Spatial Heterogeneity, Stromal Phenotypes, and Therapeutic Vulnerabilities in Colorectal Cancer Peritoneal Metastasis

作者：Chin‐Ann Johnny Ong, Joseph J. Zhao, Ying Liu, Supriya Srivastava, Daryl Kai Ann Chia, Ying En Quek, Xiaonan Fan, Haoran Ma, Kie Kyon Huang, Taotao Sheng, Qiu Xuan Tan, Gillian Ng, Joey Wee‐Shan Tan, Jia-Ying Joey Lee, Lit‐Hsin Loo, Li Yen Chong, Xuewen Ong, Su Ting Tay, Takeshi Hagihara, Angie Lay Keng Tan, Craig Ryan Joseph, Melissa C.C. Teo, Josephine Hendrikson, Clara Y.L. Chong, Wanyu Guo, Claramae S. Chia, Jolene Si Min Wong, Chin Jin Seo, Mingzhe Cai, Yvonne Tay, Kevin M.S. Sim, Ryan Yong Kiat Tay, Robert Walsh, Marcello Guagliò, Federica Morano, Ming Teh, Huey Yew Jeffrey Lum, Tony Kiat Hon Lim, Louis Vermeulen, Maarten F. Bijlsma, Kristiaan Lenos, Samuel J. Klempner, Joe Yeong, Wei Peng Yong, Filippo Pietrantonio, Patrick Tan, Raghav Sundar · 发表于：Clinical Cancer Research · 年份：2025 · DOI：10.1158/1078-0432.ccr-24-3780 · 被引用次数：13 · 研究领域：Intraperitoneal and Appendiceal Malignancies、Ferroptosis and cancer prognosis、Cancer Cells and Metastasis

PURPOSE: Peritoneal metastases (PM) in colorectal cancer portend a poor prognosis. We sought to elucidate molecular features differentiating primary tumors (PT) from PMs and actionable targets facilitating transcoelomic dissemination and progression. EXPERIMENTAL DESIGN: We performed multiomic profiling of 227 samples from 136 patients, including 56 PTs and 120 synchronous PMs comprising 34 matched PT-PM pairs. Whole-exome and bulk RNA sequencing analyses were conducted to identify underlying genomic aberrations and transcriptomic differences between primary and peritoneal lesions. We spatially characterized the microenvironment of tumor-stroma compartments and studied the roles of stromal phenotypes in promulgating tumorigenesis. RESULTS: Whole-exome sequencing found that genomic alterations and clonality patterns between PTs and PMs remain broadly similar. Transcriptomic profiles, however, suggest a transition as tumors reach the peritoneum toward a more mesenchymal tumor profile and fibrotic tumor microenvironment. Applying spatial profiling, we identify a fibro-collagenous and immune-infiltrated stromal phenotype [stromal cluster (SC) 2] characterized by increased cancer-associated fibroblasts, memory B cells, M2 macrophages, and T-cell exhaustion. These findings were orthogonally validated by multiplex IHC. Patients with SC2 stroma had poorer survival and were characterized by high SERPINE-1 (PAI-1) expression. PMs in patients with SC2 stroma were associated with enriche...