Peter Friedl & Katarina Wolf on Invading Cancer Cells

Fast Moving Fronts Commentary, March 2011

Peter Friedl
Katarina Wolf

Article: Multi-step pericellular proteolysis controls the transition from individual to collective cancer cell invasion


Authors: Wolf, K;Wu, YI;Liu, Y;Geiger, J;Tam, E;Overall, C;Stack, MS;Friedl, P
Journal: NAT CELL BIOL, 9 (8): 893-U39, AUG 2007
Addresses: Univ Wurzburg, DFG Res Ctr Expt Biomed, Rudolf Virchow Ctr, Josef Schneider Str 2, D-97080 Wurzburg, Germany.
Univ Wurzburg, DFG Res Ctr Expt Biomed, Rudolf Virchow Ctr, D-97080 Wurzburg, Germany.
Univ Wurzburg, Dept Dermatol, D-97080 Wurzburg, Germany.
Northwestern Univ, Feinberg Med Sch, Dept Cell & Mol Biol, Chicago, IL 60611 USA.
Univ Wurzburg, Inst Clin Biochem & Pathobiochem, D-97080 Wurzburg, Germany.
Univ British Columbia, Dept Biochem & Mol Biol, Vancouver, BC V6T 1Z3, Canada.

Photos: Top-bottom: Peter Friedl, and Katarina Wolf.

Peter Friedl & Katarina Wolf talk with ScienceWatch.com and answer a few questions about this month's Fast Moving Fronts paper in the field of Molecular Biology & Genetics.


SW: Why do you think your paper is highly cited?

It is a mechanistic story about how invading cancer cells navigate through three-dimensional (3D) interstitial collagen-rich tissue, thereby remodeling the extracellular matrix and paving the way for even more tumor cells to follow and adopt a multicellular, collective invasion mode. We used 3D and 4D confocal microscopy to show at high resolution where, when, and with which consequences the surface matrix metalloproteinase (MT1-MMP, MMP-14) cleaves collagen fibers.

Because the newly generated, remodeled matrix track represent paths of least resistance, following cells preferentially use the same trail, keeping cell-cell junctions active to ultimately form finger-like protrusions to penetrate the tissue in a coordinated manner. Researchers have imagined for years how mechanotransduction and tissue degradation during cell invasion might be coordinated, but only live-cell visualization has directly shown how adhesion/traction and proteolytic action occur in spatially and mechanically separate regions. In conclusion, the study describes how groups of cells free the way to move collectively through the tissue.

SW: Does it describe a new discovery, methodology, or synthesis of knowledge?

Figure 1:
Modes and transitions of cell migration.
Modes and transitions of cell migration.

Figure 2:
Visualization of pericellular proteolysis at the leading edge of an invading cancer cell.
Visualization of pericellular proteolysis at the leading edge of an invading cancer cell.

Figure 3:
Collective invasion in the 3D spheroid model.
Collective invasion in the 3D spheroid model.

View larger images & complete descriptions in tabs below.

Indeed, we developed several tools to visualize MMP-14 localization and activity in fixed and also live-cell cultures, so we could see precisely which collagen fibers were cleaved and which were not. By combining molecular and structural imaging, here using confocal reflection microscopy which we had already introduced in live-cell imaging back in 1997 with fluorescence, the fate of cleaved fibers could be detected. After cleavage, the loose ends of fibers still remain in contact with the cell surface and become transported in forward direction by the moving cell body.

We concluded that this physicochemical event underlies tissue remodeling by mesenchymal cells and the transition from random to ordered tissue structure. We further introduced the spheroid invasion assay as a versatile tool to monitor both single-cell and collective invasion, as well as a way to quantify this transition. Thus, using molecular imaging, a long-standing open question of the interdependence of proteolytic cell movement, pattern change in tissues, and plasticity of cell invasion were unified to a sequence of cellular and molecular events.

SW: Would you summarize the significance of your paper in layman's terms?

We have provided the first images and movies showing how cancer cells invade tissue, where and how they destroy normal tissue structures to replace it with themselves, and that they use MMP-14 predominantly. Because inhibition of MMP-14 was sufficient to stop tissue destruction, the data implicate MMP-14 inhibition as candidate approach to therapeutically inhibit of tissue destruction by aggressively growing cancer in patients.

SW: How did you become involved in this research, and how would you describe the particular challenges, setbacks, and successes that you've encountered along the way?

We have a long-standing interest in the types and mechanisms of cell migration in 3D tissue, such as the crawling of immune cells or the tissue invasion by cancer cells. Before, we had noticed that immune cells use different migration mechanisms than cancer cells, because they usually do not digest and/or destroy interstitial tissue structures as they move. And we also knew using confocal reflection imaging that many cancer cells eat up the tissue while moving.

So we were desperate to find out how the cancer cells on the one hand adhere and pull on the tissue to move, and on the other hand degrade it, without compromising their migration efficiency. It turned out to become a five-year endeavor that depended upon the development of novel visualization tools of proteolytic activity in 3D tissues and was challenged by the complexity of dissecting the individual-cell and collective migration modes in a clean, definitive manner.

SW: Where do you see your research leading in the future?

We have recently started to study cancer invasion in the living animal, using multiphoton microscopy. Mid-term, we hope to develop similar high-resolution imaging of the tumor in the more complex microenvironment in the living animal over time, to validate the role of MMPs in vivo. We aim to clarify for which tumors and stages of tissue invasion and destruction MMP-14 might serve as a good therapeutic target.

SW: Do you foresee any social or political implications for your research?

Because of their resolution and instructive quality our images and movies are popular for teaching, as they show a complex multi-step process of cancer invasion in a simple, linear manner. We hope that eventually patients will benefit from novel therapy that prevents or reverts tissue destruction in cancer and, potentially, other consuming processes, such as chronic wounds or ulcerating inflammation.End

Peter Friedl, M.D., Ph.D.
Professor
Microscopical Imaging of the Cell
Department of Cell Biology
NCMLS, Radboud University Nijmegen Medical Centre
Nijmegen, The Netherlands

Katarina Wolf, Ph.D.
Microscopical Imaging of the Cell
Department of Cell Biology
NCMLS, Radboud University Nijmegen Medical Centre
Nijmegen, The Netherlands

KEYWORDS: MULTI-STEP PERICELLULAR PROTEOLYSIS, CENCER CELL INVASION, INDIVIDUAL, COLLECTIVE, TYPE 1 MATRIX METALLOPROTEINASE, HEMOPEXIN-C DOMAIN, EXTRACELLULAR MATRIX, I COLLAGEN, MASENCHYMAL TRANSITION, BINDING PROPERTIES, CARCINOMA CELLS, TUMOR INVASION, MIGRATION, MEMBRANE.

 
Click tabs above to view figures and descriptions.

Figure 1:

Figure 1: Modes and transitions of cell migration.

The steps and mechanisms underlying the transition from single-cell to collective invasion as identified by advanced live-cell microscopy.

Image taken from P. Friedl and K. Wolf, J. Cell Biol. 188: 11-19 (2010). Used with permission.

© P. Friedl and K. Wolf (2010).

Figure 2:

Figure 2: Visualization of pericellular proteolysis at the leading edge of an invading cancer cell.

A) Collagen fibers contain FITC-labelled monomers with quenched fluorescence. After proteolytic cleavage, the dequenching leads to green fluorescence in live-cell culture.

B) Scheme showing the leading edge (right) generating traction of collagen fibers adjacent to a second zone some micrometer rearward executing degradation of collagen fibers.

© P. Friedl and K. Wolf (2008).

Figure 3:

Figure 3: Collective invasion in the 3D spheroid model.

Modified from Friedl, P. and K. Wolf, Cancer Res. 68:7247-2749 (2008).

ADAPTED AND REPRINTED BY PERMISSION FROM THE AMERICAN ASSOCIATION FOR CANCER RESEARCH: FRIEDL P, AND WOLF K, "TUBE TRAVEL: THE ROLE OF PROTEASES IN INDIVIDUAL AND COLLECTIVE CANCER CELL INVASION," CANCER RESEARCH, 2008, 68, 18, 7247-9.

 

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