Immune cells enables escape from oncogenic KRAS dependency in pancreatic cancer

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 and Ronald A. DePinho

Oncogenic KRAS (KRAS*) is a key tumor maintenance gene in pancreatic ductal adenocarcinoma (PDAC), motivating pharmacological 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 KrasG12D p53 null (iKPC) PDAC mouse model, gain-of-function screens of epigenetic regulators identified 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 (TAMs) in turn provide cancer cell with trophic support including TGFB to enable KRAS* bypass in a Smad4-dependent manner. Our work uncovers a KRAS* resistance mechanism involving immune cell remodeling of the PDAC TME.

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