Integrative Analysis of the Aging Peritoneum in Metastatic Receptivity

本提案的总体目标是提供一个全面的研究培训和职业发展计划，使首席研究员能够顺利完成博士学位，并获得在衰老和癌症领域进行转化研究的有竞争力的博士后职位。第一阶段的重点是完成正在进行的博士培训，研究衰老微环境在卵巢癌（OvCa）转移中的作用。OvCa是最致命的妇科恶性肿瘤，也是美国女性5年生存率较低的第五大癌症死亡原因，75%的女性被诊断为弥漫性腹膜内（IP）转移。OvCa转移与大多数其他癌症的不同之处在于，细胞从原发肿瘤脱离，脱落到腹膜腔，粘附在腹膜间皮细胞（MC）单层上，嵌入该层，并侵入间皮下层基质，在那里增殖并形成继发性病变。衰老是OvCa发病的最大危险因素。一半的OvCa患者年龄在63岁以上，年龄较大的OvCa患者死亡的风险更高。尽管如此，年龄在OvCa领域还没有得到充分的研究。尽管腹膜的表面积与皮肤接近，但年龄对腹膜的影响尚未得到系统的评估。使用三种不同的小鼠衰老和OvCa转移的临床前模型，我们的实验室先前证明了老年小鼠腹膜结构的转移播种增强伴随着免疫细胞浸润的改变。目前本应用的初步数据显示，在比较年轻动物和老年动物主要转移部位的腹膜胶原超微结构时，观察到明显的差异。此外，在一组体外实验中，使用来自年轻小鼠和年老小鼠的纯化胶原蛋白，我们发现，相对于年轻小鼠，衰老胶原蛋白对OvCa细胞的侵袭增加，尽管在粘附和增殖方面没有差异。对蛋白水解重塑的不同易感性也被观察到。这一数据支持了我们的假设，即与年龄相关的转移环境改变会增强老年患者卵巢癌的转移。该研究的I期目标是确定小分子，这些小分子可以靶向胶原蛋白中与年龄相关的结构修饰，以减少老年小鼠的转移性传播。进一步的研究将评估腹腔的其他主要组成部分，内脏脂肪细胞，以及脂肪细胞蛋白质组的年龄相关变化特征。第二阶段的目标将集中在衰老癌症的免疫景观上。研究将集中在T细胞浸润和免疫衰老与衰老。在整个培训过程中，强调衰老的多学科方面，结合博士前对肿瘤转移微环境的关注和博士后对肿瘤免疫系统的关注，将使候选人成为研究衰老在免疫治疗中的作用和改善老年癌症患者免疫治疗反应的机制的转化职业。

The overall goal of this proposal is to provide a comprehensive plan of research training and career development to enable the principal investigator to successfully complete her PhD and acquire a competitive postdoctoral position performing translational research in the fields of aging and cancer. Phase I focuses on completion of ongoing PhD training investigating the role of the aging microenvironment in ovarian cancer (OvCa) metastasis. OvCa is the most fatal gynecologic malignancy and the 5th leading cause of overall cancer death among American women with a low 5-year survival rate, as 75% of women are diagnosed with disseminated intra-peritoneal (IP) metastasis. OvCa metastasis differs from most other cancers in that cells detach from the primary tumor, shed into the peritoneal cavity, adhere to the peritoneal mesothelial cell (MC) monolayer, intercalate within this layer, and invade into the submesothelial matrix, where they proliferate and form secondary lesions. Aging is the biggest risk factor for the development of OvCa. Half of OvCa diagnoses are in women over the age of 63, and older OvCa patients have a higher risk of mortality. Despite this, age is understudied in the OvCa field. Even though the peritoneum has near the same surface area as the skin, the effect of age on the peritoneum has not been systematically evaluated. Using three distinct murine pre-clinical models of aging and OvCa metastasis, our lab previously demonstrated enhanced metastatic seeding of peritoneal structures in aged mice accompanied by altered immune cell infiltration. Current preliminary data in this application show that there are distinct differences observed when comparing peritoneal collagen ultrastructure in young and aged animals at major metastatic sites. Moreover, using purified collagen from young versus aged mice in a panel of in vitro assays, we showed increased invasion of OvCa cells through aged collagen relative to young, despite no difference in adhesion or proliferation. Differential susceptibility to proteolytic remodeling was also observed. This data supports our hypothesis that age-related changes to the metastatic environment enhance ovarian cancer metastasis in aged patients. The Phase I goal of the proposed research is to identify small molecules that can target these age-related structural modifications in collagen with the goal of reducing metastatic dissemination in aged mice. Additional studies will evaluate the other major component of the peritoneal cavity, the visceral adipocytes, with characterization of age-related changes in the adipocytes proteome. The Phase II goal will focus on the immune landscape of an aging cancer. Studies will focus on T cell infiltration and immunosenescence with aging. The emphasis on multi-disciplinary aspects of aging throughout the training, combining a predoctoral focus on the tumor metastatic microenvironment and a postdoctoral focus on the tumor immune system will position the candidate for a translational career investigating the role of aging on immunotherapy and mechanisms by which to improve immunotherapy responses in aged cancer patients.