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

肿瘤-TAM 串扰能够绕过胰腺癌中致癌的 KRAS 依赖

• 批准号: 10533258
• 负责人: Pingping Hou
• 金额: $ 20.03万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10533258
• 关键词: Advisory Committees; Bioinformatics; Bypass; Cancer Center; Cell Maintenance; Cell Survival; Cells; Chemicals; Clinical; Co-Immunoprecipitations; Collaborations; Complex; Data; Data Set; Dependence; Doxycycline; Environment; Epigenetic Process; Faculty; Genetic; Goals; HDAC5 gene; Head; Heterogeneity; Human; Immunology; Immunosuppression; Immunotherapy; Impairment; In Vitro; Infiltration; Institution; K22 Award; KRAS oncogenesis; KRAS2 gene; KRASG12D; Knock-out; Laboratories; MADH3 gene; MADH4 gene; Macrophage; Malignant Neoplasms; Malignant neoplasm of pancreas; Mass Spectrum Analysis; Medical Research; Mentors; Modeling; Molecular; Mus; Neoplasm Metastasis; Oncogenes; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Pharmacologic Substance; Phenotype; Physicians; Pilot Projects; Play; Positioning Attribute; Postdoctoral Fellow; Publications; Recruitment Activity; Recurrent disease; Regulation; Relapse; Research; Research Personnel; Resistance; Role; S100A8 gene; Scientist; Signal Transduction; Students; TP53 gene; Therapeutic; Transforming Growth Factor beta; Tumor-associated macrophages; Up-Regulation; Writing; Xenograft Model; antitumor effect; cancer therapy; career development; clinical development; cytokine; dimensional analysis; disorder control; gain of function; improved; in vivo; independency; inhibitor; insight; loss of function; mouse model; mutant; neoplastic cell; novel; novel strategies; pancreatic cancer cells; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; patient derived xenograft model; preclinical development; prevent; programs; receptor; recruit; response; screening; single-cell RNA sequencing; skills; synergism; targeted cancer therapy; targeted treatment; transcriptome; translational study; tumor; tumor growth; tumor heterogeneity; tumor progression

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.

项目总结/摘要 本研究旨在探索延长癌症靶向治疗疾病控制的新策略。 致癌性KRAS（KRAS*）是胰腺癌的关键驱动因素，并且使用药物抑制KRAS是胰腺癌的关键驱动因素。 化学和其它方法近年来得到广泛发展。利用强力霉素诱导的 我们先前的出版物表明，胰腺中条件性p53敲除的KRASG 12 D小鼠模型（iKPC） 70%的PDAC肿瘤在KRAS* 耗竭后0.5-1年复发。我发现肿瘤之间的串扰 细胞和肿瘤相关巨噬细胞（TAM）促进PDAC中的KRAS* 耗竭抗性。我 未发表的数据显示，iKPC细胞中HDAC 5的强制表达导致Ccl 2和Ccl 7的上调 招募技术援助人员。S100 A8 + TAM表达丰富的TGFβ，使KRAS* 非依赖性肿瘤 增长我假设HDAC 5-TAMs-TGFβ轴可能作为治疗的一般机制 PDAC中KRAS* 耗尽后的耐药性。在这个建议中，我将评估靶向治疗的潜力， 通过功能丧失研究，在几种人类和小鼠PDAC模型中观察HDAC 5、TAM和TGFβ通路。 具体而言，在目标1中，我将确定HDAC 5在KRAS* 旁路中的重要性，以及TAM的调节 通过内源性HDAC 5募集。在目标2中，我将利用多维分析来说明表型 KRAS* 耗竭后TAM的动态和异质性，并证明TAM对于 肿瘤绕过KRAS* 依赖性。在目标3中，我将利用SMAD 4缺陷模型来评估 TGFβ/SMAD 4通路激活的KRAS* 旁路，并描绘TGFβ驱动的分子机制， KRAS* 旁路。拟议的研究计划将帮助我在一个独立的教师职位， 学术/医学研究机构。与此同时，我将继续扩大我在生物信息学方面的研究技能， 免疫学、表观遗传学和转化研究。在我的职业发展方面，我将致力于提高 我在管理实验室，指导博士后和学生，科学写作和演讲，以及寻找 合作，除此之外。MD安德森癌症中心和罗纳德德皮尼奥博士的实验室提供了一个 这是一个很好的环境来实现这些目标。我还组建了一个特别顾问委员会 由Giulio Draetta博士、Raghu Kadhi博士和Anirban Maitra博士组成。他们不仅会为我提供技术支持 支持我拟议的研究，但也帮助我寻求教师的立场，并成功地作为一个独立的 调查员在K22奖的帮助下，我将有一个良好的开端来实现我的长期目标，即 作为实验室负责人，继续进行胰腺癌的基础和转化研究，包括但不限于靶向 治疗耐药性，并与其他科学家，医生和 制药公司作为一个团队。