美国纪念斯隆凯特琳癌症中心 K.Ganesh课题组在研究中取得进展。他们报道了结直肠癌转移过程中的进行性可塑性。这一研究成果于2024年10月30日发表在国际顶尖学术期刊《自然》上。

研究人员表示，随着癌症的发展，它们变得越来越具有侵略性——转移性肿瘤对一线治疗的反应不如原发肿瘤，它们对连续治疗产生抗药性，最终导致死亡。来自同一患者的原发性和转移性肿瘤的突变在很大程度上是保守的，这表明非遗传表型可塑性在癌症发展和治疗耐药性中起着重要作用。然而，目前缺乏对转移细胞状态及其转移机制的理解。

在一组来自同一患者的正常结肠癌、原发性和转移性结直肠癌的生物标本中，课题组发现，尽管原发性肿瘤大多采用LGR5⁺肠道干细胞样状态，但转移性肿瘤表现出进行性可塑性。

癌细胞失去肠细胞特性并重编程为高度保守的胚胎祖细胞状态，然后经历非典型分化为发散的鳞状细胞和神经内分泌样状态，这一过程在转移和化疗中加剧，并与患者生存率低相关。

使用匹配患者来源的类器官，研究组证明，与肠道谱系限制的原发肿瘤相比，转移细胞在响应微环境线索时，表现出更大的细胞自主多谱系分化潜力。研究人员发现PROX1是胚胎祖细胞状态下非肠道谱系的抑制因子，并表明PROX1的下调允许非经典重编程。

附：英文英文

Title: Progressive plasticity during colorectal cancer metastasis

Author: Moorman, A. R., Benitez, E. K., Cambuli, F., Jiang, Q., Mahmoud, A., Lumish, M., Hartner, S., Balkaran, S., Bermeo, J., Asawa, S., Firat, C., Saxena, A., Wu, F., Luthra, A., Burdziak, C., Xie, Y., Sgambati, V., Luckett, K., Li, Y., Yi, Z., Masilionis, I., Soares, K., Pappou, E., Yaeger, R., Kingham, P., Jarnagin, W., Paty, P., Weiser, M. R., Mazutis, L., DAngelica, M., Shia, J., Garcia-Aguilar, J., Nawy, T., Hollmann, T. J., Chalign, R., Sanchez-Vega, F., Sharma, R., Peer, D., Ganesh, K.

Issue&Volume: 2024-10-30

Abstract: As cancers progress, they become increasingly aggressive—metastatic tumours are less responsive to first-line therapies than primary tumours, they acquire resistance to successive therapies and eventually cause death1,2. Mutations are largely conserved between primary and metastatic tumours from the same patients, suggesting that non-genetic phenotypic plasticity has a major role in cancer progression and therapy resistance3,4,5. However, we lack an understanding of metastatic cell states and the mechanisms by which they transition. Here, in a cohort of biospecimen trios from same-patient normal colon, primary and metastatic colorectal cancer, we show that, although primary tumours largely adopt LGR5+ intestinal stem-like states, metastases display progressive plasticity. Cancer cells lose intestinal cell identities and reprogram into a highly conserved fetal progenitor state before undergoing non-canonical differentiation into divergent squamous and neuroendocrine-like states, a process that is exacerbated in metastasis and by chemotherapy and is associated with poor patient survival. Using matched patient-derived organoids, we demonstrate that metastatic cells exhibit greater cell-autonomous multilineage differentiation potential in response to microenvironment cues compared with their intestinal lineage-restricted primary tumour counterparts. We identify PROX1 as a repressor of non-intestinal lineage in the fetal progenitor state, and show that downregulation of PROX1 licenses non-canonical reprogramming.

DOI: 10.1038/s41586-024-08150-0

Source: https://www.nature.com/articles/s41586-024-08150-0