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Dynamic and adaptive cancer stem cell population admixture in colorectal neoplasia
Cell Stem Cell ( IF 23.9 ) Pub Date : 2022-08-04 , DOI: 10.1016/j.stem.2022.07.008
Ester Gil Vasquez 1 , Nadia Nasreddin 1 , Gabriel N Valbuena 1 , Eoghan J Mulholland 1 , Hayley L Belnoue-Davis 1 , Holly R Eggington 1 , Ryan O Schenck 1 , Valérie M Wouters 2 , Pratyaksha Wirapati 3 , Kathryn Gilroy 4 , Tamsin R M Lannagan 4 , Dustin J Flanagan 4 , Arafath K Najumudeen 4 , Sulochana Omwenga 1 , Amy M B McCorry 5 , Alistair Easton 6 , Viktor H Koelzer 7 , James E East 8 , Dion Morton 9 , Livio Trusolino 10 , Timothy Maughan 6 , Andrew D Campbell 4 , Maurice B Loughrey 5 , Philip D Dunne 5 , Petros Tsantoulis 11 , David J Huels 2 , Sabine Tejpar 12 , Owen J Sansom 13 , Simon J Leedham 14
Affiliation  

Intestinal homeostasis is underpinned by LGR5+ve crypt-base columnar stem cells (CBCs), but following injury, dedifferentiation results in the emergence of LGR5−ve regenerative stem cell populations (RSCs), characterized by fetal transcriptional profiles. Neoplasia hijacks regenerative signaling, so we assessed the distribution of CBCs and RSCs in mouse and human intestinal tumors. Using combined molecular-morphological analysis, we demonstrate variable expression of stem cell markers across a range of lesions. The degree of CBC-RSC admixture was associated with both epithelial mutation and microenvironmental signaling disruption and could be mapped across disease molecular subtypes. The CBC-RSC equilibrium was adaptive, with a dynamic response to acute selective pressure, and adaptability was associated with chemoresistance. We propose a fitness landscape model where individual tumors have equilibrated stem cell population distributions along a CBC-RSC phenotypic axis. Cellular plasticity is represented by position shift along this axis and is influenced by cell-intrinsic, extrinsic, and therapeutic selective pressures.



中文翻译:

结直肠肿瘤中的动态和适应性癌症干细胞群混合物

肠道稳态由LGR5+ ve 隐窝基柱状干细胞 (CBC) 支撑,但在损伤后,去分化导致LGR5的出现-ve 再生干细胞群 (RSC),以胎儿转录谱为特征。肿瘤劫持再生信号,因此我们评估了 CBC 和 RSC 在小鼠和人类肠道肿瘤中的分布。通过结合分子形态学分析,我们证明了干细胞标记物在一系列病变中的可变表达。CBC-RSC 混合的程度与上皮突变和微环境信号中断有关,并且可以跨疾病分子亚型进行映射。CBC-RSC 平衡是适应性的,对急性选择压力有动态反应,适应性与化学耐药性有关。我们提出了一个适应性景观模型,其中个体肿瘤沿 CBC-RSC 表型轴平衡了干细胞群分布。

更新日期:2022-08-05
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