DLC1 loss drives multicellular streaming invasion by enforcing spatially coordinated Rho and β1 integrin signaling
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Efficient cancer cell invasion requires coordinated control of actomyosin contractility, extracellular matrix (ECM) engagement and remodeling, yet how these processes are integrated in complex, three-dimensional (3D) environments remains unclear. Here, we identify the tumor suppressor and RhoGAP protein DLC1 as molecular brake on multicellular streaming invasion in collagen-rich ECM. Using CRISPRoff-engineered breast cancer spheroids, DLC1 reconstitution models and patient-derived organoids embedded in collagen gels, we show that DLC1 downregulation promotes an efficient multicellular streaming phenotype. This invasion program requires matrix metalloproteinase activity, β1 integrin engagement and Rho–ROCK-dependent actomyosin contractility. Mechanistically, DLC1 downregulation stabilized the rear-polarization of RhoA activity and increased β1 integrin abundance, plasma membrane localization and activation. Separation-of-function mutants revealed that DLC1 restrains invasion through a dual mechanism: its RhoGAP activity limited actomyosin-driven streaming, whereas its LD-like talin-binding motif controlled β1 integrin enrichment at the plasma membrane. Together, our findings provide a molecular basis for the prominent role of DLC1 as a metastasis suppressor.
