Breast cancer cells with decreased fibronectin-integrin adhesion strength attenuate the malignancy of its microenvironment

Fibronectin (FN), a key component of many solid tumors microenvironment, increases their mechanical stiffening and promotes cancer progression and metastasis. We studied Fn1syn/syn;PyMT mice carrying the breast cancer-inducing PyMT oncogene and a Fn1 gene with a nonfunctional synergy site (FNsyn), which impairs the reinforcement of the a5b1 integrin adhesion to the FN-RGD motif. Here, we show that Fn1syn/syn;PyMT mice exhibit delayed tumor onset in the mammary glands and reduced lung metastasis associated with decreased tumor vascularization, reduced cancer cell proliferation and lower abundance of ECM fibrillar proteins within the tumor stroma. Isolated cancer-associated fibroblasts (CAFs) and tumor cells reveal that FNsyn makes them unresponsive to changes in substrate stiffness. Consequently, Fn1syn/syn CAFs cannot be activated, express low a-SMA and reduced Lysyl-2 and -3 oxidases leading to the assembly of loose fibrotic ECMs. Moreover, luminal beast cancer cells grown as organoids failed to acquire invasive traits on stiff FNsyn substrates. Importantly, these key alterations were strongly correlated with the phenotypic changes observed in the stroma of Fn1syn/syn;PyMT tumors, contributing to the establishment of a microenvironment characterized by a reduced abundance of immunosuppressive cytokines and an increased infiltration of immune cells. Therapeutic targeting of FNsyn is sufficient to reprogram the tumor microenvironment toward a less fibrotic and immunoactive state.

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