英国伦敦大学学院癌症研究所Christopher J. Tape团队发现结肠干细胞极化的致瘤现象。该研究于2023年12月7日发表于国际一流学术期刊《细胞》杂志上。

为了从功能上描绘细胞内在和细胞外在线索如何共同调节细胞命运，他们对1107种结肠类器官培养物进行了系统的单细胞分析，这些培养物受(1)结直肠癌(CRC)致癌突变、(2)微环境成纤维细胞和巨噬细胞、(3)基质配体和(4)信号抑制剂的调节。多重单细胞分析揭示了由癌基因和基质配体组合决定的逐步上皮分化现象，从成纤维细胞诱导的群集素(CLU)+再生结肠干细胞(revCSCs)到癌基因驱动的LRIG1+超增殖CSCs (proCSCs)。

从revCSCs到proCSCs的转变是通过减少WNT3A和TGF-β驱动的YAP信号和增加KRASG12D或基质EGF/ epiregulin激活的MAPK/PI3K通量来调节的。他们发现APC缺失和KRASG12D共同限制了对revCSCs的访问，并破坏了proCSC命运中的间质-上皮通讯捕获上皮。这些结果表明，致癌突变通过阻碍细胞命运可塑性的细胞外源调节来主导稳态分化。

据悉，癌细胞受致瘤突变和微环境信号的调控，但这些过程通常是分开研究的。

附：英文原文

Title: An oncogenic phenoscape of colonic stem cell polarization

Author: Xiao Qin, Ferran Cardoso Rodriguez, Jahangir Sufi, Petra Vlckova, Jeroen Claus, Christopher J. Tape

Issue&Volume: 2023/12/07

Abstract: Cancer cells are regulated by oncogenic mutations and microenvironmental signals, yet these processes are often studied separately. To functionally map how cell-intrinsic and cell-extrinsic cues co-regulate cell fate, we performed a systematic single-cell analysis of 1,107 colonic organoid cultures regulated by (1) colorectal cancer (CRC) oncogenic mutations, (2) microenvironmental fibroblasts and macrophages, (3) stromal ligands, and (4) signaling inhibitors. Multiplexed single-cell analysis revealed a stepwise epithelial differentiation phenoscape dictated by combinations of oncogenes and stromal ligands, spanning from fibroblast-induced Clusterin (CLU)+ revival colonic stem cells (revCSCs) to oncogene-driven LRIG1+ hyper-proliferative CSCs (proCSCs). The transition from revCSCs to proCSCs is regulated by decreasing WNT3A and TGF-β-driven YAP signaling and increasing KRASG12D or stromal EGF/Epiregulin-activated MAPK/PI3K flux. We find that APC loss and KRASG12D collaboratively limit access to revCSCs and disrupt stromal-epithelial communication—trapping epithelia in the proCSC fate. These results reveal that oncogenic mutations dominate homeostatic differentiation by obstructing cell-extrinsic regulation of cell-fate plasticity.

DOI: 10.1016/j.cell.2023.11.004

Source: https://www.cell.com/cell/fulltext/S0092-8674(23)01221-7