCα depending on what the endogenous state of the PI 3-kinase pathway was. So, for example, there are PKCα inhibitors out there. It has not been as widely pursued for therapeutics as some other drugs, but they are out there, and you would imagine that you could get completely opposite effects depending on what the endogenous state of the PI 3-kinase pathway was in the tumors that you’re trying to target.

Interviewer – Annalisa VanHookRight. So, determining the PI 3-kinase status of the tumors would be important before deciding whether to inhibit or stimulate PKCα.

Interviewee – Alissa WeaverThat’s right.

Interviewer – Annalisa VanHookWhy specifically did you look at head and neck cancers? Are those particularly aggressive?

Interviewee – Alissa WeaverWell, some of that is just fortuitous. So, we do a lot of work on head and neck cancer, and we had a collaboration with a translational researcher—a long-time collaborator of ours, Dell Yarbrough—and he had some reverse-phase protein array signaling state data, which is still fairly unique data to get—good, large signaling data sets with follow-up data. So, some of it was availability. Also, a thing with head and neck cancer is they do tend to be invasive, and then when they do recur, it happens pretty fast, so you don’t need a long follow-up time. Two years of follow-up is pretty good to assess recurrence.

Interviewer – Annalisa VanHookIn your cell culture assays, PI 3-kinase and PKCα signaling played an important role in allowing cells to switch between making focal adhesions and making invadopodia. But do you know if that pathway plays a role in mediating the switch between adherent and invasive states in cancers in vivo?

Interviewee – Alissa WeaverSo, we don’t know that. And part of the challenge there is assessing invasiveness in cancers. So, there’s not really very great ways to assess that. We use recurrence as a surrogate for aggressiveness. And in some ways that tends to be associated, but it’s not exactly like measuring invasiveness per se. You can look at metastasis, but that also relies on a number of other processes, not just invasiveness. So, for example, not only do cells need to invade out of the primary tumor, they need to be able to grow back out once they lodge at a different site, which doesn’t necessarily require only the invasive processes. Probably the best way to assess this would be in an in vivo mouse model where one can sort of control the conditions and quantitate in a controlled manner, but we do also have some collaborations with pathologists to look at histochemical correlations with invasiveness.

Interviewer – Annalisa VanHookThank you for taking the time to speak with me.

Interviewee – Alissa WeaverMy pleasure.

Host – Annalisa VanHookThat was Alissa Weaver, senior author of a Research Article published in the September 11th issue of Science Signaling. That paper is by Hoshino and colleagues, and it’s titled “Network Analysis of the Focal Adhesion to Invadopodia Transition Identifies a PI3K-PKCα Invasive Signaling Axis” (1).

music

And that wraps up this Science Signaling Podcast. If you have any questions or suggestions, you can write to us at sciencesignalingeditors{at}aaas.org. This show is a production of Science Signaling and of AAAS—Advancing Science, Serving Society. I'm Annalisa VanHook, and on behalf of Science Signaling and its publisher, the American Association for the Advancement of Science, thanks for listening.

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