ALK7 Signaling Manifests a Homeostatic Tissue Barrier That Is Abrogated during Tumorigenesis and Metastasis
Open accessAbstract
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.
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- Authors
- Michael, I. P., Saghafinia, S., Tichet, M., Zangger, N., Marinoni, I., Perren, A., & Hanahan, D.
- Affiliations
- École Polytechnique Fédérale de Lausanne (CH)
- SIB Swiss Institute of Bioinformatics (CH)
- University of Bern (CH)
- Corresponding author
- Hanahan, Douglas
- ORCID
- Venue
- Developmental Cell
- Publisher
- Elsevier BV
- Published
- 2019-05
- Volume
- 49
- Issue
- 3
- Pages
- 409-424.e6
- ISSN
- 1534-5807 (ISSN-L)
- OpenAlex
- W2944356931
- Cited by
- 42
- References
- 74
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 7 · 2023: 3 · 2022: 5 · 2021: 10 · 2020: 7 · 2019: 3
- FWCI
- 2.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Developmental Cell (publishedVersion)
- PubMed (publishedVersion)
- Bern Open Repository and Information System (University of Bern) (submittedVersion)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- Funders
- Swiss National Science Foundation
- Canadian Institutes of Health Research
- Human Frontier Science Program Organization
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Keywords
- ALK7, activin B, tumor suppressor, metastasis, carcinogenesis, luminal breast cancer, apoptosis, tissue barriers, metastatic seeding, relapse-free survival, distant metastasis-free survival, tumor microenvironment
- MeSH terms
- Animals, Breast Neoplasms, Cell Transformation, Neoplastic, Female, Homeostasis, Humans, Male, Mice, Inbred A, Mice, Inbred C57BL, Neoplasm Metastasis, Neoplasms, Pancreatic Neoplasms, Signal Transduction, Transforming Growth Factor beta, Mice, SCID, Apoptosis, Activins, Activin Receptors, Type I, Cell Line, Tumor, Mice, Smad2 Protein, Tumor Microenvironment, Carcinogenesis, Heterografts
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