Shaping of the Microenvironment in Colonic Pre-Cancer by Epithelia and Microbiota

Vanderbilt tbel中心召集了一支由特定领域的专家组成的多学科团队，以协作 研究结肠癌前病变进展的基本途径和翻译途径。我们在以下方面的基础工作 结肠癌前病变的两种亚型，腺瘤(ADS)和固定性锯齿状病变(SSLS)，描绘了早期 肿瘤发生的起源是通过肿瘤细胞和免疫微环境的调节而形成的 微生物区系。我们已经证明SSLS起源于胃粘膜表面的化生。 细胞毒性免疫微环境，而ADS来自干细胞来源的WNT在隐窝的激活 基地。在这个中心，我们将把我们对特定生物学机制的研究扩展到发育 这些癌前病变的发展轨迹或迟缓。基本项目1调查 中性粒细胞-AD串扰的贡献，主要是通过细胞表面和释放的二肽酶1(DPEP1) 在小的细胞外小泡中，在AD进展过程中。翻译项目2调查，在人类 前瞻性研究：PKS+大肠埃希菌诱导基因毒性应激与癌前病变的关系 进展，以及可能有助于促进息肉形成的结肠上皮细胞和粘膜机制 微环境。基础项目3研究在调节抗原呈递的过程中获得干性 肿瘤细胞和免疫系统之间协同进化背景下的细胞毒性T细胞。联合分析 共同的结直肠癌前组织将促进持续的迭代和整合 项目。我们的塔贝尔中心提供了从简化论者和系统生物学方法到 研究结肠癌前病变进展为结直肠癌的关键因素。这项工作 将在人体组织上利用尖端技术，包括单细胞和空间转录，小 细胞外小泡轮廓、多路成像、纵向数据分析和下一代计算 算法。此外，范德比尔特大兵以前建立的大量人类息肉资源 卓越研究专业计划和NCI月球人类肿瘤图集网络将 被塔贝尔中心的同一组调查人员利用。此外，创新共生文化体系 将被每个项目使用，其中极化癌前有机物可以与KEY共培养 从管腔或基底部暴露于肿瘤细胞的微环境元素。这项工作将向 对肿瘤发展轨迹进行建模，并确定将使 改善结直肠前病变患者的风险分层、精准预防和拦截 癌症。

The Vanderbilt TBEL Center assembles a multi-disciplinary team of field-specific experts to collaboratively investigate the basic and translational pathways of colonic pre-cancer progression. Our foundational work on two subtypes of colonic pre-cancers, adenomas (ADs) and sessile serrated lesions (SSLs), depicts the early origins of tumorigenesis that are shaped by modulation of the immune microenvironment via neoplastic cells and the microbiota. We have shown that SSLs originate from gastric metaplasia arising from the mucosal surface in a cytotoxic immune microenvironment, whereas ADs arise from stem cell-derived WNT activation at the crypt base. In this center, we will extend our investigation of specific biological mechanisms towards the developmental trajectories of these pre-malignant lesions into progression or indolence. Basic Project 1 investigates the contribution of neutrophil-AD crosstalk, largely via dipeptidase 1 (DPEP1) both at the cell surface and released in small extracellular vesicles, in the course of AD progression. Translational Project 2 investigates, in human prospective studies, the association of pks+ Escherichia coli that induces genotoxic stress with pre-cancer progression, as well as colon epithelial cell and mucosa mechanisms that may contribute to a polyp-promoting microenvironment. Basic Project 3 investigates acquisition of stemness in modulating antigen presentation to cytotoxic T cells in the context of co-evolution between neoplastic cells and the immune system. Joint analysis of common colorectal pre-cancer tissues will facilitate an ongoing process of iteration and integration across all projects. Our TBEL Center offers a complementary blend, from reductionist and systems biology approaches, to investigate critical factors involved in the progression of pre-cancerous tumors of the colon to CRC. The work will utilize cutting-edge technologies on human tissues, including single-cell and spatial transcriptomics, small extracellular vesicle profiling, multiplex imaging, longitudinal data analysis, and next-generation computational algorithms. In addition, substantial human polyp resources previously established by the Vanderbilt GI Specialized Programs of Research Excellence and the NCI Moonshot Human Tumor Atlas Network will be leveraged by the same team of investigators in the TBEL Center. In addition, an innovative co-culture system will be employed by each project, where polarizing pre-cancer organoids can be co-cultured with key microenvironment elements exposed to neoplastic cells from the luminal or basal side. This work will inform the modeling of tumor development trajectories and identify mechanisms of progression that will enable improvements in risk stratification, precision prevention, and interception for individuals with colorectal pre- cancers.