An oncogenic phenoscape of colonic stem cell polarization
An oncogenic phenoscape of colonic stem cell polarization
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DOI：
10.1016/j.cell.2023.11.004
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发表时间：
2023-12
期刊：
影响因子：
64.5
通讯作者：
X. Qin;F. Cardoso Rodriguez;J. Sufi;P. Vlckova;Jeroen Claus;C. Tape
中科院分区：
文献类型：
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作者：
X. Qin;F. Cardoso Rodriguez;J. Sufi;P. Vlckova;Jeroen Claus;C. Tape
癌细胞受致癌基因突变和微环境信号的调控，但这些过程往往是单独研究的。为了从功能上绘制细胞内和细胞外信号如何共同调节细胞命运的图，我们对1,107种结肠类器官培养进行了系统的单细胞分析，这些细胞受到(1)结直肠癌(CRC)癌基因突变、(2)微环境成纤维细胞和巨噬细胞、(3)基质配体和(4)信号抑制物的调控。多重单细胞分析显示，从成纤维细胞诱导的集落蛋白(CLU)+复兴结肠干细胞(RevCSCs)到癌基因驱动的LRIG1+超增殖CSCs(ProCSCs)，癌基因和基质配体的组合决定了上皮细胞的逐步分化现象。通过减少WNT3a和转化生长因子β驱动的YAP信号和增加KRASG12D或间质EGF/EpiRegulin激活的MAPK/PI3K信号通路来调节从revCSCs到proCSCs的转变。我们发现，APC丢失和KRASG12D协同限制了对revCSC的访问，并在proCSC的命运中扰乱了基质-上皮通讯-陷阱上皮细胞。这些结果表明，致癌基因突变通过阻碍细胞命运可塑性的外在调节来主导内稳态分化。
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 KRASG12Dor stromal EGF/Epiregulin-activated MAPK/PI3K flux. We find that APC loss and KRASG12Dcollaboratively 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.