Restored rigidity sensing fails to induce anoikis in cancer cells due to Akt activation and cell cell interactions
Nir, G.; Vivante, A. G.; Dwivedi, N.; Sheetz, M.
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Rigidity sensing enables cells to detect and respond to extracellular matrix stiffness, directing survival and apoptotic decisions. Tropomyosin 2.1 (Tpm2.1), a key actin-binding protein, is essential for this process and is frequently downregulated in cancer. While Tpm2.1 overexpression restores rigidity sensing and suppresses malignant growth, the downstream pathways governing cell fate remain poorly defined. Here, we show that Tpm2.1-mediated rigidity sensing represses anchorage-independent growth by downregulating oncogenic networks, including PI3K-Akt and EphA2 signaling. Unexpectedly, a majority of Tpm2.1-overexpressing cells remained viable in suspension, revealing a previously unrecognized decoupling between rigidity sensing and anoikis. Transcriptomic profiling of apoptotic and non-apoptotic cells in suspension identified compensatory survival programs marked by PI3K-Akt activation and induction of cell-cell adhesion genes. These findings uncover a dominant anoikis-resistant state that persists despite cytoskeletal normalization, suggesting that rigidity sensing alone is insufficient to reestablish anchorage dependence in cancer cells.
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