Pancreatic Cancer-Associated Fibroblasts: Function, Detection, and Regulation

胰腺癌相关成纤维细胞：功能、检测和调节

• 批准号: 10767490
• 负责人: Edna Cukierman
• 金额: $ 25.5万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10767490
• 关键词: Administrative Supplement; Affect; Anoikis; Anxiety; Area; Automobile Driving; Biological; Biological Markers; Biological Process; Black Populations; Black race; Blood; Blood specimen; Brain; Cancer Patient; Cell Death; Cells; Chronic; Chronic stress; Couples; Data; Dedications; Detection; Disparity; Endosomes; Environment; Ethnic Origin; Exposure to; Extracellular Matrix; Fibroblasts; Fright; Functional disorder; Generations; Genetic Transcription; Geographic Locations; Glutamate Metabolism Pathway; Glutamates; Health Services Accessibility; Homeostasis; Housing; Immunosuppression; Individual; Institutional Racism; Link; Location; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Mental Health; Modeling; Neighborhoods; Nutritional Support; Organ; Outcome; Pancreas; Pathway interactions; Patient-Focused Outcomes; Patients; Physiological; Poverty; Production; Proteins; Psyche structure; Psychosocial Factor; Race; Racial Segregation; Regulation; Reporting; Research; Research Personnel; Resources; Stress; Survival Rate; Synapses; Testing; Time; Tumor Promotion; Vesicle; cancer cell; cancer health disparity; cancer survival; circulating biomarkers; early detection biomarkers; environmental disparity; extracellular vesicles; forging; genetic signature; health disparity; multidisciplinary; novel; pancreatic cancer cells; pancreatic cancer patients; pancreatic neoplasm; parent grant; post-traumatic stress; prevent; prognostic; receptor; scaffold; socioeconomics; stressor; tumor; tumor microenvironment; tumor progression; tumorigenesis; tumorigenic

PROJECT SUMMARY/ABSTRACT Pancreatic Cancer (PC) survival rates are very low and even lower for patients from low socioeconomic backgrounds/circumstances (SES), often living in geographic locations with limited access to care. One explanation for this disparity could be chronic stress. Several researchers, including our Collaborative Investigator, have shown that Black individuals and those living in neighborhoods with low SES endure sustained exposure to stressful circumstances (e.g. systemic racism, lack of resources), which impact mental health (e.g. anxiety, fear) and augment PC. Neighborhood SES (nSES) hence serve as a macro-environmental indicator of chronic stress, independent of a patient’s SES and mental health. Low nSES, can for example prevent cancer cell death and promote its aggressiveness. If the biologic basis of PC health disparities is to be elucidated, studies proposing to understand how, for example, nSES impacts PC are needed. The parent grant focuses on studying the non-cancerous cells and natural scaffold units of the pancreas in PC. Of note, the specific molecules studied are implicated in chronic stress. In fact, some chronic stress features, such as glutamate excess, are simulated by the non-cancerous units of the pancreas during PC. We reported that pro-tumorigenic activation of these units are indicative of unfavorable PC patient outcomes. Interestingly the same units also are implicated in synapse stability in brain and in the generation of small membranous vesicles that are produced by these units and can be detected in blood. Building on this, our parent grant proposes to: i) reveal how the natural scaffold of these units regulates pro tumoral unit functions; ii) assess whether detection of the unique unit-generated membranous vesicles inform on the pancreatic tumor-promoting vs. tumor-suppressing, status of PC patient’s organ; and iii) question if the molecules relevant for driving pro-tumoral function of the units can be targeted. Here we plan to expand this scope by forging a multidisciplinary partnership with a disparity research expert Dr. Shannon Lynch in the form of 3 specific new aims: Aim 1: Measure biomarkers (high Glu, & others) and macro-environmental measures of chronic stress (nSES; racial segregation) to determine if high levels of environmental stress correlate with biologic stress. Aim 2: Evaluate the correlation between chronic stress measures (biomarkers, macro-environmental measures) and pro-tumoral circulating biomarkers in vesicles informing on local stress-like microenvironments. Aim 3: Determine if microenvironment-indicative biomarkers are associated with PC patient survival time, alone and after adjustment for comprehensive chronic stress measures and race/ethnicity in multivariable regression models.

项目摘要/摘要 胰腺癌(PC)的生存率非常低，对于来自低社会经济背景的患者来说，甚至更低 背景/环境(SES)，通常生活在地理位置上，获得护理的机会有限。一 造成这种差异的原因可能是长期的压力。几位研究人员，包括我们的协作 调查表明，黑人个人和那些生活在低SES社区的人 暴露在有压力的环境中(例如系统性种族主义、缺乏资源)，这会影响心理健康(例如： 焦虑、恐惧)和增强PC。因此，邻里社会经济状况(NSE)可作为 慢性压力，与患者的自尊和心理健康无关。例如，低NSE可以预防癌症 细胞死亡，并促进其侵略性。如果要阐明PC健康差异的生物学基础， 例如，建议理解NSE如何影响PC的研究是必要的。家长助学金的重点是 对PC中胰腺的非癌细胞和天然支架单位进行研究。值得注意的是，特定的分子 被研究的人与慢性压力有关。事实上，一些慢性应激特征，如谷氨酸过量，是 在PC期间由胰腺的非肿瘤单位模拟。我们报告了促肿瘤激活 这些单位中的每一个都预示着PC患者的不良结局。有趣的是，同样的单位也牵涉其中 在脑中突触的稳定性以及由这些单位产生的小膜泡的产生中 并且可以在血液中检测到。在此基础上，我们的母公司赠款建议：i)揭示 这些单位调节亲肿瘤单位的功能；ii)评估独特单位的检测是否产生 膜泡对胰腺癌患者胰腺促癌与抑瘤状态的影响 器官；以及iii)质疑与驱动这些单位的亲肿瘤功能相关的分子是否可以成为靶点。 在这里，我们计划通过与差异研究专家Dr. 香农·林奇以3个具体新目标的形式： 目的1：测量生物标记物(高谷氨酸等)和慢性应激的宏观环境指标(NSE； 种族隔离)，以确定高水平的环境压力是否与生物压力相关。 目标2：评估慢性压力测量(生物标记物、宏观环境)之间的相关性 措施)和囊泡中的亲肿瘤循环生物标记物，告知局部应激样微环境。 目的3：确定指示微环境的生物标志物是否与PC患者的生存时间有关， 在多变量中单独和在调整综合慢性应激措施和种族/民族之后 回归模型。