Inactivation of Cancer-Associated-Fibroblasts Disrupts Oncogenic Signaling in Pancreatic Cancer Cells and Promotes Its Regression.

Abstract

Resident fibroblasts that contact tumor epithelial cells (TEC) can become irreversibly activated as cancer-associated-fibroblasts (CAF) that stimulate oncogenic signaling in TEC. In this study, we evaluated the cross-talk between CAF and TEC isolated from tumors generated in a mouse model of KRAS/mut p53-induced pancreatic cancer (KPC mice). Transcriptomic profiling conducted after treatment with the anticancer compound Minnelide revealed deregulation of the TGFβ signaling pathway in CAF, resulting in an apparent reversal of their activated state to a quiescent, nonproliferative state. TEC exposed to media conditioned by drug-treated CAFs exhibited a decrease in oncogenic signaling, as manifested by downregulation of the transcription factor Sp1. This inhibition was rescued by treating TEC with TGFβ. Given promising early clinical studies with Minnelide, our findings suggest that approaches to inactivate CAF and prevent tumor-stroma cross-talk may offer a viable strategy to treat pancreatic cancer.Significance: In an established mouse model of pancreatic cancer, administration of the promising experimental drug Minnelide was found to actively deplete reactive stromal fibroblasts and to trigger tumor regression, with implications for stromal-based strategies to attack this disease. Cancer Res; 78(5); 1321-33. ©2018 AACR.

• Authors: Patricia Dauer, Xianda Zhao, Vineet K Gupta, Nikita Sharma, Kousik Kesh, Prisca Gnamlin, Vikas Dudeja, Selwyn M Vickers, Sulagna Banerjee, Ashok Saluja
• Journal: Cancer research (Cancer Res) Vol. 78 Issue 5 Pg. 1321-1333 (03 01 2018) ISSN: 1538-7445 [Electronic] United States
• PMID: 29259015 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Diterpenes
• Epoxy Compounds
• Organophosphates
• Phenanthrenes
• Transforming Growth Factor beta
• Trp53 protein, mouse
• Tumor Suppressor Protein p53
• 14-O-phosphonooxymethyltriptolide disodium salt
• Hras protein, mouse
• Proto-Oncogene Proteins p21(ras)

Topics

• Animals
• Apoptosis
• Cancer-Associated Fibroblasts (drug effects, metabolism, pathology)
• Carcinogenesis
• Carcinoma, Pancreatic Ductal (drug therapy, genetics, pathology)
• Cell Proliferation
• Disease Models, Animal
• Diterpenes
• Epithelial Cells (drug effects, metabolism, pathology)
• Epoxy Compounds
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Mice
• Mice, Inbred C57BL
• Mutation
• Organophosphates (pharmacology)
• Pancreatic Neoplasms (drug therapy, genetics, pathology)
• Phenanthrenes (pharmacology)
• Proto-Oncogene Proteins p21(ras) (genetics)
• Signal Transduction
• Transforming Growth Factor beta (metabolism)
• Tumor Cells, Cultured
• Tumor Suppressor Protein p53 (genetics)