Metastases from gastric adenocarcinoma (GAC) lead to high morbidity and mortality. Developing innovative and effective therapies requires a comprehensive understanding of the tumor and immune biology of advanced GAC. Yet, collecting matched specimens from advanced, treatment-naïve GAC patients poses a significant challenge, limiting the scope of current research, which has predominantly focused on localized tumors. This gap hinders a deeper insight into the metastatic dynamics of GAC. 

In a recent study published in Gastroenterology, Dr. CHENG Xiangdong and Dr. QIN Jiangjiang from the Hangzhou Institute of Medicine, Chinese Academy of Sciences (CAS), in collaboration with the team of Dr. WANG Linghua, Dr. AJANI Jaffer A., and Dr. MAZUR Pawel K. from the University of Texas MD Anderson Cancer Center performed in-depth single-cell transcriptome and immune profiling on 68 paired, treatment-naïve, primary-metastatic tumors to delineate alterations in cancer cells and their tumor microenvironment (TME) during metastatic progression. 

To validate their observations, the researchers conducted comprehensive functional studies both in vitro and in vivo, employing cell lines, multiple PDX and novel mouse models of GAC. Liver and peritoneal metastases exhibited distinct properties in cancer cells and dynamics of TME phenotypes, supporting the notion that cancer cells and their local TMEs co-evolve at metastatic sites. Theri study also revealed differential activation of cancer meta-programs across metastases. They observed evasion of cancer cell ferroptosis via GPX4 upregulation during GAC progression. Conditional depletion of Gpx4 or pharmacological inhibition of ferroptosis resistance significantly attenuated tumor growth and metastatic progression. Additionally, ferroptosis-resensitizing treatments augmented the efficacy of CAR T-cell therapy. 

This study represents the largest single-cell dataset of metastatic GACs to date. High-resolution mapping of the molecular and cellular dynamics of GAC metastasis has revealed a rationale for targeting ferroptosis defense in combination with CAR T-cell therapy as a novel therapeutic strategy with potential immense clinical implications.

Original link: https://doi.org/10.1053/j.gastro.2024.07.038