Tumor-TAMs crosstalk enables bypass of oncogenic KRAS dependency in pancreatic cancer

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Project Summary/Abstract The proposed study is to explore novel strategies to prolong disease control of cancer targeted therapy. Oncogenic KRAS (KRAS*) is the key driver of pancreatic cancer, and pharmaceutical inhibition of KRAS using chemical and other approaches is extensively developed in recent years. Utilizing a doxycycline inducible KRASG12D mouse model with conditional p53 knockout in pancreas (iKPC), our previous publication indicates that 70% PDAC tumors relapsed 0.5-1 year after KRAS* depletion. I identified that the crosstalk between tumor cells and tumor associated macrophages (TAMs) promotes KRAS* depletion resistance in PDAC. My unpublished data shows that forced expression of HDAC5 in iKPC cells leads to upregulation of Ccl2 and Ccl7 and recruitment of TAMs. S100A8+ TAMs express abundant TGFβ that enables KRAS*-independent tumor growth. I hypothesize that the HDAC5-TAMs-TGFβ axis may serve as a general mechanism for therapy resistance after KRAS* depletion in PDAC. In this proposal, I will evaluate the therapeutic potential of targeting HDAC5, TAMs and TGFβ pathway in several human and mouse PDAC models by loss-of-function study. Specifically, In Aim 1, I will determine the essentiality of HDAC5 in KRAS* bypass, and the regulation of TAM recruitment by endogenous HDAC5. In Aim 2, I will utilize multi-dimensional analysis to illustrate the phenotypic dynamics and heterogeneity of TAMs after KRAS* depletion, and demonstrate the essentiality of TAMs for tumors to bypass KRAS* dependency. In Aim 3, I will utilize SMAD4 deficient models to access the essentiality of TGFβ/SMAD4 pathway activation in KRAS* bypass, and delineate the molecular mechanisms of TGFβ-driven KRAS* bypass. The proposed research program will help me to launch an independent faculty position in an academic/medical research institution. Meanwhile, I will keep expanding my research skills in bioinformatics, immunology, epigenetics and translational studies. In terms of my career development, I will devote to improve my skills on managing lab, mentoring postdocs and students, scientific writing and presentation, and seeking for collaborations, among others. MD Anderson Cancer Center and Dr. Ronald DePinho’s laboratory provide an excellent environment for me to achieve these goals. I have also formed an extraordinary advisory committee composed of Drs. Giulio Draetta, Raghu Kalluri, and Anirban Maitra. They will not only provide me technical support for my proposed study, but also assist me to seek a faculty position and succeed as an independent investigator. With the help of K22 award, I will have a good start to achieve my long-term goals, which are to continue basic and translational studies in pancreatic cancer as a lab head, including but not limited to targeted therapy resistance, and to contribute to developing novel cancer therapies with other scientists, physicians and pharmaceutical companies as a team player.