美国范德比尔特大学Ken S. Lau和Robert J. Coffey共同合作，近期取得重要工作进展。他们通过绘制分子图谱揭示散发性结直肠肿瘤的演化和微环境动力学。相关研究成果2023年12月7日在线发表于《细胞》杂志上。

据介绍，结直肠癌在从前驱病变发展为恶性肿瘤的过程中表现出动态的细胞和遗传异质性。

研究人员对31个人类结肠直肠标本的空间多组学数据的分析使肿瘤演化的系统地理学图谱得以绘制，揭示了个体化的进展轨迹以及伴随的微环境和克隆变化。系统发育地理学对遗传事件进行排序，根据其演化动力学对肿瘤进行分类，并将克隆区域沿着包括染色体不稳定性（CIN+）和超突变（HM）途径在内的全局拟时间进展轨迹放置。综合的单细胞和空间转录组数据揭示了拟时间过程中反复出现的上皮程序和浸润的免疫状态。研究人员发现了一种免疫排斥信号（IEX），由细胞外基质调节因子DDR1、TGFBI、PAK4和DPEP1组成，它与CIN+肿瘤进展有关，与细胞毒性细胞浸润减少有关，并在独立队列中显示出预后价值。

总之，这一空间多组图谱为结直肠肿瘤微环境的共同演化提供了见解，为分层和靶向治疗提供了资源。

附：英文原文

Title: Molecular cartography uncovers evolutionary and microenvironmental dynamics in sporadic colorectal tumors

Author: Cody N. Heiser, Alan J. Simmons, Frank Revetta, Eliot T. McKinley, Marisol A. Ramirez-Solano, Jiawei Wang, Harsimran Kaur, Justin Shao, Gregory D. Ayers, Yu Wang, Sarah E. Glass, Naila Tasneem, Zhengyi Chen, Yan Qin, William Kim, Andrea Rolong, Bob Chen, Paige N. Vega, Julia L. Drewes, Nicholas O. Markham, Nabil Saleh, Fotis Nikolos, Simon Vandekar, Angela L. Jones, M. Kay Washington, Joseph T. Roland, Keith S. Chan, Thomas Schürpf, Cynthia L. Sears, Qi Liu, Martha J. Shrubsole, Robert J. Coffey, Ken S. Lau

Issue&Volume: 2023/12/07

Abstract: Colorectal cancer exhibits dynamic cellular and genetic heterogeneity during progression from precursor lesions toward malignancy. Analysis of spatial multi-omic data from 31 human colorectal specimens enabled phylogeographic mapping of tumor evolution that revealed individualized progression trajectories and accompanying microenvironmental and clonal alterations. Phylogeographic mapping ordered genetic events, classified tumors by their evolutionary dynamics, and placed clonal regions along global pseudotemporal progression trajectories encompassing the chromosomal instability (CIN+) and hypermutated (HM) pathways. Integrated single-cell and spatial transcriptomic data revealed recurring epithelial programs and infiltrating immune states along progression pseudotime. We discovered an immune exclusion signature (IEX), consisting of extracellular matrix regulators DDR1, TGFBI, PAK4, and DPEP1, that charts with CIN+ tumor progression, is associated with reduced cytotoxic cell infiltration, and shows prognostic value in independent cohorts. This spatial multi-omic atlas provides insights into colorectal tumor-microenvironment co-evolution, serving as a resource for stratification and targeted treatments.

DOI: 10.1016/j.cell.2023.11.006

Source: https://www.cell.com/cell/fulltext/S0092-8674(23)01222-9