Fibroblasts generate topographical cues that steer cancer cell migration

Abstract

Fibroblasts play a fundamental role in tumor development. Among other functions, they regulate cancer cells’ migration through rearranging the extracellular matrix, secreting soluble factors, and establishing direct physical contacts with cancer cells. Here, we report that migrating fibroblasts deposit on the substrate a network of tubular structures that serves as a guidance cue for cancer cell migration. Such membranous tubular network, hereafter called tracks, is stably anchored to the substrate in a β5-integrin–dependent manner. We found that cancer cells specifically adhere to tracks by using clathrin-coated structures that pinch and engulf tracks. Tracks thus represent a spatial memory of fibroblast migration paths that is read and erased by cancer cells directionally migrating along them. We propose that fibroblast tracks represent a topography-based intercellular communication system capable of steering cancer cell migration.

Force-mediated recruitment and reprogramming of healthy endothelial cells drive vascular lesion growth

“…The most noteworthy conceptual advance of our study is the establishment of a novel model in which CCM mutants use force- and ECM-mediated physical mechanisms to attract and reprogram wild-type cells from the healthy endothelium, potentially exacerbating lesion growth (Fig.5). This cooperative invasion strategy involving force transmission and microenvironmental cues bears striking resemblance to mechanisms observed in cancer progression 22,23,47 . The highly contractile, tip-like, leading CCM2 mutant ECs exhibit a competitive angiogenic advantage, allowing them to assert a stalk position upon neighboring wild-type ECs.…”

“…Expanding upon the cancer-like mechanisms identified for CCM formation 20,21 , we asked if cooperative migration strategies such as those used by fibroblasts to regulate tumor cell invasion 22,23 might also contribute to recruitment and reprogramming of WT ECs by CCM mutants. Since this multifactorial question requires an approach to systematically explore the mechanics of both cell-matrix and cell-cell interactions, we leveraged our three-dimensional (3D) biomimetic model of angiogenesis 24 integrated with biophysical computations using 3D traction force microscopy and molecular investigations using single-cell RNA sequencing.…”

Aging and freezing of active nematic dynamics of cancer-associated fibroblasts by fibronectin matrix remodeling

“…This intercellular communication favors alignment within the fibroblasts, and coordinates CAFs' supracellular contractility and dynamics 3 . This results in a reciprocal relationship between ECM-induced cell activities and cell-driven ECM alterations 10,12 , that were also reported for other cell types at the single cell level [13][14][15] ; yet the impact of this interaction on the integrated organization of the ECM/CAF capsule and tumor progression is still to be understood.…”

“…Because nematic ordering affects the local cell density (especially at defects) 15,19 and is thus expected to affect fibronectin deposition, we quantified the local density of cells and the amount of fibronectin at defects compared to aligned areas ( Fig. 1D ).…”

Near-Infrared Light-Activatable DNA Tentacles for Efficient Inhibition of Tumor Metastasis by Bio-Orthogonal Cell Assembly

“…Tumor metastasis remains the major cause of death in cancer patients. − To date, various strategies, including the blockade of specific biosignaling pathways or the direct capture and killing of tumor cells, have been developed to inhibit tumor metastasis. − Despite considerable advancements in treating primary tumors, the success rate in eradicating metastatic tumors has fallen short of expectations, often leading to severe side effects or increased spread of the cancer . Abundant evidence indicates that cancer cell metastasis correlates with the remodeling of the extracellular matrix (ECM). , A three-dimensional porous network surrounds tumor cells in the interstitial matrix, facilitating cell communication and controlling cell migration and differentiation. , The remodeling of the tumor’s interstitial matrix induces a broad range of physiological changes that, in turn, affect numerous signal pathways, cell adhesion, migration, and tumor progression. , These changes facilitate the invasion of tumor cells through the stroma and their migration to nearby vessels, the first step of the metastatic cascade . Moreover, tumor cells engage in multiple intercellular communications within the tumor microenvironment, utilizing chemokines, cytokines, and immune cells to control the course of tumor development. − Recently, some attempts have been made to mimic the cell immobilizing effect of the tumor ECM by using artificial materials .…”