胃腺癌（GAC）转移导致高发病率和死亡率。开发创新且有效的疗法需要全面了解先进 GAC 的肿瘤和免疫生物学。然而，从晚期、未接受过治疗的 GAC 患者中收集匹配的标本构成了重大挑战，限制了目前主要集中于局部肿瘤的研究范围。这一差距阻碍了对 GAC 转移动力学的更深入了解。我们对 68 个配对的、未经治疗的原发性转移肿瘤进行了深入的单细胞转录组和免疫分析，以描绘癌细胞及其肿瘤微环境 (TME) 的变化在转移进展期间。为了验证我们的观察结果，我们使用细胞系、多种 PDX 和新型 GAC 小鼠模型进行了体外和体内全面的功能研究。肝脏和腹膜转移在癌细胞和 TME 表型动态中表现出独特的特性，支持了以下观点：癌细胞及其局部 TME 在转移部位共同进化。我们的研究还揭示了跨转移的癌症元程序的激活差异。我们观察到 GAC 进展过程中通过上调 GPX4 来逃避癌细胞铁死亡。有条件地消耗 Gpx4 或药理学抑制铁死亡抗性可显着减弱肿瘤生长和转移进展。此外，铁死亡再敏化治疗增强了 CAR T 细胞疗法的疗效。这项研究代表了迄今为止最大的转移性 GAC 单细胞数据集。 GAC 转移的分子和细胞动力学的高分辨率图谱揭示了将铁死亡防御与 CAR T 细胞疗法相结合作为一种具有潜在巨大临床意义的新型治疗策略的基本原理。版权所有 © 2024 AGA Institute。由爱思唯尔公司出版。保留所有权利。

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.We 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 our observations, we 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. Our study also revealed differential activation of cancer meta-programs across metastases. We 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.Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.