RhoA Y42C drives cell plasticity and PD-1-mediated immune evasion of diffuse gastric cancer
Abstract
Diffuse gastric cancer (DGC) is an aggressive gastric cancer subtype with a poor prognosis. The RHOA Y42C mutation is recurrent in DGC, but its independent oncogenic role is unclear. Next-Generation Sequencing of 431 DGC cases revealed that most RHOA mutations occurred without CDH1 alterations. Using genetically engineered gastric organoids, we show that RhoaY42C, along with KrasG12D and Trp53 loss (RKP), induces DGC, independently of Cdh1 loss. Single-cell and spatial transcriptomics reveal that RKP tumors exhibit mucinous histopathology and a specific lineage trajectory from Aqp5⁺ cells to Muc1/Muc4⁺ cells. RKP tumors create an immunosuppressive tumor microenvironment where AREG, transactivated by RhoA Y42C-YAP1, causes T cell exhaustion via PD-1 upregulation. Unlike E-cadherin loss-associated DGC, RKP tumors are highly susceptible to PD-1 blockade. Additionally, the RHOA Y42C mutation correlates with PD-1 upregulation in human DGC samples. These findings redefine the oncogenic role of RhoA Y42C, confirming its sufficiency for DGC development and suggesting PD-1 inhibition as a viable therapeutic option for DGC patients carrying this mutation.
Related
- PTTG1 drives intestinal-type gastric cancer progression via G2/M checkpoint-mediated cell-cycle reprogramming
- LAMB3 drives gastric cancer progression through SAMD4A-mediated degradation of PHLPP2 mRNA leading to sustained PI3K-Akt activation
- CGRP–RAMP1/CALCRL Signaling Drives TGF-β2-Mediated Immune Evasion and Pancreatic Cancer Progression
- SIRT7 Mediated-PTEN Desuccinylation Drives Gastric Tumorigenesis by Activating PI3K/AKT Pathway.
- METTL7A Downregulation Drives SLC1A5‐Mediated Glutamine Competition to Promote Tumor Proliferation and Suppress CD8+ T Cell Immunity in Gastric Cancer
BibTeX
@article{ko2026rhoa,
title = {{RhoA Y42C drives cell plasticity and PD-1-mediated immune evasion of diffuse gastric cancer}},
author = {Kyung-Pil Ko and Sangmin Kim and Jinho Jang and Yoojeong Seo and Gengyi Zou and Jie Zhang and Sohee Jun and Brittany Morrow and Jaffer A. Ajani and Ryan J. Park and Yuan-Hung Lo and Michael A. Curran and Kim Hyunki and Jae-Il Park},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-78304-3},
url = {https://www.nature.com/articles/s41467-026-78304-3},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - RhoA Y42C drives cell plasticity and PD-1-mediated immune evasion of diffuse gastric cancer
AU - Kyung-Pil Ko
AU - Sangmin Kim
AU - Jinho Jang
AU - Yoojeong Seo
AU - Gengyi Zou
AU - Jie Zhang
AU - Sohee Jun
AU - Brittany Morrow
AU - Jaffer A. Ajani
AU - Ryan J. Park
AU - Yuan-Hung Lo
AU - Michael A. Curran
AU - Kim Hyunki
AU - Jae-Il Park
PY - 2026
DA - 2026/10/06
JO - Nature Communications
DO - 10.1038/s41467-026-78304-3
UR - https://www.nature.com/articles/s41467-026-78304-3
AB - Diffuse gastric cancer (DGC) is an aggressive gastric cancer subtype with a poor prognosis. The RHOA Y42C mutation is recurrent in DGC, but its independent oncogenic role is unclear. Next-Generation Sequencing of 431 DGC cases revealed that most RHOA mutations occurred without CDH1 alterations. Using genetically engineered gastric organoids, we show that RhoaY42C, along with KrasG12D and Trp53 loss (RKP), induces DGC, independently of Cdh1 loss. Single-cell and spatial transcriptomics reveal that RKP tumors exhibit mucinous histopathology and a specific lineage trajectory from Aqp5⁺ cells to Muc1/Muc4⁺ cells. RKP tumors create an immunosuppressive tumor microenvironment where AREG, transactivated by RhoA Y42C-YAP1, causes T cell exhaustion via PD-1 upregulation. Unlike E-cadherin loss-associated DGC, RKP tumors are highly susceptible to PD-1 blockade. Additionally, the RHOA Y42C mutation correlates with PD-1 upregulation in human DGC samples. These findings redefine the oncogenic role of RhoA Y42C, confirming its sufficiency for DGC development and suggesting PD-1 inhibition as a viable therapeutic option for DGC patients carrying this mutation.
SN - 2041-1723
ER -