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

TY - JOUR

T1 - Tumor microenvironment remodeling enables bypass of oncogenic KRAS dependency in pancreatic cancer

AU - Hou, Pingping

AU - Kapoor, Avnish

AU - Zhang, Qiang

AU - Li, Jiexi

AU - Wu, Chang Jiun

AU - Li, Jun

AU - Lan, Zhengdao

AU - Tang, Ming

AU - Ma, Xingdi

AU - Ackroyd, Jeffrey J.

AU - Kalluri, Raghu

AU - Zhang, Jianhua

AU - Jiang, Shan

AU - Spring, Denise J.

AU - Wang, Y. Alan

AU - DePinho, Ronald A.

N1 - Publisher Copyright: © 2020 American Association for Cancer Research.

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85086564403

UR - https://www.scopus.com/pages/publications/85086564403#tab=citedBy

U2 - 10.1158/2159-8290.CD-19-0597

DO - 10.1158/2159-8290.CD-19-0597

M3 - Article

C2 - 32341020

SN - 2159-8274

VL - 10

SP - 1058

EP - 1077

JO - Cancer Discovery

JF - Cancer Discovery

IS - 7

ER -