title: Bidirectional cross talk between patient-derived melanoma and cancer-associated fibroblasts promotes invasion and proliferation.
abstract: Tumor-stroma interactions are critical for epithelial-derived tumors, and among the stromal cell types, cancer-associated fibroblasts (CAFs) exhibit multiple functions that fuel growth, dissemination, and drug resistance. However, these interactions remain insufficiently characterized in non-epithelial tumors such as malignant melanoma. We generated monocultures of melanoma cells and matching CAFs from patients' metastatic lesions, distinguished by oncogenic drivers and immunoblotting of characteristic markers. RNA sequencing of CAFs revealed a homogenous epigenetic program that strongly resembled the signatures from epithelial cancers, including enrichment for an epithelial-to-mesenchymal transition (EMT). Melanoma CAFs in monoculture displayed robust invasive behavior while patient-derived melanoma monocultures showed very little invasiveness. Instead, melanoma cells showed increased invasion when co-cultured with CAFs. In turn, CAFs showed increased proliferation when exposed to melanoma conditioned media (CM), mediated in part by melanoma-secreted transforming growth factor-alpha that acted on CAFs via the epidermal growth factor receptor. This study provides evidence that bidirectional interactions between melanoma and CAFs regulate progression of metastatic melanoma.
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Brigham and Womens Hospital, Boston, MA, USA.|The Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Izar
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Department of Cancer Immunology, Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: Cailin E
authors.initials: CE
authors.lastname: Joyce
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Brigham and Womens Hospital, Boston, MA, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Goff
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Brigham and Womens Hospital, Boston, MA, USA.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Cho
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: Parin M
authors.initials: PM
authors.lastname: Shah
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Brigham and Womens Hospital, Boston, MA, USA.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Sharma
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: Nageatte
authors.initials: N
authors.lastname: Ibrahim
authors.affiliation: Department of Surgery, VA Boston Health Care Service, Surgical Service, West Roxbury, MA, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Gold
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, USA.|Department of Cancer Immunology, Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: Carl D
authors.initials: CD
authors.lastname: Novina
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Brigham and Womens Hospital, Boston, MA, USA.
authors.forename: Monica M
authors.initials: MM
authors.lastname: Bertagnolli
authors.affiliation: Division of Surgical Oncology, Department of Surgery, Brigham and Womens Hospital, Boston, MA, USA.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Yoon
mesh_terms: D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D049109:Cell Proliferation; D018920:Coculture Techniques; D017077:Culture Media, Conditioned; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D008545:Melanoma / Q000378:metabolism / Q000473:pathology*; D009361:Neoplasm Invasiveness; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology*; D014407:Tumor Cells, Cultured
chemical_list: D017077:Culture Media, Conditioned
keywords: CAFs; TGFα/EGFR; melanoma; metastasis; tumor stroma