Spatial Heterogeneity, Stromal Phenotypes, and Therapeutic Vulnerabilities in Colorectal Cancer Peritoneal Metastasis.
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Ong Chin-Ann Johnny, Zhao Joseph J, Liu Ying, Srivastava Supriya, Chia Daryl K A, Quek Ying En, Fan Xiaonan, Ma Haoran, Huang Kie Kyon, Sheng Taotao, Tan Qiu Xuan, Ng Gillian, Tan Joey W S, Lee Jia-Ying Joey, Loo Lit-Hsin, Chong Li Yen, Ong Xue Wen, Tay Su Ting, Hagihara Takeshi, Tan Angie, Joseph Craig Ryan Cecil, Teo Melissa C C, Hendrikson Josephine, Chong Clara Y L, Guo Wanyu, Chia Claramae S, Wong Jolene S M, Seo Chin Jin, Cai Mingzhe, Tay Yvonne, Sim Kevin M S, Tay Ryan Y K, Walsh Robert, Guaglio Marcello, Morano Federica, Teh Ming, Lum Huey Yew Jeffrey, Lim Tony K H, Vermeulen Louis, Bijlsma Maarten F, Lenos Kristiaan, Klempner Samuel J, Yeong Joe P S, Yong Wei Peng, Pietrantonio Filippo, Tan Patrick, Sundar Raghav
Аннотация
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 enriched oncogenic pathways such as TGF-β. PAI-1 inhibition of colorectal cancer PM cell lines with a novel biologic demonstrated reduced IL2-STAT5 and TGF-β pathways and cell death.
CONCLUSIONS: Our findings unveil distinctive and actionable molecular signatures, offering deeper insights into the intricate cross-talk between tumor cells and stromal microenvironments enabling PM in colorectal cancer.