Mechanics of Cancer granted .

Our NWO-EW Groot program grant was granted. In this program we seek for a physical understanding of the processes involved in metastases. The dream would be that such understanding might lead to novel intervention strategies.

Genetic programs driving metastasis of solid tumors vary between cancer types and even between people carrying the same cancer type. Nevertheless, the ultimate outcome is shared: cancer cells are empowered to pass a series of physical hurdles to escape the original tumor and disseminate to other organs. Accumulating evidence suggests that metastasis in most cases involves collective cell behavior whereby cell clusters pass these hurdles more successfully than individual cancer cells. This collective advantage is not understood but in recent years, “active matter” has emerged as a new paradigm to describe collective behavior across length scales: from bird flocks down to artificial self-propelled particles. This paradigm was recently found to describe cellular collectivity in biological processes like embryonic development and wound healing with surprising accuracy. In our program, we will develop and experimentally test a new theoretical framework based on concepts from active matter physics to understand how the collective behavior of cancer cells drives the early stages of metastasis. Multiscale theoretical models will be combined with in vitro and in vivo experimental biology and biophysics to unravel how motile clusters originate and dissociate from the primary tumor; how they navigate the mechanically complex environment as they invade surrounding tissues; and how they enter the blood stream to spread to distant organs. Our program identifies the key physical determinants of the early steps leading to systemic metastasis, providing new handles for rational design of future cancer therapy targeting principles shared across solid tumors.

Groups involved: Danen (LU), Friedl (RUMC), Giomi (UL), Janssen (TUe), Koenderink (TUD), de Roij (UMC), Schmidt (UL), den Toonder (TUe)

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Cecilia and Alessandro – welcome .

Cecilia and Alessandro started their PhD on a collaborative project funded by the Dutch Cancer Research Foundation (KWF) together with the groups of Elisa Giovannetti (VUmc), and Eric Danen (LACDR).

Integrative mechanobiology and genomics profiling of resistance patterns to foster novel therapeutics in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease that is notoriously chemoresistant. Despite extensive genetic mapping, the identification of specific subtypes, and the realization that the tumor microenvironment, including desmoplasia, contributes to chemoresistance, the clinical perspective for PDAC patients remains grim. Tumors have been described to mechanically alter their microenvironment, for instance through extracellular-matrix (ECM) stiffening, which in turn drives survival and growth of tumor cells. Interestingly, PDAC is extremely rich in ECM suggesting that such a positive feedback loop is highly relevant in this context. Indeed, recent reports implicate biomechanical aspects of PDAC-stroma interactions in PDAC progression. We were able to further substantiate and extend those observations. Our new findings suggest that the force-transducing cell adhesion signaling machinery (integrins, FAK/Src) contributes to the chemoresistant phenotype of PDAC.

In this project, we will investigate how PDAC cells stiffen their environment and how this in turn affects growth and chemoresistance of cells, unravel the underlying molecular machinery that leads to mechano-chemical feedback, and identify new targets to interfere with this process for the development of new therapeutic strategies.

Cecilia and Alessandro – welcome to the team!

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Hemidesmosome mechanics, JCB 219, e201904137

Wang, W., A. Zuidema, L. te Molder, L. Nahidiazar, L. Hoekman, T. Schmidt, S. Coppola, and A. Sonnenberg. 2020. Hemidesmosomes modulate force generation via focal adhesions. The Journal of Cell Biology 219(2).

Hemidesmosomes are specialized cell-matrix adhesion structures that are associated with the keratin cytoskeleton. Although the adhesion function of hemidesmosomes has been extensively studied, their role in mechanosignaling and transduction remains largely unexplored. Here, we show that keratinocytes lacking hemidesmosomal integrin α6β4 exhibit increased focal adhesion formation, cell spreading, and traction-force generation. Moreover, disruption of the interaction between α6β4 and intermediate filaments or laminin-332 results in similar phenotypical changes. We further demonstrate that integrin α6β4 regulates the activity of the mechanosensitive transcriptional regulator YAP through inhibition of Rho–ROCK–MLC– and FAK–PI3K–dependent signaling pathways. Additionally, increased tension caused by impaired hemidesmosome assembly leads to a redistribution of integrin αVβ5 from clathrin lattices to focal adhesions. Our results reveal a novel role for hemidesmosomes as regulators of cellular mechanical forces and establish the existence of a mechanical coupling between adhesion complexes.

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Brillouin Imaging: BOE 5, 2202 –

Coppola, S., T. Schmidt, G. Ruocco, and G. Antonacci. 2019. “Quantifying cellular forces and biomechanical properties by correlative micropillar traction force and Brillouin microscopy”. Biomed. Opt. Express 10(5):2202-2212.
[DOI] [pdf]

Cells sense and respond to external physical forces and substrate rigidity by regulating their cell shape, internal cytoskeletal tension, and stiffness. Here we show that the combination of micropillar traction force and noncontact Brillouin microscopy provides access to cell-generated forces and intracellular mechanical properties at optical resolution. Actin-rich cytoplasmic domains of 3T3 fibroblasts showed significantly higher Brillouin shifts, indicating a potential increase in stiffness when adhering on fibronectin-coated glass compared to soft PDMS micropillars. Our findings demonstrate the complementarity of micropillar traction force and Brillouin microscopy to better understand the relation between cell force generation and the intracellular mechanical properties.

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First Person: Veer Keizer –

Interview with Veer on GR mobility in JCS.

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