Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain.
Nat Cancer. 2022 Sep;3(9):1052-1070. doi: 10.1038/s43018-022-00402-0. Epub 2022 Jun 30.
Colorectal cancer (CRC) patient-derived organoids predict responses to chemotherapy. Here we used them to investigate relapse after treatment. Patient-derived organoids expand from highly proliferative LGR5 tumor cells; however, we discovered that lack of optimal growth conditions specifies a latent LGR5 cell state. This cell population expressed the gene MEX3A, is chemoresistant and regenerated the organoid culture after treatment. In CRC mouse models, Mex3a cells contributed marginally to metastatic outgrowth; however, after chemotherapy, Mex3a cells produced large cell clones that regenerated the disease. Lineage-tracing analysis showed that persister Mex3a cells downregulate the WNT/stem cell gene program immediately after chemotherapy and adopt a transient state reminiscent to that of YAP fetal intestinal progenitors. In contrast, Mex3a-deficient cells differentiated toward a goblet cell-like phenotype and were unable to resist chemotherapy. Our findings reveal that adaptation of cancer stem cells to suboptimal niche environments protects them from chemotherapy and identify a candidate cell of origin of relapse after treatment in CRC.
结直肠癌（CRC）患者来源的类器官可预测化疗反应。在这里，我们使用它们来研究治疗后的复发情况。患者来源的类器官由高增殖的 LGR5 肿瘤细胞扩增而来；然而，我们发现缺乏最佳的生长条件会指定一个潜伏的 LGR5 细胞状态。该细胞群体表达基因 MEX3A，具有抗药性，并在治疗后再生类器官培养物。在 CRC 小鼠模型中，Mex3a 细胞对转移性生长的贡献很小；然而，在化疗后，Mex3a 细胞产生了大量的细胞克隆，使疾病再生。谱系追踪分析表明，在化疗后，持久性 Mex3a 细胞立即下调 WNT/干细胞基因程序，并采用类似于 YAP 胎儿肠前体细胞的短暂状态。相比之下，Mex3a 缺陷细胞分化为杯状细胞样表型，无法抵抗化疗。我们的研究结果表明，癌症干细胞适应次优生态位环境可保护其免受化疗的影响，并确定了 CRC 治疗后复发的起源细胞候选物。
