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

Prashanthi Ramesh; Tamsin R M Lannagan; Rene Jackstadt; Lidia Atencia Taboada; Nico Lansu; Pratyaksha Wirapati; Sander R van Hooff; Danielle Dekker; Jessica Pritchard; Aleksandar B Kirov; Sanne M van Neerven; Sabine Tejpar; Geert J P L Kops; Owen J Sansom; Jan Paul Medema

doi:10.1038/s41418-021-00816-w

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

Prashanthi Ramesh, Tamsin R M Lannagan, Rene Jackstadt, Lidia Atencia Taboada, Nico Lansu, Pratyaksha Wirapati, Sander R van Hooff, Danielle Dekker, Jessica Pritchard, Aleksandar B Kirov, Sanne M van Neerven, Sabine Tejpar, Geert J P L Kops, Owen J Sansom, Jan Paul Medema

Hubrecht Institute

Onderzoeksoutput: Bijdrage aan wetenschappelijk tijdschrift/periodieke uitgave › Artikel › Wetenschappelijk › peer review

33 Citaten (Scopus)

Samenvatting

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.

Originele taal-2	Engels
Pagina's (van-tot)	3282-3296
Aantal pagina's	15
Tijdschrift	Cell Death and Differentiation
Volume	28
Nummer van het tijdschrift	12
DOI's	https://doi.org/10.1038/s41418-021-00816-w
Status	Gepubliceerd - dec. 2021

Toegang tot document

10.1038/s41418-021-00816-w

Citeer dit

Ramesh, P., Lannagan, T. R. M., Jackstadt, R., Atencia Taboada, L., Lansu, N., Wirapati, P., van Hooff, S. R., Dekker, D., Pritchard, J., Kirov, A. B., van Neerven, S. M., Tejpar, S., Kops, G. J. P. L., Sansom, O. J., & Medema, J. P. (2021). BCL-XL is crucial for progression through the adenoma-to-carcinoma sequence of colorectal cancer. Cell Death and Differentiation, 28(12), 3282-3296. https://doi.org/10.1038/s41418-021-00816-w

@article{da3d3c13c1fd43928e20d5b858c2d6fd,

title = "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.",

author = "Prashanthi Ramesh and Lannagan, {Tamsin R M} and Rene Jackstadt and {Atencia Taboada}, Lidia and Nico Lansu and Pratyaksha Wirapati and {van Hooff}, {Sander R} and Danielle Dekker and Jessica Pritchard and Kirov, {Aleksandar B} and {van Neerven}, {Sanne M} and Sabine Tejpar and Kops, {Geert J P L} and Sansom, {Owen J} and Medema, {Jan Paul}",

note = "{\textcopyright} 2021. The Author(s).",

year = "2021",

month = dec,

doi = "10.1038/s41418-021-00816-w",

language = "English",

volume = "28",

pages = "3282--3296",

journal = "Cell Death and Differentiation",

issn = "1350-9047",

publisher = "Nature Publishing Group",

number = "12",

}

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 2021, 'BCL-XL is crucial for progression through the adenoma-to-carcinoma sequence of colorectal cancer', Cell Death and Differentiation, vol. 28, nr. 12, blz. 3282-3296. https://doi.org/10.1038/s41418-021-00816-w

TY - JOUR

T1 - BCL-XL is crucial for progression through the adenoma-to-carcinoma sequence of colorectal cancer

AU - Ramesh, Prashanthi

AU - Lannagan, Tamsin R M

AU - Jackstadt, Rene

AU - Atencia Taboada, Lidia

AU - Lansu, Nico

AU - Wirapati, Pratyaksha

AU - van Hooff, Sander R

AU - Dekker, Danielle

AU - Pritchard, Jessica

AU - Kirov, Aleksandar B

AU - van Neerven, Sanne M

AU - Tejpar, Sabine

AU - Kops, Geert J P L

AU - Sansom, Owen J

AU - Medema, Jan Paul

PY - 2021/12

Y1 - 2021/12

N2 - 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.

AB - 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.

U2 - 10.1038/s41418-021-00816-w

DO - 10.1038/s41418-021-00816-w

M3 - Article

C2 - 34117376

SN - 1350-9047

VL - 28

SP - 3282

EP - 3296

JO - Cell Death and Differentiation

JF - Cell Death and Differentiation

IS - 12

ER -

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

Samenvatting

Toegang tot document

Vingerafdruk

Citeer dit