BCL-XL is crucial for progression through the adenoma-to-carcinoma sequence of colorectal cancer

Abstract

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.

An atlas of inter- and intra-tumor heterogeneity of apoptosis competency in colorectal cancer tissue at single-cell resolution

“…This finding may have implications regarding the possible use of BCL2 antagonists for the treatment of CRC, and BCL2 mRNA or protein levels as stratification tool for such therapy. Medema et al also demonstrated an enrichment of BCL-2 in immune cells, and a limited window of BCL-2 reliance in CRC cells during disease progression [24]. Their study also demonstrated that expression of BCL(X)L, but not BCL2 or MCL1, correlated with outcome in chemotherapy-treated CRC patients.…”

Modeling Colorectal Cancer Progression Reveals Niche-Dependent Clonal Selection

“…Furthermore, virus particles can be used for localized recombination when containing the coding sequence for Cre recombinase [ 12 , 31 ]. Additionally, the focal injection of 4-OHT leads to colon tumor formation when a villin Cre ER background is used ( Figure 1 A,B) [ 13 , 15 , 32 ]. In this study, colonoscopy-guided injections could be performed on a benchtop or under a biosafety hood, depending on the specific application and local regulations.…”

“…Hence, with local application of 4-OHT, the number of tumors can be controlled and tumor formation is achieved exclusively at the site of injection [ 12 , 13 , 14 ]. The preclinical use of this model was utilized to validate novel therapeutic strategies and demonstrated that BCL-XL inhibition causes impaired adenoma outgrowth [ 15 ].…”

Bcl-xL is a key mediator of apoptosis following KRASG12C inhibition in KRASG12C mutant colorectal cancer

“…S3D) (44), leading to robust increases in apoptosis when ABT-737 was combined with KRAS G12C inhibition in our study. Alongside its pivotal role in regulating MOMP, Bcl-xL has been identified as a critical mediator of stem cell survival through the adeno-to-colon carcinoma sequence (45). Additionally, a number of studies have shown that Bcl-xL plays an important role in regulating sensitivity to chemotherapy and other targeted therapies (45)(46)(47).…”