Abstract 5017: A single-cell atlas of tumor microenvironment defines the continuum of gastric adenocarcinoma tumorigenesis and progression
Authors: Wang Ruiping , Song Shumei , Qin Jiangjiang , Li Yuan , Fan Yibo , Chatterjee Deyali , Tatlonghari Ghia , Xu Zhiyuan , Hu Can , Mo Shaowei , Sewastjanow Matheus D. , Abdelhakeem Ahmed Adel Fouad , Wang Zhenning , Cheng Xiangdong , Ajani Jaffer A. , Wang Linghua 
Published: June 2022

Abstract
Gastric adenocarcinoma (GAC), a global health burden, lacks detail understanding of the evolution-driven cellular/molecular programs that lead to GAC tumorigenesis followed by progression/metastases. The definition of the interplay(s) between immune/stromal cells and premalignant/malignant GAC cells could propel us into a new dimension of understanding and therapeutics. Here, we performed a comprehensive single-cell profiling of 68 specimens collected from 43 subjects including non-neoplastic tumor adjacent tissue, precancerous lesions, localized, and metastatic GACs. We profiled a total of 77,392 high-quality cells which revealed 62 unique cell states uncovering varying profiles. We define alterations in TMEs that underscore initiation of tumorigenesis to eventual progression. For instance, we found a striking preponderance of B lineage cells, primarily the IgA+ plasma cells, in TMEs of the precancerous lesions, whereas 3 immunosuppressive myeloid subsets with high expression of genes signature including SPP1, LAIR1, SIRPA, TIM-3, TGFB1, and MARCO dominated in advanced GACs. We observed that fractions of GZMK+ effector CD8 T cells and progenitor exhausted CD8 T cells gradually increased as GACs progressed to advanced stages with highest abundant in metastatic GACs. In addition, our analysis revealed extensive stromal remodeling along the GAC continuum, which may have contributed to enhanced angiogenesis and progressive immune suppressive signaling. Notably, we uncovered 3 unique TME interactomes that are defined by 6 cellular environtypes that provide context-dependent definition and granularity to GAC networks inhabited by 62 TME cell subsets giving GAC to a novel landscape not yet defined. The two distinct environtypes in GAC primaries are validated in three independent large-scale GAC cohorts, giving credence and definition to previously established histopathological variables, genomic/molecular subtypes and clinical outcomes. The analysis of tumor associated stromal cells discovered SDC2 as an exploitable target to pursue. SDC2 was not only abundant in the stroma, but the abundance is validated in 3 independent single-cell GAC cohorts as well as at the protein level using independent approaches. Overexpression of SDC2 formed a gradient from early GAC to metastatic and is prognostic in large-scale GAC cohorts examined. This study provides an atlas of GAC TMEs from tumorigenesis to advanced GAC that could be further developed for novel therapeutics but also serves as a community resource.
Citation Format: Ruiping Wang, Shumei Song, Jiangjiang Qin, Yuan Li, Yibo Fan, Deyali Chatterjee, Ghia Tatlonghari, Zhiyuan Xu, Can Hu, Shaowei Mo, Matheus D. Sewastjanow, Ahmed Adel Fouad Abdelhakeem, Zhenning Wang, Xiangdong Cheng, Jaffer A. Ajani, Linghua Wang. A single-cell atlas of tumor microenvironment defines the continuum of gastric adenocarcinoma tumorigenesis and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5017.