Purpose: Consensus molecular subtypes (CMS) are mainly used for biological interpretability and clinical stratification of colorectal cancer (CRC) in primary tumors (PT) but few in metastases. The heterogeneity of CMS distribution in metastases and the concordance of CMS between PT and metastases still lack sufficient study. We used CMS to classify CRC metastases and combine it with histopathological analysis to explore differences between PT and distant metastases.
Patients and Methods: We obtained gene expression profiles for 942 PT samples from TCGA database (n=376) and GEO database (n=566), as well as 442 metastasis samples from GEO database. Among these, 765 PT samples and 442 metastasis samples were confidently identified with CMS using the “CMS classifier” and enrolled for analysis. Clinicopathological manifestation and CMS classification of CRC metastases were assessed with data from GEO, TCGA, and cBioPortal. Overall, 105 PT-metastasis pairs were extracted from 10 GEO datasets to assess CMS concordance. Tumor microenvironment (TME) features between PT and metastases were analyzed by immune-stromal infiltration with ESTIMATE and xCell algorithms. Finally, TME features were validated with multiplex immunohistochemistry in 27 PT-metastasis pairs we retrospectively collected.
Results: Up to 64% of CRC metastases exhibited concordant CMS groups with matched PT, and the TME of metastases was similar to that of PT. For most common distant metastases, liver metastases were predominantly CMS2 and lung and peritoneal metastases were mainly CMS4, highlighting “seed” of tumor cells of different CMS groups had a preference for metastasis to “soil” of specific organs. Compared with PT, cancer-associated fibroblasts (CAF) reduced in liver metastases, CD4+T cells and M2-like macrophages increased in lung metastases, and M2-like macrophages and CAF increased in peritoneal metastases.
Conclusion: Our findings underscore the importance of CMS-guided specific organ monitoring and treatment post-primary tumor surgery for patients. Differences in immune-stromal infiltration among different metastases provide targeted therapeutic opportunities for metastatic CRC.

Keywords: colorectal cancer, primary tumors, metastases, consensus molecular subtypes, tumor microenvironment


中文翻译：

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种子和土壤：结直肠癌不同器官部位原发灶和转移灶之间的共识分子亚群（CMS）和肿瘤微环境特征

目的：共识分子亚型（CMS）主要用于结直肠癌（CRC）原发肿瘤（PT）的生物学解释和临床分层，但很少用于转移瘤。转移灶中 CMS 分布的异质性以及 PT 和转移灶之间 CMS 的一致性仍缺乏足够的研究。我们使用 CMS 对 CRC 转移进行分类，并将其与组织病理学分析相结合，以探讨 PT 和远处转移之间的差异。
患者和方法：我们从TCGA数据库（n = 376）和GEO数据库（n = 566）中获得了942个PT样本的基因表达谱，以及从GEO数据库中获得了442个转移样本的基因表达谱。其中，765 个 PT 样本和 442 个转移样本通过 CMS 使用“CMS 分类器”进行了自信的识别，并登记进行分析。使用 GEO、TCGA 和 cBioPortal 的数据评估 CRC 转移的临床病理表现和 CMS 分类。总体而言，从 10 个 GEO 数据集中提取了 105 个 PT 转移对来评估 CMS 一致性。使用 ESTIMATE 和 xCell 算法通过免疫基质浸润分析 PT 和转移瘤之间的肿瘤微环境 (TME) 特征。最后，我们通过多重免疫组织化学在我们回顾性收集的 27 个 PT 转移对中验证了 TME 特征。
结果：高达 64% 的 CRC 转移灶表现出与匹配的 PT 一致的 CMS 组，并且转移灶的 TME 与 PT 相似。在最常见的远处转移中，肝转移以CMS2为主，肺和腹膜转移以CMS4为主，凸显出不同CMS组肿瘤细胞的“种子”偏好向特定器官的“土壤”转移。与PT相比，肝转移灶中癌症相关成纤维细胞（CAF）减少，肺转移灶中CD4+T细胞和M2样巨噬细胞增加，腹膜转移灶中M2样巨噬细胞和CAF增加。
结论：我们的研究结果强调了 CMS 引导的特定器官监测和原发性肿瘤手术后治疗对患者的重要性。不同转移灶之间免疫基质浸润的差异为转移性结直肠癌提供了针对性的治疗机会。

关键词:结直肠癌, 原发肿瘤, 转移, 共有分子亚型, 肿瘤微环境