• 结直肠癌患者来源的类器官其是从高度增殖的LGR5+肿瘤细胞中扩增而来;
  • 次最佳生长条件诱导CRC细胞表达MEX3A基因,获得LGR5+潜在表型,并获得对化疗的内在耐药性,能产生类器官;
  • CRC小鼠模型中,Mex3a+细胞对肿瘤转移的贡献较小,但化疗后,Mex3a+细胞长生大细胞克隆,导致复发;
  • Mex3a+细胞在化疗后立即下调WNT/干细胞基因程序,并采取类似于YAP+胎儿肠祖细胞的瞬态状态;
  • 相反,Mex3a缺陷细胞向杯状细胞样表型分化,无法抵抗化疗。
Nature Cancer近期发表的文章,发现次最佳的生长条件诱导结直肠癌干细胞表达Mex3a,这种状态的细胞可抵抗化疗,介导肿瘤复发。
Nature Cancer [IF:23.177]

Mex3a marks drug-tolerant persister colorectal cancer cells that mediate relapse after chemotherapy



2022-06-30, Article

Abstract & Authors:展开

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.

First Authors:
Adrián Álvarez-Varela

Correspondence Authors:
Eduard Batlle

All Authors:
Adrián Álvarez-Varela,Laura Novellasdemunt,Francisco M Barriga,Xavier Hernando-Momblona,Adrià Cañellas-Socias,Sara Cano-Crespo,Marta Sevillano,Carme Cortina,Diana Stork,Clara Morral,Gemma Turon,Felipe Slebe,Laura Jiménez-Gracia,Ginevra Caratù,Peter Jung,Giorgio Stassi,Holger Heyn,Daniele V F Tauriello,Lidia Mateo,Sabine Tejpar,Elena Sancho,Camille Stephan-Otto Attolini,Eduard Batlle