Yang Mingli, Nebozhyn Michael V, Schell Michael J, Gandhi Nishant, Pflieger Lance, Loboda Andrey, Pledger W Jack, Soundararajan Ramani, Maurin Michelle, Wang Heiman, Silva Jetsen Rodriguez, Alden Ashley, Coppola Domenico, Elliott Andrew, Sledge George, Khushman Moh'd, Lou Emil, Goel Sanjay, Yeatman Timothy J
Department of Surgery, University of South Florida, 560 Channelside Drive, Tampa, FL, 33602, USA.
Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA, 02115, USA.
BMC Cancer. 2025 Mar 12;25(1):441. doi: 10.1186/s12885-025-13829-2.
Accumulating evidence has suggested that cancer progression and therapeutic response depend on both tumor epithelium (EPI) and tumor microenvironment (TME). However, the dependency of clinical outcomes on the tumor EPI vs. the TME has neither been clearly defined nor quantified.
We classified 2373 colorectal cancer (CRC) tumors into the consensus molecular subtypes (CMS1-4) and generated the 10-gene TME and the 10-gene EPI signatures as the serendipitous derivatives of the most (positively vs. negatively) correlated genes of a highly-prognostic, ~ 500-gene signature we previously identified. Distinct TME vs. EPI cellular features of the signature genes were identified by CIBERSORT deconvolution and validated by scRNASEQ in an independent public dataset.
The TME signature was strongly associated with the immune/stromal TME-rich CMS1/CMS4 subtypes that portended worse survival, whereas the EPI signature was predominantly related to the TME-poor, epithelial CMS2/CMS3 classes that portended better survival. Multivariable Cox regression analysis against 29 TME-related signatures revealed that the TME signature was the most strikingly impacted by the "Cancer-associated fibroblasts" signature (HR: 10.87 vs. 0.13, both P < 0.0001). Moreover, the TME score was strongly correlated with EMT, SRC activation and MEK inhibitor resistance in 2373 CRC tumors (Spearman r = 0.727, 0.802, 0.824, respectively), which was validated in two independent CRC datasets (n = 626 and n = 566). By contrast, the EPI score was the dominant force in associating with longer progression free survival in cetuximab-treated metastatic CRC patients derived from two independent clinical trials (Logrank trend P = 0.0005/n = 80; P = 0.0013/n = 44). This finding was further validated in a large real-world clinico-genomics dataset with EGFR inhibitor therapy, which demonstrated that higher EPI scores were associated with increased overall survival (EGFRi, Logrank trend P < 0.0001/n = 2343) and time on treatment (cetuximab, P = 0.003/n = 953; panitumumab, P < 0.0001/n = 1307).
Here we identified a pair of new, distinct 10-gene signatures (the EPI vs. the TME) capable of distinguishing the cellular contribution of the tumor EPI vs. the TME in determining CRC prognosis and therapeutic outcomes. With targeted approaches emerging to address both tumor epithelial cells and the TME, the EPI vs. TME signature scores may have a novel biomarker role to permit optimization of CRC therapy by identifying sensitive vs. resistant subpopulations.
越来越多的证据表明，癌症进展和治疗反应取决于肿瘤上皮（EPI）和肿瘤微环境（TME）。然而，临床结果对肿瘤EPI与TME的依赖性尚未得到明确界定和量化。
我们将2373例结直肠癌（CRC）肿瘤分类为共识分子亚型（CMS1 - 4），并生成了10基因TME和10基因EPI特征，作为我们之前鉴定的一个高度预后的约500基因特征中最（正相关与负相关）相关基因的意外衍生物。通过CIBERSORT反卷积鉴定特征基因的不同TME与EPI细胞特征，并在一个独立的公共数据集中通过scRNASEQ进行验证。
TME特征与富含免疫/基质TME的CMS1/CMS4亚型密切相关，这些亚型预示着较差的生存率，而EPI特征主要与TME较少的上皮CMS2/CMS3类别相关，这些类别预示着较好的生存率。对29个与TME相关的特征进行多变量Cox回归分析显示，TME特征受“癌症相关成纤维细胞”特征的影响最为显著（风险比：10.87对0.13，P均<0.0001）。此外，在2373例CRC肿瘤中，TME评分与EMT、SRC激活和MEK抑制剂耐药性密切相关（Spearman相关系数分别为0.727、0.802、0.824），这在两个独立的CRC数据集中得到了验证（n = 626和n = 566）。相比之下，在两项独立临床试验的西妥昔单抗治疗的转移性CRC患者中，EPI评分是与更长无进展生存期相关的主导因素（对数秩趋势P = 0.0005/n = 80；P = 0.0013/n = 44）。这一发现在一个接受EGFR抑制剂治疗的大型真实世界临床基因组数据集中得到了进一步验证，该数据集表明较高的EPI评分与总生存期延长（EGFRi，对数秩趋势P < 0.0001/n = 2343）和治疗时间延长相关（西妥昔单抗，P = 0.003/n = 953；帕尼单抗，P < 0.0001/n = 1307）。
在此，我们鉴定出一对新的、不同的10基因特征（EPI与TME），它们能够区分肿瘤EPI与TME在确定CRC预后和治疗结果中的细胞贡献。随着针对肿瘤上皮细胞和TME的靶向方法不断涌现，EPI与TME特征评分可能具有新的生物标志物作用，通过识别敏感与耐药亚群来优化CRC治疗。
