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Title: Uncoupling oncogenic and tumor-suppressive Activin functions in melanoma

Daniel B. Constam

Ecole Polytechnique Fédérale Lausanne (EPFL), Switzerland

Biography

Daniel Constam studied natural sciences at ETH Zürich. After a doctoral thesis in neuroimmunology (ETH & Univ. Zürich), postdoctoral research as an EMBO fellow at Harvard University identified proteases that activate TGFb-related precursor proteins. In 2000, he became a group leader at the Swiss institute for experimental cancer research ISREC (Lausanne). Since 2007, he has been an Associate Professor at the EPFL School of Life Sciences where his lab currently studies the function and regulation of TGFβ signaling pathways in development and cancer.

Abstract

Melanoma and squamous cell carcinoma and many other cancerous cells frequently secrete Activin-A, a TGFβ-related factor that normally regulates wound healing and the menstrual cycle. Activin-A accumulation in plasma associates with poor prognosis e.g. in lung adenocarcinoma and may lead to systemic muscle wasting, and its overexpression locally within skin keratinocytes can accelerate squamous cell carcinoma progression, at least in part by stimulating tumour angiogenesis. However, in normal human melanocytes, mammary epithelial cells and liver hepatocytes Activin-A primarily inhibits cell proliferation. How cancer cells might co-opt this factor to unleash oncogenic signals and whether the underlying mechanism is druggable remains to be determined. Using human and mouse melanoma grafts, we found that lentiviral expression of constitutively active mutant receptor in such pre-clinical models potently restores cytostatic and cell death signaling, indicating that evasion of tumour-suppressive activity likely involves inhibition of autocrine signaling. In sharp contrast, Activin-A secretion and paracrine signaling stimulated primary and metastatic growth instead of suppressing it. We show that such oncogenic activity is mediated by inhibition of cytotoxic CD8 T-cells, and we shed light on the underlying mechanism. Targeting paracrine Activin-A signaling emerges as an attractive new avenue to stimulate anti-tumour immunity in a subset of human melanoma and possibly other solid cancers.