Inducing ferroptosis to impede metastasis by inhibiting the calcium channel TRPC6
TRPC6 (transient receptor potential cation channel 6) contributes to the ability of breast cancer cells to persist after chemotherapy.  Here, we investigated a potential function of TRPC6 in enabling breast cancer cells to resist stimuli that induce ferroptosis.   A minority population of quiescent cells was isolated from triple-negative breast cancer (TNBC) cell lines using a p27 reporter.  These p27+ cells exhibited increased TRPC6 expression and resistance to ferroptosis compared to the p27- proliferating population.  The p27+ cells were also more metastatic than the p27- cells supporting the hypothesis that metastasis requires the ability of cells to evade ferroptosis. In pursuit of the mechanism involved, we discovered that the ability of TRPC6 to repress c-Myc is essential because repression of c-Myc sustains levels of glutathione that are sufficient to impede ferroptosis. Importantly, treatment of TNBC cells with a TRPC6 inhibitor reduced metastasis significantly, an effect that was mitigated by liproxstatin-1 treatment. These results support the hypothesis that a sub-population of TNBC cells characterized by TRPC6 expression has the potential to form metastases by evading ferroptosis. Overall design: RNA-seq profiling of CAL-51 cells sorted based on p27 expression following transfection with a p27-mVenus reporter plasmid.