مقاله انگلیسی بازخورد بازگشتی بین اتلاف ماتریس و سیگنالینگ شیمی-مکانیکی رشد نوسانی تهاجم سلول سرطانی را تحریک می کند
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STAR★Methods
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Summary
Most extracellular matrices (ECMs) are known to be dissipative, exhibiting viscoelastic and often plastic behaviors. However, the influence of dissipation, in particular mechanical plasticity in 3D confining microenvironments, on cell motility is not clear. In this study, we develop a chemo-mechanical model for dynamics of invadopodia, the protrusive structures that cancer cells use to facilitate invasion, by considering myosin recruitment, actin polymerization, matrix deformation, and mechano-sensitive signaling pathways. We demonstrate that matrix dissipation facilitates invadopodia growth by softening ECMs over repeated cycles, during which plastic deformation accumulates via cyclic ratcheting. Our model reveals that distinct protrusion patterns, oscillatory or monotonic, emerge from the interplay of timescales for polymerization-associated extension and myosin recruitment dynamics. Our model predicts the changes in invadopodia dynamics upon inhibition of myosin, adhesions, and the Rho-Rho-associated kinase (ROCK) pathway. Altogether, our work highlights the role of matrix plasticity in invadopodia dynamics and can help design dissipative biomaterials to modulate cancer cell motility.
Introduction
Cancer cells invade extracellular matrices (ECMs) from primary tumors and intravasate into circulation in order to metastasize to distal organs. During this process, cells can actively modify their spreading (Chaudhuri et al., 2015; Discher et al., 2005; Vogel and Sheetz, 2006) and migration (Pakshir et al., 2019; Sunyer et al., 2016; van Helvert et al., 2018) by sensing the ECM’s mechanical properties, including stiffness (Chan and Odde, 2008; Discher et al., 2005; Elosegui-Artola et al., 2014) and viscosity (Bennett et al., 2018; Charrier et al., 2018; Chaudhuri et al., 2020; Gong et al., 2018). Such mechano-sensitivity is thought to be governed by adhesion dynamics and actomyosin contractility, and several approaches have been developed to quantitatively study mechano-transduction processes, including motor clutch dynamics for adhesions (Chan and Odde, 2008; Prahl et al., 2020) and chemo-mechanical feedback models for contractility (Alisafaei et al., 2019; Shenoy et al., 2016). Beyond stiffness and viscosity, certain ECMs, such as reconstituted basement membrane (rBM) matrices and type I collagen gels, exhibit plastic behavior, in which deformation can be irreversible (Ban et al., 2018; Nam et al., 2016). Recent studies have shown that invadopodia, which are actin-rich protrusions, can deform viscoplastic ECMs to facilitate invasive cell migration through matrices by mechanical force alone, independent of proteases (Wisdom et al., 2018; Wisdom et al., 2020). As these viscoplastic ECMs can be permanently deformed and thus possess long-term mechanical memory, how cells are able to sense plastic deformation and modify their behavior is a crucial, but as yet unanswered, question.