Abstract 1305: Cellular and molecular landscape of metastatic gastric cancer
Authors: Dai Enyu , Qin Jiang-Jiang , Wu Jibo , Flores Natasha M. , Chu Yanshuo , Wang Ruiping , Dang Minghao , Xu Zhiyuan , Han Guangchun , Cao Xuanye , Hu Can , Ying Jieer , Du Yian , Yang Litao , Guan Xiaoqing , Mo Shaowei , Lu Xiaoyin , Benitez Ana Morales , Waters Rebecca E. , Pizzi Melissa Pool , Shanbhag Namita , Fan Yibo , Peng Fuduan , Futreal Andrew , Song Shumei , Yee Cassian , Mazur Pawel K. , Cheng Xiangdong , Ajani Jaffer A. , Wang Linghua 
Published: June 2023

Abstract
Metastases from gastric adenocarcinoma (GAC) lead to high morbidity and mortality in the clinic. However, to date, the study of primary tumors with matched metastases from GAC patients has not been conducted, mainly because the collection of such samples in clinics is extremely challenging. To understand the evolution of metastatic cells and their interactions with the tumor microenvironment (TME), we performed paired single-cell transcriptome and immune profiling of primary tumors, matched liver metastases (LM) and/or peritoneal carcinomatosis (PC), adjacent normal, and blood specimens, a total of 68 samples collected from 20 treatment-naïve metastatic GAC patients. Our analysis revealed differentially remodeled TMEs across primary and metastatic sites, in particular, the B, T, and myeloid cells. Relative to normal tissues, the fractions of B lineage cells decreased significantly in primary GACs and were nearly depleted in LMs and PC samples. Consistently, T and B cell clonality decreased significantly in metastatic tumors, and the majority of the top expanded T cell clones were likely non-tumor specific. We discovered divergent evolutionary paths leading to diminished anti-tumor immune responses in the liver and peritoneal TMEs. For example, the Marco_c3 (highly expressed INHBA, SDC2, and CCL20) was highly enriched in LMs, whereas Marco_c1 (highly expressed APOE, APOC1, and C1QC) and proliferative macrophages were uniquely enriched in the peritoneal TME. In addition to TME cells, we defined normal epithelial cell states, quantified, and validated cancer cell state plasticity in paired primaries/metastases, and linked it to site-specific TME architectures. Notably, unlike PC cancer cells that displayed a greater degree of chromosomal instability, most LM cancer cells lost their lineage identity, embracing markedly increased epithelial-to-mesenchymal transition and “mixed” lineage states. Significant correlations between the fractions of TME cell subsets and the abundance of tumor cells in different lineage states were observed, suggesting potential crosstalk between tumor and TME cells. Lastly, we found differential activation of cancer meta-programs and gene co-expression modules (GMs) unique to metastatic tumors. Among them, high expression of GM2 in primary GACs predicts an increased risk of distant metastasis. In summary, this study provides a much needed and detailed understanding of the cellular and molecular basis of the phenotypic diversity of matched primary-metastases from GACs that have clinical implications. The single-cell multi-omics data generated by this study can serve as a valuable resource to the community to advance scientific discoveries.
Citation Format: Enyu Dai, Jiang-Jiang Qin, Jibo Wu, Natasha M. Flores, Yanshuo Chu, Ruiping Wang, Minghao Dang, Zhiyuan Xu, Guangchun Han, Xuanye Cao, Can Hu, Jieer Ying, Yian Du, Litao Yang, Xiaoqing Guan, Shaowei Mo, Xiaoyin Lu, Ana Morales Benitez, Rebecca E. Waters, Melissa Pool Pizzi, Namita Shanbhag, Yibo Fan, Fuduan Peng, Andrew Futreal, Shumei Song, Cassian Yee, Pawel K. Mazur, Xiangdong Cheng, Jaffer A. Ajani, Linghua Wang. Cellular and molecular landscape of metastatic gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1305.