Clinical issue

Pancreatic adenocarcinoma, the most common pancreatic cancer, is almost always fatal because it is typically diagnosed at a late stage and is generally resistant to conventional therapies. The genetic alterations that occur during pancreatic carcinogenesis are a subject of intense study, but little is known about the molecular regulation of normal exocrine pancreatic development. A comprehensive understanding of both normal and neoplastic development will allow the identification of biomarkers and targets of this disease, and facilitate the design of strategies to improve the prevention, early detection and treatment of this disease.

Results

In this paper, the authors identify the ion channel kinase Trpm7 as a regulator of exocrine pancreatic development. Using zebrafish with a mutant trpm7 gene, they show that Trpm7 is required for epithelial proliferation in the exocrine pancreas: in the absence of normal Trpm7, cell-cycle progression and cell growth during morphogenesis are inhibited. Trpm7 regulates cellular Mg2+ and Ca2+ homeostasis, and adding supplementary Mg2+ partially rescues the exocrine pancreatic defects of the zebrafish trpm7 mutants. Addition of Mg2+ also represses the suppressor of cytokine signaling 3a (socs3a) gene, and the authors go on to show that simply inhibiting socs3a expression improves trpm7 mutant exocrine pancreatic growth. The proliferative role of Trpm7 is therefore sensitive to Mg2+ and also involves Socs3a-mediated signaling. These findings are shown to have relevance to pancreatic adenocarcinoma, because human TRPM7 is overexpressed in pancreatic adenocarcinoma tissues and several pancreatic cancer cell lines. Partial silencing of TRPM7 reduces proliferation in the cell lines by impairing cell-cycle progression and inducing non-apoptotic cell death. As in the zebrafish trpm7 mutants, supplementary Mg2+ rescues the proliferative defect of TRPM7-deficient pancreatic cancer cells.

Implications and future directions

This work demonstrates a growth-regulatory role for TRPM7 in the pancreas during development and in cancer. To determine its precise function, however, it will be necessary to define how signaling from TRPM7 is integrated with established signaling pathways in pancreatic epithelia and cancer cells. Given that TRPM7 is a potential biomarker for pancreatic adenocarcinoma, its expression in the development and progression of pancreatic neoplasia, and the relationship between the expression level of TRPM7 and the prognosis and treatment response of patients warrants investigation. Finally, this work also suggests that TRPM7 is a possible therapeutic target. The effects of modulating TRPM7 expression and/or activity using small molecules, either in isolation or in combination with cytotoxic chemotherapeutic agents and other targeted therapeutics, should be evaluated in appropriate tumor models.

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