We discovered that CAFs form a contractile capsule around tumors that actively compresses cancer cells via actomyosin-driven forces, rather than serving as a passive barrier. Disruption of CAF contractility reduces compression and impairs capsule formation, revealing the intrinsic, supracellular nature of force generation coordinated by fibronectin scaffolds (Barbazan et al., Nat Commun, 2023). CAF-induced compression suppresses cancer cell proliferation and may enhance chemoresistance.
To study how the CAF capsule forms, we co-cultured CAFs and tumor cells in elastic alginate shells. We found that compressive stress and fibronectin remodeling are required for CAFs to spread and encapsulate tumor aggregates (Bertillot et al., Commun Biol, 2024). Moreover, we showed that CAF alignment drives the formation of a nematic fibronectin network, which, in turn, guides further CAF organization. Over time, this feedback loop leads to a slowdown in network dynamics and creates local defects—potential weak points in the CAF capsule that may facilitate cancer cell escape (Jacques et al., BioRxiv, 2024).
We further demonstrated that cancer cell clusters, even without intrinsic polarity, can migrate persistently by generating self-induced collagen gradients and mechanical asymmetries. This reveals a novel, polarity-independent mechanism for directed migration on viscoelastic substrates (Clark et al., Nat Mater, 2022).
In the colon, we unexpectedly observed that a distinct population of macrophages extends "balloon-like" protrusions (BLPs) into the epithelial layer. Given the colon’s critical role in absorbing fluids and its exposure to microbial and fungal metabolites, we investigated the function of these structures. We found that BLPs sample absorbed fluids and block uptake when fungal toxins are detected. In the absence of these macrophages or BLPs, epithelial cells continue absorbing toxic fluids, leading to cell death and loss of barrier integrity. These findings reveal an essential, previously unrecognized role of macrophages in maintaining colonic homeostasis (Chikina et al., Cell, 2020).
We also explored how intestinal stem cells respond to mechanical cues in their niche. We showed that PIEZO ion channels act as mechanosensors required for stem cells state regulation. Activated by increased ECM stiffness and tissue tension, PIEZO channels influence stem cell maintenance and fate decisions through a defined mechanotransduction cascade (Baghdadi et al., Science, 2024).
