ALK7 Signaling Manifests a Homeostatic Tissue Barrier That Is Abrogated during Tumorigenesis and Metastasis

• Published in: Developmental cell 2019-05, Vol.49 (3), p.409-424.e6
• Main Authors: Michael, Iacovos P., Saghafinia, Sadegh, Tichet, Mélanie, Zangger, Nadine, Marinoni, Ilaria, Perren, Aurel, Hanahan, Douglas
• Format: Article
• Language: English
• Subjects: activin B; Activin Receptors, Type I - metabolism; Activins - metabolism; ALK7/Acvr1c; Animals; Apoptosis - physiology; breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Carcinogenesis; Cell Line, Tumor; Cell Transformation, Neoplastic - metabolism; endothelial cells; Female; Heterografts; Homeostasis; Humans; Male; metastasis; Mice; Mice, Inbred A; Mice, Inbred C57BL; Mice, SCID; Neoplasm Metastasis; Neoplasms - metabolism; Neoplasms - pathology; neuroendocrine tumors; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; PanNETs; Signal Transduction; Smad2 Protein - metabolism; TGFß superfamily; Transforming Growth Factor beta - metabolism; Tumor Microenvironment
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2019.04.015

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 downregulating 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 mechanistic insights 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. [Display omitted] •Activin B/ALK7 signaling acts as a barrier to tumorigenesis and metastasis•ALK7 activation by activin B induces cancer cell apoptosis•Suppression of ALK7 enables metastasis by evading apoptosis•ALK7 is associated with poorer survival of various cancers, including breast cancer Michael et al. show that the activin B/ALK7 signaling pathway acts as a barrier to de novo tumorigenesis in pancreatic neuroendocrine and breast cancers, inducing apoptosis in neoplastic cells. Activin B and/or ALK7 downregulation allow cancer cells to evade this barrier and contributes to their capacity for metastatic seeding.