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
Department of Sarcoma, Peritoneal and Rare Tumors (SPRinT), Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
Department of Sarcoma, Peritoneal and Rare Tumors (SPRinT), Division of Surgery and Surgical Oncology, Singapore General Hospital, Singapore, Singapore.
Clin Cancer Res. 2025 Jun 13;31(12):2515-2529. doi: 10.1158/1078-0432.CCR-24-3780.
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.
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.
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.
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.
结直肠癌的腹膜转移（PM）预示着预后不良。我们试图阐明区分原发性肿瘤（PT）与PM的分子特征以及促进经体腔播散和进展的可操作靶点。
我们对136例患者的227个样本进行了多组学分析，包括56个PT和120个同步PM，其中包含34对匹配的PT-PM。进行了全外显子组和大量RNA测序分析，以确定原发性和腹膜病变之间潜在的基因组畸变和转录组差异。我们在空间上对肿瘤-基质区室的微环境进行了表征，并研究了基质表型在促进肿瘤发生中的作用。
全外显子组测序发现，PT和PM之间的基因组改变和克隆模式大致相似。然而，转录组谱表明，随着肿瘤到达腹膜，会向更具间充质的肿瘤谱和纤维化肿瘤微环境转变。应用空间分析，我们确定了一种纤维胶原性和免疫浸润性基质表型[基质簇（SC）2]，其特征是癌症相关成纤维细胞、记忆B细胞、M2巨噬细胞和T细胞耗竭增加。这些发现通过多重免疫组化得到了正交验证。具有SC2基质的患者生存率较差，其特征是高SERPINE-1（PAI-1）表达。具有SC2基质患者的PM与富集的致癌途径如TGF-β相关。用一种新型生物制剂抑制PAI-1可降低结直肠癌PM细胞系中的IL2-STAT5和TGF-β途径以及细胞死亡。
我们研究结果揭示了独特且可操作的分子特征，为深入了解肿瘤细胞与基质微环境之间复杂的相互作用提供了更深刻的见解，这种相互作用导致了结直肠癌的PM。
