Pericyte-like spreading by disseminated cancer cells activates YAP and MRTF for metastatic colonization

Abstract

Metastatic seeding by disseminated cancer cells principally occurs in perivascular niches. Here, we show that mechanotransduction signalling triggered by the pericyte-like spreading of disseminated cancer cells on host tissue capillaries is critical for metastatic colonization. Disseminated cancer cells employ L1CAM (cell adhesion molecule L1) to spread on capillaries and activate the mechanotransduction effectors YAP (Yes-associated protein) and MRTF (myocardin-related transcription factor). This spreading is robust enough to displace resident pericytes, which also use L1CAM for perivascular spreading. L1CAM activates YAP by engaging β integrin and ILK (integrin-linked kinase). L1CAM and YAP signalling enables the outgrowth of metastasis-initiating cells both immediately following their infiltration of target organs and after they exit from a period of latency. Our results identify an important step in the initiation of metastatic colonization, define its molecular constituents and provide an explanation for the widespread association of L1CAM with metastatic relapse in the clinic.

Cytotoxic lymphocytes use mechanosurveillance to target biophysical vulnerabilities in cancer

“…1C-D and Fig. S1A), consistent with previous data showing that MRTF is required for metastatic seeding (Er et al, 2018; Kim et al, 2017; Medjkane et al, 2009). However, B16F10 and E0771 cell lines overexpressing MRTFB (B16F10-MRTFB and E0771-MRTFB) exhibited dramatically reduced lung colonization (Fig.…”

“…Isolated cancer cells are typically less rigid than untransformed cells from the same parent tissue (Guck et al, 2005; Hou et al, 2009; Xu et al, 2012). To occupy the metastatic niche, however, cancer cells must spread on the microvascular basement membrane (Er et al, 2018; Valiente et al, 2014), thereby increasing their rigidity to the point where they trigger robust lymphocyte activation. This coupling of colonization with biophysical vulnerability provides an explanation for why metastasis is so inefficient, and it also identifies mechanosensing of cancer cell rigidity as a novel mode of immunosurveillance.…”

“…To expand successfully in this space, metastatic cells first establish strong adhesion to the microvascular basement membrane (Shibue and Weinberg, 2009; Valiente et al, 2014). This triggers a mechanotransduction response in which cell spreading and migration are coupled to the activation of myocardin-related transcription factors (MRTF) A and B (Er et al, 2018). In the steady state, MRTF isoforms are sequestered in the cytoplasm via binding to monomeric globular actin (G-actin).…”

“…Once localized in this manner, MRTFs form complexes with the DNA-binding protein serum response factor (SRF) to drive expression of more G-actin and cytoskeletal components. Morphoregulation by MRTF is absolutely required for metastatic invasion and subsequent proliferative expansion (Er et al, 2018). However, because analogous shape changes have been shown to increase cell stifffness (Kasza et al, 2009), it is tempting to speculate that MRTF signaling might also mechanically sensitize cancer cells to cytotoxic lymphocytes.…”

Limited Environmental Serine Confers Sensitivity to PHGDH Inhibition in Brain Metastasis

“…4,[9][10][11][12][13][14][15] A classical view argues that the establishment and growth of brain metastases is in part dependent on cooperative cellular interactions between tumor cells and stromal cells (astrocytes, microglial and endothelial cells), within the metastatic niche. 9,10,14,16,17 However, while much has been learned about the cellular and molecular determinants of brain metastasis, little is known about how cancer cells adapt to the compositionally simple nutrient microenvironment of the brain, which is nearly devoid of proteins and most amino acids. Nutrient availability has emerged as an important regulator of cancer cell metabolism.…”