Tumor microenvironment remodeling enables bypass of oncogenic KRAS dependency in pancreatic cancer

Pingping Hou, Avnish Kapoor, Qiang Zhang, Jiexi Li, Chang Jiun Wu, Jun Li, Zhengdao Lan, Ming Tang, Xingdi Ma, Jeffrey J. Ackroyd, Raghu Kalluri, Jianhua Zhang, Shan Jiang, Denise J. Spring, Y. Alan Wang, Ronald A. DePinho

Research output: Contribution to journalArticlepeer-review

82 Scopus citations

Abstract

Oncogenic KRAS (KRAS*) is a key tumor maintenance gene in pancreatic ductal adenocarcinoma (PDAC), motivating pharmacologic targeting of KRAS* and its effectors. Here, we explored mechanisms involving the tumor microenvironment (TME) as a potential basis for resistance to targeting KRAS*. Using the inducible Kras G12D; Trp53 -/- PDAC mouse model, gain-of-function screens of epigenetic regulators identifi ed HDAC5 as the top hit enabling KRAS* independent tumor growth. HDAC5 -driven escaper tumors showed a prominent neutrophil-to-macrophage switch relative to KRAS*-driven tumors. Mechanistically, HDAC5 represses Socs3, a negative regulator of chemokine CCL2, resulting in increased CCL2, which recruits CCR2 + macrophages. Correspondingly, enforced Ccl2 promotes macrophage recruitment into the TME and enables tumor recurrence following KRAS* extinction. These tumor-associated macrophages in turn provide cancer cells with trophic support including TGF Β to enable KRAS* bypass in a SMAD4-dependent manner. Our work uncovers a KRAS* resistance mechanism involving immune cell remodeling of the PDAC TME. SIGNIFICANCE: Although KRAS* is required for PDAC tumor maintenance, tumors can recur following KRAS* extinction. The capacity of PDAC cancer cells to alter the TME myeloid cell composition to support KRAS*-independent tumor growth illuminates novel therapeutic targets that may enhance the effectiveness of therapies targeting KRAS* and its pathway components.

Original languageEnglish (US)
Pages (from-to)1058-1077
Number of pages20
JournalCancer Discovery
Volume10
Issue number7
DOIs
StatePublished - 2020
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology

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