Regulation and targeting of tumor cell states and plasticity in pancreatic cancer

胰腺癌肿瘤细胞状态和可塑性的调节和靶向

基本信息

批准号：
10449418
负责人：
Srivatsan Raghavan
金额：
$ 26.02万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10449418
关键词：
Address Adopted Advisory Committees Area Award Basal Cell Basal Cell Cancer Biological Markers Biomedical Engineering Biopsy CRISPR screen Cancer Biology Cells Chemoresistance Cholangiocarcinoma Chronic Clinical Clustered Regularly Interspaced Short Palindromic Repeats Committee Members Dana-Farber Cancer Institute Disease Drug resistance Environment Evolution Exhibits Faculty Genetic Genetic Screening Genetic Transcription Goals Heterogeneity Immune Infrastructure Inpatients Institutes Knock-out Laboratories Libraries Ligands MADH2 gene MADH4 gene MAP Kinase Gene MAP3K7 gene MAPK8 gene Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Malignant neoplasm of pancreas Mediating Medical Oncologist Mentors Mentorship Metastatic to Modeling Molecular Oncology Organoids Outcome Outpatients Pancreatic Ductal Adenocarcinoma Patient Care Patients Pharmacology Phenotype Physicians Prognosis Regulation Research Research Personnel Research Proposals Resistance Role Sampling Scientist Selection for Treatments Signal Pathway Signal Transduction Specific qualifier value TGF Beta Signaling Pathway Techniques Testing Therapeutic Time Training Transforming Growth Factor beta Variant Work base career development chemotherapeutic agent chemotherapy drug sensitivity effective therapy in vivo insight medical schools member neoplastic cell non-genetic overexpression p38 Mitogen Activated Protein Kinase pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model predict clinical outcome receptor research and development resistance mechanism single-cell RNA sequencing skills targeted agent therapeutic development therapy resistant treatment response tumor tumor microenvironment

Address Adopted Advisory Committees Area Award Basal Cell Basal Cell Cancer Biological Markers Biomedical Engineering Biopsy CRISPR screen Cancer Biology Cells Chemoresistance Cholangiocarcinoma Chronic Clinical Clustered Regularly Interspaced Short Palindromic Repeats Committee Members Dana-Farber Cancer Institute Disease Drug resistance Environment Evolution Exhibits Faculty Genetic Genetic Screening Genetic Transcription Goals Heterogeneity Immune Infrastructure Inpatients Institutes Knock-out Laboratories Libraries Ligands MADH2 gene MADH4 gene MAP Kinase Gene MAP3K7 gene MAPK8 gene Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Malignant neoplasm of pancreas Mediating Medical Oncologist Mentors Mentorship Metastatic to Modeling Molecular Oncology Organoids Outcome Outpatients Pancreatic Ductal Adenocarcinoma Patient Care Patients Pharmacology Phenotype Physicians Prognosis Regulation Research Research Personnel Research Proposals Resistance Role Sampling Scientist Selection for Treatments Signal Pathway Signal Transduction Specific qualifier value TGF Beta Signaling Pathway Techniques Testing Therapeutic Time Training Transforming Growth Factor beta Variant Work base career development chemotherapeutic agent chemotherapy drug sensitivity effective therapy in vivo insight medical schools member neoplastic cell non-genetic overexpression p38 Mitogen Activated Protein Kinase pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model predict clinical outcome receptor research and development resistance mechanism single-cell RNA sequencing skills targeted agent therapeutic development therapy resistant treatment response tumor tumor microenvironment

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项目摘要

Project Summary/Abstract: Metastatic pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal malignancy with few therapeutic options. Tumor transcriptional states are strongly correlated with therapeutic responses and clinical outcomes in PDAC. However, the mechanisms that regulate PDAC cell states and their roles in tumor evolution and therapeutic resistance are not well understood. In this proposal, I will investigate mechanisms regulating PDAC cell state specification, characterize tumor cell plasticity as a potential mechanism of therapeutic resistance, and identify cell state-specific therapeutic vulnerabilities using genetic and pharmacologic approaches. In Aim 1, I will investigate how TGF-β signaling specifies the basal cell state in organoid models. In Aim 2, I will examine whether TGF-β-mediated cellular plasticity drives chemo-resistance in organoid models and serially collected metastatic biopsies analyzed with single-cell RNA-sequencing. In Aim 3, I will perform compound testing and CRISPR screening in isogenic organoid models induced to adopt either basal or classical states to identify state-specific therapeutic vulnerabilities. Together, these aims will establish a rigorous framework for the analysis and modeling of PDAC evolution and will advance our mechanistic understanding of how microenvironmental factors such as TGF-β regulate PDAC cell states, plasticity, and drug resistance, thereby uncovering new avenues for therapeutic development. I am a medical oncologist with a clinical focus in gastrointestinal cancers and a research background in cancer biology and biomedical engineering. I am applying for the K08 award with the long-term goal of becoming an independent laboratory-based investigator with a translational focus in pancreatic and biliary cancers. During my K08 training, I will perform mentored research in the laboratory of Dr. William Hahn at the Dana-Farber Cancer Institute (DFCI). Dr. Brian Wolpin will serve as a co-mentor for the translational aspects of my research and will also act as my clinical mentor. I plan to spend 90% of my time performing research and 10% of my time on patient care, initially as an inpatient oncology attending but eventually transitioning to the outpatient setting where I will see patients with gastrointestinal cancers. I have organized an outstanding advisory committee consisting of faculty from DFCI, Harvard Medical School, the Broad Institute, and MIT to help guide my research and career development. In addition to Drs. Hahn and Wolpin, my committee members - Drs. Ramesh Shivdasani, Stuart Schreiber, Alex Shalek, and Stephanie Dougan - are scientific experts in specific areas of my proposed research, and their insights will prove invaluable to the successful completion of this proposal. The research environments at DFCI and the Broad Institute are unparalleled and offer numerous opportunities for scientific advancement and career development. The K08 award along with the aid of my mentors and a focused training plan will enable me to achieve my goal of becoming an independent physician-scientist.

项目摘要/摘要：转移性胰腺导管腺癌（PDAC）是一种侵略性和致命性恶性肿瘤，几乎没有治疗选择。肿瘤转录状态与治疗密切相关 PDAC的反应和临床结果。但是，调节PDAC细胞状态及其的机制在肿瘤演化中的作用和热阻力尚不清楚。在此提案中，我将调查调节PDAC细胞状态规范的机制，将肿瘤细胞塑性表征为潜在机制使用遗传和使用遗传和药理方法。在AIM 1中，我将研究TGF-β信号如何指定基本细胞状态器官模型。在AIM 2中，我将检查TGF-β介导的细胞可塑性是否驱动化学抗性通过单细胞RNA测序分析的器官模型和连续收集的转移活检。在AIM 3中，我将在诱导采用的同基因器官模型中进行复合测试和CRISPR筛选基本或经典状态以识别特异性治疗漏洞。这些目标共同确定一个严格的框架，用于分析和建模PDAC演化，并将推动我们的机械了解微环境因素（例如TGF-β）如何调节PDAC细胞态，可塑性和药物阻力，从而发现了热发育的新途径。我是一名医学肿瘤科医生癌症生物学和生物医学工程。我正在申请K08奖，其长期目标是一个独立的基于实验室的研究者，在胰腺和胆道癌中翻译了重点。期间我的K08培训，我将在Dana-Farber的William Hahn博士的实验室进行指导的研究癌症研究所（DFCI）。 Brian Wolpin博士将担任我研究的翻译方面的同名并将担任我的临床导师。我计划花90％的时间进行研究和10％的时间在患者护理方面，最初是住院肿瘤学，但最终过渡到门诊环境我将看到胃肠道癌的患者。我已经组织了一个杰出的咨询委员会由DFCI，哈佛医学院，Broad Institute和MIT的教师组成，以帮助指导我的研究和职业发展。除了Drs。 Hahn和Wolpin，我的委员会成员-Drs。拉梅什 Shivdasani，Stuart Schreiber，Alex Shalek和Stephanie Dougan-是我的特定领域的科学专家拟议的研究及其见解将证明这对于成功完成该提案将是无价的。 DFCI和Broad Institute的研究环境是无与伦比的，为许多机会提供了很多机会科学进步和职业发展。 K08奖以及我的导师和专注的帮助培训计划将使我能够实现成为独立的身体科学家的目标。