Inactivation of cancer-associated-fibroblasts disrupts oncogenic signaling in pancreatic cancer cells and promotes its regression

Patricia Dauer, Xianda Zhao, Vineet K. Gupta, Nikita Sharma, Kousik Kesh, Prisca Gnamlin, Vikas Dudeja, Selwyn M. Vickers, Sulagna Banerjee, Ashok Saluja

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1321-1333
Number of pages13
JournalCancer Research
Volume78
Issue number5
DOIs
StatePublished - Mar 1 2018

Fingerprint

Pancreatic Neoplasms
Epithelial Cells
Neoplasms
Sp1 Transcription Factor
Conditioned Culture Medium
Cancer-Associated Fibroblasts
Down-Regulation
Fibroblasts
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Inactivation of cancer-associated-fibroblasts disrupts oncogenic signaling in pancreatic cancer cells and promotes its regression. / Dauer, Patricia; Zhao, Xianda; Gupta, Vineet K.; Sharma, Nikita; Kesh, Kousik; Gnamlin, Prisca; Dudeja, Vikas; Vickers, Selwyn M.; Banerjee, Sulagna; Saluja, Ashok.

In: Cancer Research, Vol. 78, No. 5, 01.03.2018, p. 1321-1333.

Research output: Contribution to journalArticle

Dauer, Patricia ; Zhao, Xianda ; Gupta, Vineet K. ; Sharma, Nikita ; Kesh, Kousik ; Gnamlin, Prisca ; Dudeja, Vikas ; Vickers, Selwyn M. ; Banerjee, Sulagna ; Saluja, Ashok. / Inactivation of cancer-associated-fibroblasts disrupts oncogenic signaling in pancreatic cancer cells and promotes its regression. In: Cancer Research. 2018 ; Vol. 78, No. 5. pp. 1321-1333.
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