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CD38 in cancer-associated fibroblasts promotes pro-tumoral activity

Abstract

Primary and metastatic melanoma progression are supported by a local microenvironment comprising, inter alia, of cancer-associated fibroblasts (CAFs). We previously reported in orthotropic/syngeneic mouse models that the stromal ectoenzyme CD38 participates in melanoma growth and metastasis. The results presented here suggest that CD38 is a novel regulator of CAFs’ pro-tumorigenic functions. Orthotopic co-implantation of CD38 deficient fibroblasts and B16F10 melanoma cells limited tumor size, compared with CD38-expressing fibroblasts. Intrinsically, CAF-CD38 promoted migration of primary fibroblasts toward melanoma cells. Further, in vitro paracrine effects of CAF-CD38 fostered tumor cell migration and invasion as well as endothelial cell tube formation. Mechanistically, we report that CAF-CD38 drives the protein expression of an angiogenic/pro-metastatic signature, which includes VEGF-A, FGF-2, CXCL-12, MMP-9, and HGF. Data suggest that CAF-CD38 fosters tumorigenesis by enabling the production of pro-tumoral factors that promote cell invasion, migration, and angiogenesis.

Fig. 1: Fibroblastic CD38 regulates melanoma outgrowth.
Fig. 2: CD38 in fibroblasts regulates migration of fibroblasts and B16F10 melanoma cells.
Fig. 3: CD38 regulates the effect of fibroblast’s CM on B16F10 invasion.
Fig. 4: CD38 regulates the effect of fibroblast’s CM on MECs tube formation.
Fig. 5: CD38 in MTAF cells regulates B16F10 cells migration and invasion and endothelial tube formation.
Fig. 6: CD38-dependent differential expression of angiogenic proteins and genes in MTAF cells.

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Acknowledgements

We thank Prof. Neta Erez and Prof. Ronit Satchi-Fainaro for fruitful discussions and for providing the PDSC5 and B16F10 cells respectively. This work was supported in part by research grants from: Cancer Biology Research Center of TAU (to RS). Support was also obtained from The Marvin and Concetta Greenberg Pancreatic Cancer Institute, Marianne DiNofrio Pancreatic Research Foundation, a philanthropic gift from Jeanne Leinen, Pennsylvania’s DOH Health Research Formula Funds, the 5th AHEPA Cancer Research Foundation, the Worldwide Cancer Research Award, as well as NIH/NCI grants R21CA231252 (EC), R21CA228187 (EC), R01CA232256 (EC, JFB), and core grant CA06927 to support the Bio Sample Repository, Immune Monitoring, and Cell Culturing facilities at Fox Chase.

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Ben Baruch, B., Mantsur, E., Franco-Barraza, J. et al. CD38 in cancer-associated fibroblasts promotes pro-tumoral activity. Lab Invest 100, 1517–1531 (2020). https://doi.org/10.1038/s41374-020-0458-8

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