Cancer cells are subjected to fluid shear stress during passage through the venous and lymphatic system. Caveolin-1 (Cav-1), a principal structural component of caveolar membrane domains, contributes to cancer development but its mechanobiological roles under low shear stress (LSS) conditions remain largely unknown. Here, we identified Cav-1 is mechanosensitive to LSS exposure, and its activation-induced PI3K/Akt/mTOR signaling promotes motility, invadopodia formation and metastasis of breast carcinoma MDA-MB-231 cells. Application of LSS (1.8 and 4.0 dynes/cm2) to MDA-MB-231 cells significantly increased the cell motility, invadopodia formation, MT1-MMP expression, ECM degradation, and also induced a sustained activation of Cav-1 and PI3K/Akt/mTOR signaling cascades. Methyl-β-cyclodextrin-caused caveolae destruction markedly decreased LSS-induced activation of both Cav-1 and PI3K/Akt/mTOR, leading to suppress MT1-MMP expression, inhibit invadopodia formation and ECM degradation, suggesting that caveolae integrity also involved in metastasis. Immunocytochemical assay showed that LSS induces the Cav-1 clustering in lipid rafts and co-localization of Cav-1 and MT1-MMP on invadopodia. Immunofluorescence confocal analysis demonstrated that Cav-1 activation were required for the acquisition of a polarized phenotype in MDA-MB-231 cells. Finally, Cav-1 knockdown significantly suppressed tumor colonization in the lungs and distant metastases in animal models. Our findings highlight the importance of Cav-1 in hematogenous metastasis, and provide new insights into the underlying mechanisms of mechanotransduction induced by LSS.

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Migratory dynamics of collective cells is central to the morphogenesis of biological tissues. The statistical distribution of cell velocities in 2D confluent monolayers is measured through large‐scale and long‐term experiments of various cell types lying on different substrates. A linear relation is discovered between the variability and the mean of cell speeds during the jamming process of confluent cell monolayers, suggesting time‐invariant distribution profile of cell velocities. It is further found that the probability density function of cell velocities obeys the non‐canonical q‐Gaussian statistics, regardless of cell types and substrate stiffness. It is the Tsallis entropy, instead of the classical Boltzmann–Gibbs entropy, that dictates the universal statistical laws of collective cell migration. The universal statistical law stems from cell–cell interactions, as demonstrated by the wound healing experiments. This previously unappreciated finding provides a linkage between cell‐level heterogeneity and tissue‐level ensembles in embryonic development and tumor growth.

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Cell polarization, a process depending on both intracellular and intercellular interactions, is crucial for collective cell migration that commonly emerges in embryonic development, tissue morphogenesis, wound healing and cancer metastasis. Although invasive cancer cells display weak cell–cell interactions, they can invade host tissues through a collective mode. Yet, how cancer cells without stable cell–cell junctions polarize collectively to migrate and invade is not fully understood. Here, using a wound-healing assay, we elucidate the polarization of carcinoma cells at the population level. We show that with loose intercellular connections, the highly polarized leader cells can induce the polarization of following cancer cells and subsequent transmission of polarity information by membrane protrusions, leading to gradient polarization at the monolayer boundary. Unlike the polarization of epithelial monolayer where Rac1/Cdc42 pathway functions primarily, our data show that collective polarization of carcinoma cells is predominantly controlled by Golgi apparatus, a disruption of which results in the destruction of collective polarization over a large scale. We reveal that the Golgi apparatus can sustain membrane protrusion formation, polarized secretion, intracellular trafficking, and F-actin polarization, which contribute to collective cancer cell polarization and its transmission between cells. These findings could advance our understanding of collective cancer invasion in tumors.