Investigating Cellular Communication in the Tumor Microenvironment in Pancreatic Cancer

研究胰腺癌肿瘤微环境中的细胞通讯

• 批准号: 10284422
• 负责人: Nina G Steele
• 金额: $ 13.51万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10284422
• 关键词: Address; Advisory Committees; Angiogenic Factor; Award; Behavior; Biology; Blood Vessels; Cancer Biology; Cancer Control; Cancer Etiology; Cell physiology; Cells; Cessation of life; Clinical Trials; Coculture Techniques; Collaborations; Communication; Complex; Cre driver; Data; Development; Development Plans; Disease; Endothelial Cells; Endothelium; Epithelial; Erinaceidae; Fibroblasts; Fibrosis; Future; Gene Expression; Genes; Genetic study; Goals; Human; Immune; Immune Targeting; Immune response; Immunology; Immunosuppression; Individual; Infiltration; Inflammatory; International; Investigation; Laboratories; Laboratory Research; Lead; Ligands; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mentors; Mentorship; Michigan; Myeloid Cells; Myeloid-derived suppressor cells; Neoplasm Metastasis; Pancreas; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Pericytes; Pharmacology Study; Phase; Play; Population; Population Heterogeneity; Reaction; Research; Role; SHH gene; Signal Transduction; Survival Rate; T-Lymphocyte; Testing; Therapeutic; Tumor Angiogenesis; Tumor-Derived; Universities; Vascularization; Work; angiogenesis; base; career development; dosage; effective therapy; experimental study; gene function; immunoregulation; in vivo; inhibitor/antagonist; mouse model; neoplastic cell; novel; novel strategies; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; paracrine; patient response; receptor; relating to nervous system; response; skills; smoothened signaling pathway; tumor; tumor growth; tumor metabolism; tumor microenvironment; tumor-immune system interactions

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDA) is projected to become the 2nd leading cause of cancer-related deaths world-wide by 2030, largely due a lack of effective treatments. A major barrier to successful therapy is the abundant fibrotic reaction in PDA, which includes cancer-associated fibroblasts (CAFs). While many pancreatic tumors are hypovascularized, endothelial cells regulate immune maturation and infiltration, tumor cell metabolism, and metastatic dissemination. In PDA, Hedgehog (HH) signaling functions in a paracrine manner, whereby tumor cells produce HH ligands and signal to CAFs via the canonical HH receptor PTCH1, leading to downstream pathway activation. There have been contradictory genetic and pharmacologic studies in mouse models, as well as disappointing clinical trials with HH pathway inhibitors, indicating the role of HH signaling in PDA is highly complex and context dependent. This proposal aims to uncover two key aspects of HH signaling in PDA: a) HH-dependent alterations in the immune landscape through fibroblast-immune cross talk (Aim 1), and b) HH-dependent changes in endothelial cell gene expression and function through fibroblast-endothelial cross talk (Aim 2). I hypothesize that combined targeting of HH signaling in combination with the immune response or the vasculature will be required to effectively treat PDA. Our preliminary data indicate that Slit2, which regulates angiogenesis, is reduced during HH pathway inhibition in PDA. Previous work showed that epithelial Slit2 deletion promotes neural invasion and metastasis in PDA. However, I find the majority of Slit2 is produced by fibroblasts, while Robo receptors are expressed in endothelial cells. In Aim 3 of this proposal, I will determine the fibroblast-specific contribution of Slit2 to pancreatic angiogenesis and tumor growth. Overall, the proposed experiments will provide a fundamentally new understanding of cellular cross talk within the pancreatic TME, including addressing fibroblast-immune and fibroblast-endothelial communication as well as a specific investigation of SLIT-ROBO signaling in pancreatic cancer. The mentored phase of this award will be overseen by Drs. Allen and Pasca di Magliano at the University of Michigan (UM). I have developed an additional advisory team to include internationally known leaders in the fields of cancer biology (Dr. Andrzej Dlugosz), endothelial biology (Dr. Jason Spence), and immunology (Dr. Bethany Moore). Combined, this mentorship team has set forth a career development plan focused on research, collaboration, presentations, mentorship, grantsmanship, and the furthering of management skills required to successfully lead an independent research laboratory.

项目总结/文摘