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

项目总结/摘要 胰腺癌（PC）的生存率非常低，对于来自低社会经济地位的患者甚至更低 社会经济背景/环境（SES），往往生活在地理位置有限的照顾。一 造成这种差异的原因可能是长期压力。一些研究人员，包括我们的合作伙伴， 调查人员表明，黑人和那些生活在社会经济地位低的社区的人， 暴露于压力环境（如系统性种族主义，缺乏资源），影响心理健康（如， 焦虑，恐惧）和增强PC。因此，社区SES（nSES）可以作为一个宏观环境指标， 慢性压力，独立于患者的SES和心理健康。低nSES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，需要研究如何理解nSES对PC的影响。父母补助金的重点是 研究PC中胰腺的非癌细胞和天然支架单位。值得注意的是， 与慢性压力有关。事实上，一些慢性压力的特征，如谷氨酸盐过量， 在PC期间由胰腺的非癌单位模拟。我们报道了促肿瘤激活 这些单位中的每一个都指示不利的PC患者结局。有趣的是，同样的单位也被牵连 在大脑中突触的稳定性和由这些单位产生的小膜囊泡的产生中 并且可以在血液中检测到。在此基础上，我们的母基金建议：i）揭示天然支架的 这些单位调节促肿瘤单位功能; ii）评估是否检测到独特的单位产生的 膜囊泡告知胰腺肿瘤促进与肿瘤抑制，PC患者的状态 iii）质疑与驱动所述单元的促肿瘤功能相关的分子是否可以被靶向。 在这里，我们计划通过与差异研究专家Dr。 Shannon Lynch提出了三个具体的新目标： 目的1：测量生物标志物（高血糖等）和慢性应激的宏观环境指标（nSES; 种族隔离）以确定高水平的环境压力是否与生物压力相关。 目的2：评估慢性应激指标（生物标志物、宏观环境指标）之间的相关性。 测量）和囊泡中的促肿瘤循环生物标志物，其告知局部应激样微环境。 目的3：确定微环境指示性生物标志物是否与PC患者生存时间相关， 单独和调整综合慢性应激指标和种族/民族后，多变量 回归模型

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.