BCL-XL is crucial for progression through the adenoma-to-carcinoma sequence of colorectal cancer.
BCL-XL is crucial for progression through the adenoma-to-carcinoma sequence of colorectal cancer.
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DOI：
10.1038/s41418-021-00816-w
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发表时间：
2021-12
影响因子：
12.4
通讯作者：
Medema JP
中科院分区：
文献类型：
--
作者：
Ramesh P;Lannagan TRM;Jackstadt R;Atencia Taboada L;Lansu N;Wirapati P;van Hooff SR;Dekker D;Pritchard J;Kirov AB;van Neerven SM;Tejpar S;Kops GJPL;Sansom OJ;Medema JP
细胞凋亡的逃避是癌症的标志，其通常由抗细胞凋亡BCL-2家族蛋白的上调介导。在结直肠癌（CRC）中，以前的工作强调了由疾病阶段决定的差异抗凋亡蛋白依赖性。虽然肠干细胞（ISCs）需要BCL-2的腺瘤生长和转化过程中的生存，ISC特异性MCL 1缺失导致肠内稳态紊乱，最终导致肿瘤发生。然而，结肠癌干细胞（CSC）不再需要BCL-2，主要依赖BCL-XL存活。因此，我们假设随着疾病从正常发展到腺瘤再到癌，抗凋亡蛋白依赖性发生了变化。通过在CRC进展的类器官模型中用特异性BH 3模拟物靶向抗凋亡蛋白，我们发现BCL-2仅在ISC转化期间是必需的，而MCL 1抑制并不影响腺瘤生长。另一方面，BCL-XL在整个腺瘤到癌的序列中对干细胞存活至关重要。此外，我们确定BCL-2依赖的有限窗口是其被miR-17- 5 p下调的结果，miR-17- 5 p是一种在APC突变驱动的转化后上调的microRNA。在这里，我们表明，BCL-XL抑制有效地损害腺瘤生长在体内，提高化疗的疗效。与这种依赖性一致，BCL-XL的表达，而不是BCL-2或MCL 1的表达，与化疗治疗的CRC患者的结果直接相关。我们的研究结果提供了见解，使BH 3模拟物在CRC管理中的合理使用，特别是强调了BCL-XL靶向模拟物在早期和晚期疾病中的治疗潜力。
Evasion of apoptosis is a hallmark of cancer, which is frequently mediated by upregulation of the antiapoptotic BCL-2 family proteins. In colorectal cancer (CRC), previous work has highlighted differential antiapoptotic protein dependencies determined by the stage of the disease. While intestinal stem cells (ISCs) require BCL-2 for adenoma outgrowth and survival during transformation, ISC-specific MCL1 deletion results in disturbed intestinal homeostasis, eventually contributing to tumorigenesis. Colon cancer stem cells (CSCs), however, no longer require BCL-2 and depend mainly on BCL-XL for their survival. We therefore hypothesized that a shift in antiapoptotic protein reliance occurs in ISCs as the disease progresses from normal to adenoma to carcinoma. By targeting antiapoptotic proteins with specific BH3 mimetics in organoid models of CRC progression, we found that BCL-2 is essential only during ISC transformation while MCL1 inhibition did not affect adenoma outgrowth. BCL-XL, on the other hand, was crucial for stem cell survival throughout the adenoma-to-carcinoma sequence. Furthermore, we identified that the limited window of BCL-2 reliance is a result of its downregulation by miR-17-5p, a microRNA that is upregulated upon APC-mutation driven transformation. Here we show that BCL-XL inhibition effectively impairs adenoma outgrowth in vivo and enhances the efficacy of chemotherapy. In line with this dependency, expression of BCL-XL, but not BCL-2 or MCL1, directly correlated to the outcome of chemotherapy-treated CRC patients. Our results provide insights to enable the rational use of BH3 mimetics in CRC management, particularly underlining the therapeutic potential of BCL-XL targeting mimetics in both early and late-stage disease.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.5
作者：
Mason, Kylie D.;Carpinelli, Marina R.;Kile, Benjamin T.
通讯作者：
Kile, Benjamin T.
影响因子：
50.3
作者：
Li Y;Choi PS;Casey SC;Dill DL;Felsher DW
通讯作者：
Felsher DW
使用PTK7的表面表达分离人类结肠干细胞。
影响因子：
5.9
作者：
Jung P;Sommer C;Barriga FM;Buczacki SJ;Hernando-Momblona X;Sevillano M;Duran-Frigola M;Aloy P;Selbach M;Winton DJ;Batlle E
通讯作者：
Batlle E
影响因子：
11.1
作者：
Fessler E;Drost J;van Hooff SR;Linnekamp JF;Wang X;Jansen M;De Sousa E Melo F;Prasetyanti PR;IJspeert JE;Franitza M;Nürnberg P;van Noesel CJ;Dekker E;Vermeulen L;Clevers H;Medema JP
通讯作者：
Medema JP