Abstract 1497: Humanized mouse model unveils niche conditioning in gastric cancer peritoneal metastasis
Authors: Zhao Joseph J. , Chia Daryl Kai Ann , Her Zhisheng , Ma Haoran , Ong Xuewen , Tay Su Ting , So Jimmy Bok Yan , Chen Qingfeng , Tan Patrick , Sundar Raghav 
Published: March 2024

Background: Peritoneal metastases (PM) in gastric cancer (GC) portend a poor prognosis. Yet, biological mechanisms underpinning peritoneal colonization and transcoelomic metastases remain unclear. Utilizing a novel humanized mouse model of GCPM, we seek to understand the evolution of the peritoneum to allow for peritoneal dissemination. The humanized mouse model, defined as mice engrafted with functional human cells or tissues, was selected as the host immune system appears to play a significant role in the mechanisms of transcoelomic metastases.

Methodology: Humanized (humice) and NOD-scid Il2rγnull (NSG) mice models were injected with GSU (diffuse type) GC cell lines in the flank (subcutaneous), stomach (orthotopic) and directly into the peritoneum (intra-peritoneal). After 1 month, the mouse models were sacrificed and samples from the primary tumor (PT), PM and adjacent peritoneum were retrieved. The tumors were then harvested, along with normal/adjacent peritoneum and bulk RNA-seq was performed and analyzed.

Results: Fifty-six samples including PT, PM were harvested from 10 humice and 11 NSG models and were analysed with whole transcriptome sequencing. All models with orthotopic inoculation were found to create PM while no gross PM were appreciated in models with flank inoculation. Principal component analysis mapping of samples demonstrated transcriptomic distinction between normal peritoneum from the flank humice model and adjacent normal samples in the orthotopic and intra-peritoneal humice model. Compared to adjacent peritoneum of the intra-peritoneal humanized mouse model, the orthotopic model appeared to be more tumorigenic with enriched epithelial mesenchymal transition (EMT), stromal and immune infiltration, inflammatory response (IL2-STAT5, IL6-JAK-STAT3, TGF-β signaling), IFN-γ response signatures. Enrichment scores of these pathways were likewise more pronounced in adjacent normal peritoneal samples in the orthotopic humanized mouse model when contrasted against other sample types. Higher expression of M2 macrophages, B cells and T regs, dendritic cells (activating and resting) was found in adjacent peritoneum in the orthotopic model. Collectively, these describe a phenomenon in which the adjacent uninvolved peritoneum has evolved into a tumorigenic environment to facilitate transcoelomic metastasis. These unique niche changes of the peritoneum were conversely not appreciated in the NSG model.

Conclusion: We unveil novel insights that delve into the mechanistic role of the host immune system in orchestrating tumorigenic microenvironmental alterations to support peritoneal organotropism. These provide functional proof alluding to the phenomenon of peritoneal niche conditioning in GC PM.

Citation Format: Joseph J. Zhao, Daryl Kai Ann Chia, Zhisheng Her, Haoran Ma, Xuewen Ong, Su Ting Tay, Jimmy Bok Yan So, Qingfeng Chen, Patrick Tan, Raghav Sundar. Humanized mouse model unveils niche conditioning in gastric cancer peritoneal metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1497.