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结直肠癌的转移性复发源于残余的EMP1+细胞
2022-11-13 10:35

西班牙巴塞罗那科技学院Eduard Batlle课题组发现,结直肠癌的转移性复发源于残余的EMP1+细胞。2022年11月9日,国际知名学术期刊《自然》在线发表了这一成果。

研究人员揭示了导致结直肠癌(CRC)复发的残余肿瘤细胞的身份和特征。对CRC患者样本的单细胞转录组的分析显示,大多数与预后不良有关的基因是由一个独特的肿瘤细胞群表达的,被称为高复发细胞(HRC)。研究人员建立了一个类似人类微卫星稳定的CRC小鼠模型,该模型在手术切除原发肿瘤后会发生转移复发。原发性CRC手术后隐藏在小鼠肝脏中的残留HRC随着时间的推移产生了多种细胞类型,包括LGR5+干性肿瘤细胞,并引起明显的转移性疾病。

使用Emp1(编码上皮膜蛋白1)作为HRC的标记基因,研究人员追踪并选择性地消除了这一细胞群。EMP1high细胞的遗传去除防止了转移性复发,小鼠在手术后仍然无病。研究人员还发现,富含HRC的微转移灶被T细胞浸润,但在生长过程中逐渐被免疫排斥。新辅助免疫治疗消除了残留的转移细胞,并防止小鼠术后复发。总之,这些研究结果揭示了CRC残余疾病的细胞状态动态,并预计靶向HRC的疗法可能有助于避免转移性复发。

据了解,在接受原发肿瘤治愈性切除的CRC患者中,约有30-40%的患者在随后的几年里会出现转移。防止疾病复发的治疗方法仍然是一个未满足的医疗需求。

附:英文原文

Title: Metastatic recurrence in colorectal cancer arises from residual EMP1+ cells

Author: Caellas-Socias, Adri, Cortina, Carme, Hernando-Momblona, Xavier, Palomo-Ponce, Sergio, Mulholland, Eoghan J., Turon, Gemma, Mateo, Lidia, Conti, Sefora, Roman, Olga, Sevillano, Marta, Slebe, Felipe, Stork, Diana, Caball-Mestres, Adri, Berenguer-Llergo, Antonio, lvarez-Varela, Adrin, Fenderico, Nicola, Novellasdemunt, Laura, Jimnez-Gracia, Laura, Sipka, Tamara, Bardia, Lidia, Lorden, Patricia, Colombelli, Julien, Heyn, Holger, Trepat, Xavier, Tejpar, Sabine, Sancho, Elena, Tauriello, Daniele V. F., Leedham, Simon, Attolini, Camille Stephan-Otto, Batlle, Eduard

Issue&Volume: 2022-11-09

Abstract: Around 30–40% of patients with colorectal cancer (CRC) undergoing curative resection of the primary tumour will develop metastases in the subsequent years1. Therapies to prevent disease relapse remain an unmet medical need. Here we uncover the identity and features of the residual tumour cells responsible for CRC relapse. An analysis of single-cell transcriptomes of samples from patients with CRC revealed that the majority of genes associated with a poor prognosis are expressed by a unique tumour cell population that we named high-relapse cells (HRCs). We established a human-like mouse model of microsatellite-stable CRC that undergoes metastatic relapse after surgical resection of the primary tumour. Residual HRCs occult in mouse livers after primary CRC surgery gave rise to multiple cell types over time, including LGR5+ stem-like tumour cells2,3,4, and caused overt metastatic disease. Using Emp1 (encoding epithelial membrane protein 1) as a marker gene for HRCs, we tracked and selectively eliminated this cell population. Genetic ablation of EMP1high cells prevented metastatic recurrence and mice remained disease-free after surgery. We also found that HRC-rich micrometastases were infiltrated with T cells, yet became progressively immune-excluded during outgrowth. Treatment with neoadjuvant immunotherapy eliminated residual metastatic cells and prevented mice from relapsing after surgery. Together, our findings reveal the cell-state dynamics of residual disease in CRC and anticipate that therapies targeting HRCs may help to avoid metastatic relapse.

DOI: 10.1038/s41586-022-05402-9

Source: https://www.nature.com/articles/s41586-022-05402-9

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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