Regulation of cancer cell metabolism and growth by the pancreatic tumor stroma

 描述（由申请人提供）：候选人的短期目标是在学术研究机构获得教职;她的长期目标是更好地了解胰腺癌中肿瘤-间质串扰的性质和分子基础，并利用这种改进的理解来治疗人类疾病。她打算专注于胰腺星状细胞，肿瘤微环境的肌纤维母细胞样细胞，并研究这些独特的脂质储存细胞如何与肿瘤细胞相互作用，以影响基因表达，代谢和生长。候选人在癌症生物学和基因表达分析方面的背景将得到实验室和本机构在高通量测序和代谢生理学方面的专业知识的补充，以帮助她实现目标。此外，广泛的指导 顾问的经验和一个平衡良好的指导委员会的贡献将在候选人向独立过渡时促进其科学和专业发展。本文提出的研究将评估PDAC肿瘤-间质相互作用的新机制，具体目标如下。目的1：检测间质VDR/NF-kB串扰在PDAC结缔组织增生和肿瘤生长中的作用。最近的数据表明，维生素D受体（VDR）负调控PSC激活，导致减少表达的PSC中的促炎基因和减少旁分泌诱导的因子，支持肿瘤生长，通过抑制NF-κ B染色质占用和靶基因的表达。间质VDR/NF-κ B串扰的作用将在患者来源的PSC细胞系和具有显著结缔组织增生的PDAC的新同种异体移植模型中进行检查。这些实验将确定这些因子在激活已知调节胰腺癌细胞生长和代谢的关键途径中的重要性。目的2：了解PSC分泌因子对癌细胞脂质代谢的影响。使用最近开发的系统分析肿瘤间质串扰，候选人将询问脂质代谢和基因表达之间的联系，在PSC分泌因子的背景下。初步数据表明，PSC分泌促进Kras转化细胞最近建立的脂肪酸清除表型的因子，同时提供影响乙酰辅酶A作为组蛋白乙酰化底物的可用性的信号传导调节剂。这些研究的结果将有助于了解PDAC细胞独特的代谢特性。目的3：评价旁分泌调节氧化还原稳态的PDAC基质线索。 将在面临与肿瘤微环境相关的细胞应激的肿瘤细胞中评估肿瘤间质的结构和扩散特征的贡献。 这些研究将有助于确定旁分泌促生存途径的性质，有助于肿瘤室的氧化还原平衡，并可能作为新的治疗靶点。总之，拟议的实验将探索PDAC生物学以前未探索的方面，有可能发现新的治疗干预漏洞。

 DESCRIPTION (provided by applicant): The candidate's short-term goal is to obtain a faculty position at an academic research institute; her long-term goal is to better understand the nature and molecular underpinnings of tumor-stroma crosstalk in pancreatic cancer, and to harness this improved understanding to treat the human disease. She intends to focus on pancreatic stellate cells, myofibroblast-like cells of the tumor microenvironment, and study how these unique lipid-storing cells interact with tumor cells to effect gene expression, metabolism, and growth. The candidate's background in cancer biology and gene expression analysis will be supplemented by the expertise in high-throughput sequencing and metabolic physiology in the lab and at the present institution to help her realize her goals. Further, the extensive mentorship experience of the advisor and the contributions of a well-balanced mentorship committee will enhance the candidate's scientific and professional development as she transitions to independence. The studies proposed here will evaluate novel mechanisms underlying PDAC tumor-stroma interactions with the following specific aims. Aim 1: Examine the role of stromal VDR/NF-kB crosstalk in PDAC desmoplasia and tumor growth. Recent data suggest that the vitamin D receptor (VDR) negatively regulates PSC activation, leading to reduced expression of pro-inflammatory genes in PSCs and decreased paracrine induction of factors that support tumor growth, by inhibiting NF-kB chromatin occupancy and target gene expression. The role of stromal VDR/NF-kB crosstalk will be examined in patient-derived PSC lines and in a new allograft model of PDAC featuring prominent desmoplasia. These experiments will determine the significance of these factors in the activation of key pathways known to regulate pancreatic cancer cell growth and metabolism. Aim 2: Understand the effect of PSC secreted factors on cancer cell lipid metabolism. Using recently developed systems for analysis of tumor-stroma crosstalk, the candidate will interrogate the link between lipid metabolism and gene expression, in the context of PSC secreted factors. Preliminary data suggest that PSCs secrete factors that foster the recently established fatty acid scavenging phenotype of Kras- transformed cells while providing signaling modulators that impact the availability of acetyl-CoA as a substrate for histone acetylation. The results from these studies will be useful in understanding the unique metabolic properties of PDAC cells. Aim 3: Evaluate paracrine regulation of redox homeostasis by PDAC stromal cues. The contribution of structural and diffusible features of the tumor stroma will be assessed in tumor cells faced with cellular stress relevant to the tumor microenvironment. These studies will help to define the nature of paracrine pro-survival pathways that contribute to redox balance in the neoplastic compartment, and that may serve as new therapeutic targets. Together, the proposed experiments will probe previously unexplored aspects of PDAC biology, with the potential to uncover novel vulnerabilities for therapeutic intervention.