Cancer Research UK Edinburgh Centre, MRC Institute of Genetics & Molecular Medicine, The University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh, EH4 2XU, UK.
Inflammatory Bowel Disease Unit, Department of Gastroenterology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) - CIBEREHD, Barcelona, Spain.
Cell Death Dis. 2021 Sep 25;12(10):873. doi: 10.1038/s41419-021-04177-7.
RAC1B is a tumour-related alternative splice isoform of the small GTPase RAC1, found overexpressed in a large number of tumour types. Building evidence suggests it promotes tumour progression but compelling in vivo evidence, demonstrating a role in driving tumour invasion, is currently lacking. In the present study, we have overexpressed RAC1B in a colorectal cancer mouse model with potential invasive properties. Interestingly, RAC1B overexpression did not trigger tumour invasion, rather it led to an acceleration of tumour initiation and reduced mouse survival. By modelling early stages of adenoma initiation we observed a reduced apoptotic rate in RAC1B overexpressing tumours, suggesting protection from apoptosis as a mediator of this phenotype. RAC1B overexpressing tumours displayed attenuated TGFβ signalling and functional analysis in ex vivo organoid cultures demonstrated that RAC1B negatively modulates TGFβ signalling and confers resistance to TGFβ-driven cell death. This work defines a novel mechanism by which early adenoma cells can overcome the cytostatic and cytotoxic effects of TGFβ signalling and characterises a new oncogenic function of RAC1B in vivo.
RAC1B 是小 GTP 酶 RAC1 的肿瘤相关可变剪接异构体，在大量肿瘤类型中过表达。越来越多的证据表明它促进肿瘤进展，但目前缺乏令人信服的体内证据来证明其在驱动肿瘤侵袭中的作用。在本研究中，我们在具有潜在侵袭特性的结直肠癌小鼠模型中过表达了 RAC1B。有趣的是，RAC1B 的过表达并没有引发肿瘤侵袭，而是导致肿瘤起始加速和小鼠存活率降低。通过模拟腺瘤起始的早期阶段，我们观察到 RAC1B 过表达肿瘤中的细胞凋亡率降低，这表明细胞凋亡保护作为这种表型的介质。RAC1B 过表达肿瘤显示 TGFβ 信号减弱，并且在体外类器官培养中的功能分析表明 RAC1B 负调节 TGFβ 信号并赋予对 TGFβ 驱动的细胞死亡的抗性。这项工作定义了早期腺瘤细胞可以克服 TGFβ 信号的细胞停滞和细胞毒性作用的新机制，并在体内描述了 RAC1B 的新致癌功能。
