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Cancer cells have many different behaviors from epithelial to mesenchymal forms. We report here that 36 distinct tumor cell lines regardless of EMT form or other features lack the ability to sense rigidity and will grow on soft surfaces. In the majority of lines, cells were missing at least one protein needed for rigidity sensing (primarily tropomyosin2.1 (Tpm2.1) but also PTPN12, FilaminA (FLNA), and myosinIIA) while all had high levels of Tpm3. In the few cases where the major rigidity sensing components were present, those tumor cells were not able to sense rigidity. Thus, we suggest that tumor cells can lose the ability to sense rigidity by many different means and that the loss of rigidity sensing is sufficient to cause the transformed phenotype that enables targeted treatments.
Activating BRAF mutations are thought to drive melanoma tumorigenesis and metastasis by constitutively activating MEK and ERK. Small molecule inhibitors (SMIs) of BRAF or MEK have shown promise as melanoma therapeutics. However, the development of resistance to these inhibitors in both the short-and long-term is common; warranting investigation into how these SMIs influence ERK signaling dynamics. Quantitative single cell imaging of ERK activity in living cells reveals both intra-and inter-cell heterogeneity in this activity in isogenic melanoma populations harboring a BRAFV600E mutation. This heterogeneity is largely due to a cell-cycle dependent bifurcation of ERK activity.Moreover, we show there are also cell-cycle dependent responses in ERK activity following BRAF or MEK inhibition. Prior to, but not following, CDK4/6-mediated passage through the Restriction Point (RP) ERK activity is sensitive to BRAF and MEK inhibitors. In contrast, for cells that have passed the RP, ERK activity will remain elevated in the presence of BRAF or MEK inhibition until mitosis. Our results show that ERK activityeven in the presence of activating BRAF mutations -is regulated by both positive and negative feedback loops that are engaged in cell-cycle dependent fashions. CDK4/6 inhibition sensitizes ERK activity to BRAF or MEK inhibition by preventing passage the transition from a BRAF/MEK dependent to independent state. Our results have implications for the use of MEK and BRAF inhibitors as melanoma therapeutics, and offer a rational basis for the use of these inhibitors in combination with CDK4/6 inhibition during cancer therapy.
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