Characterization of the ALK7 signaling pathway in PanNET, using cell lines that either express constitutively active ALK7 (ALK7-CA) or treated with activin B

Herein we report that the TGFß superfamily receptor ALK7 is a suppressor of tumorigenesis and metastasis, as revealed by functional studies in mouse models of pancreatic neuroendocrine and luminal breast cancer, complemented by experimental metastasis assays. Activation in neoplastic cells of the ALK7 signaling pathway by its principal ligand activin B induces apoptosis. During tumorigenesis, cancer cells use two different approaches to evade this barrier, either downregulating activin B and/or ALK7. Suppressing ALK7 expression additionally contributes to the capability for metastatic seeding. ALK7 is associated with shorter relapse-free survival of various human cancers and distant-metastasis-free survival of breast cancer patients. This study introduces a new mechanistic insight into primary and metastatic tumor development, in the form of a protective barrier that triggers apoptosis in cells that are not 'authorized' to proliferate within a particular tissue, by virtue of those cells expressing ALK7 in a tissue microenvironment bathed in its ligand. Overall design: We performed RNA-seq of ßTC3 and AJ-5257-1 cells subjected to either DOX-inducible expression of ALK7-CA, or treatment with activin B.