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Sci Signal. 2019 Jul 23;12(591). pii: eaav6847. doi: 10.1126/scisignal.aav6847.

Adipocytes sensitize melanoma cells to environmental TGF-β cues by repressing the expression of miR-211.

Author information

1
Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
2
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan 5290002, Israel.
3
Department of Structural Biology, Weizmann Institute of Science, Rehovot 7610001, Israel.
4
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
5
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
6
Institute of Pathology, E. Wolfson Medical Center, Holon 58100, Israel.
7
Institute of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv 6423906, Israel.
8
Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
9
Institute of Endocrinology, Chaim Sheba Medical Center, Tel Hashomer, Israel.
10
Department of Dermatology, Sheba Medical Center, Tel Hashomer 52621, Israel.
11
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
12
INSERM 1186, Gustave Roussy, Université Paris-Saclay, Villejuif 94805, France.
13
Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel. carmitlevy@post.tau.ac.il.

Abstract

Transforming growth factor-β (TGF-β) superfamily members are critical signals in tissue homeostasis and pathogenesis. Melanoma grows in the epidermis and invades the dermis before metastasizing. This disease progression is accompanied by increased sensitivity to microenvironmental TGF-β. Here, we found that skin fat cells (adipocytes) promoted metastatic initiation by sensitizing melanoma cells to TGF-β. Analysis of melanoma clinical samples revealed that adipocytes, usually located in the deeper hypodermis layer, were present in the upper dermis layer within proximity to in situ melanoma cells, an observation that correlated with disease aggressiveness. In a coculture system, adipocytes secreted the cytokines IL-6 and TNF-α, which induced a proliferative-to-invasive phenotypic switch in melanoma cells by repressing the expression of the microRNA miR-211. In a xenograft model, miR-211 exhibited a dual role in melanoma progression, promoting cell proliferation while inhibiting metastatic spread. Bioinformatics and molecular analyses indicated that miR-211 directly targeted and repressed the translation of TGFBR1 mRNA, which encodes the type I TGF-β receptor. Hence, through this axis of cytokine-mediated repression of miR-211, adipocytes increased the abundance of the TGF-β receptor in melanoma cells, thereby enhancing cellular responsiveness to TGF-β ligands. The induction of TGF-β signaling, in turn, resulted in a proliferative-to-invasive phenotypic switch in cultured melanoma cells. Pharmacological inhibition of TGF-β prevented these effects. Our findings further reveal a molecular link between fat cells and metastatic progression in melanoma that might be therapeutically targeted in patients.

PMID:
31337739
DOI:
10.1126/scisignal.aav6847

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