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CD38 in cancer-associated fibroblasts promotes pro-tumoral activity

Laboratory Investigation volume 100, pages1517–1531(2020)Cite this article

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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.

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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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  1. Eran Blacher

    Present address: Department of Neurology & Neurological Sciences, Stanford School of Medicine, Stanford, CA, USA

Affiliations

  1. Department of Neurobiology, School of Neurobiology, Biochemistry and Biophysics, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv-Yafo, Israel

    Bar Ben Baruch, Einav Mantsur, Eran Blacher & Reuven Stein

  2. Cancer Biology, the Marvin & Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Philadelphia, PA, USA

    Janusz Franco-Barraza & Edna Cukierman

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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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