TRPM7 is an intriguing bifunctional protein that constitutes the fusion between a cation channel and a serine/threonine protein
kinase domain. It has been proposed to function in several fundamental physiological processes, including cell adhesion and
migration. Biological dysfunctioning of TRPM7 has in turn been associated with several diseases, such as cancer. We show that
TRPM7 contributes to the migration of tumor cells in vitro and the formation of metastasis in vivo. Moreover, high(er) TRPM7
mRNA levels correlate with poor disease outcome and metastasis formation in two independent breast cancer cohorts, independently
of other clinical parameters such as tumor size. Cell proliferation of breast cancer cells (MDA-MB-231) and neuroblastoma
cells (N1E-115) in cell culture conditions was not affected by TRPM7 knockdown and overexpression, respectively, neither was
the size of metastases in experimental metastasis assays. We demonstrate that manipulating the expression levels of TRPM7
particularly affects cell-matrix adhesions in both breast cancer cells and neuroblastoma cells. TRPM7 downregulation in breast
cancer cells results in a contractile phenotype and increased focal adhesion numbers. TRPM7 overexpression in neuroblastoma
cells, on the other hand, is associated with increased cell flattening (a ‘relaxed morphology’) and cell-adhesive properties,
accompanied by the formation of invadosomes. We find that TRPM7 acts as a regulator of cellular tension, cell adhesion dynamics
and migration independent from mediating (localized) Ca2+-signaling. Rather our proteomics results and our analyses using
the TRPM7 inhibitor Waixenicin-A suggest that TRPM7 may control these processes by functioning as a scaffold.
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