Targeting protein hyperSUMOylation halts cholangiocarcinoma progression by impairing cancer cell viability and tumor-stroma crosstalk

Paula Olaizola; Irene Olaizola; Marta Fernandez de Ara; Ainhoa Lapitz; Beatriz Val; Laura Izquierdo-Sanchez; Maite G Fernandez-Barrena; Laura Alvarez; Colm J. O'Rourke; Pui Y Lee-Law; Kyle Davies; Andreea Gradinaru; Raul Jimenez-Agüero; Adelaida La Casta; Ioana Riaño; Rocio I. R. Macias; Jose J. G. Marin; Maria L Martinez-Chantar; Matias A. Avila; Patricia Aspichueta; Jesper B. Andersen; Luke Boulter; Luis Bujanda; Pedro M Rodrigues; Maria J. Perugorria; Jesus M Banales

doi:10.1097/HEP.0000000000001259

Targeting protein hyperSUMOylation halts cholangiocarcinoma progression by impairing cancer cell viability and tumor-stroma crosstalk

Paula Olaizola, Irene Olaizola, Marta Fernandez de Ara, Ainhoa Lapitz, Beatriz Val, Laura Izquierdo-Sanchez, Maite G Fernandez-Barrena, Laura Alvarez, Colm J. O'Rourke, Pui Y Lee-Law, Kyle Davies, Andreea Gradinaru, Raul Jimenez-Agüero, Adelaida La Casta, Ioana Riaño, Rocio I. R. Macias, Jose J. G. Marin, Maria L Martinez-Chantar, Matias A. Avila, Patricia AspichuetaJesper B. Andersen, Luke Boulter, Luis Bujanda, Pedro M Rodrigues, Maria J. Perugorria, Jesus M Banales^*

^*Corresponding author af dette arbejde

Andersen Group

Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › peer review

Abstract

BACKGROUND AND RATIONALE: Cholangiocarcinoma (CCA) includes a diverse group of biliary malignancies with poor prognosis. Alterations in post-translational modifications contribute to disrupted protein dynamics, cellular disturbances, and disease. This study investigates the role of protein SUMOylation in cholangiocarcinogenesis and its potential as a therapeutic target.

APPROACH AND RESULTS: Analysis of CCA tumors from four patient cohorts and CCA cell lines, revealed increased expression of the SUMOylation machinery genes SAE1 and UBE2I , regardless of the tumor's molecular profile, resulting in elevated levels of SUMO1-conjugated proteins. Higher SAE1 and UBE2I levels were both indicative of unfavorable clinical outcomes. Deregulated SUMOylated proteins in CCA, mostly linked to cell proliferation, survival, and homeostasis, were identified through immunoprecipitation and mass spectrometry. Genetic ( UBE2I -knockdown) and pharmacological (ML792 and SAMe) inhibition of SUMOylation effectively suppressed tumorigenesis in subcutaneous and oncogene-driven CCA models, reducing the presence of cancer-associated fibroblasts (CAFs) and increasing the recruitment of anti-tumor immune cells. In vitro , targeting SUMOylation induced CCA cell death and reduced cell proliferation, colony formation, and spheroid growth. Importantly, ML792 and SAMe did not adversely affect normal human cholangiocytes. Moreover, co-culture of wild-type or UBE2I -knockdown CCA cells with CAFs revealed that depleting SUMOylation in CCA cells impaired CAF cell growth and altered their protein secretome, ultimately disrupting CCA growth through a regulatory feedback loop.

CONCLUSION: Aberrant SUMOylation drives CCA progression by enhancing cell survival, proliferation, and shaping the tumor microenvironment. Targeting SUMOylation shows potential in inhibiting CCA growth, representing a promising therapeutic strategy.

Originalsprog	Engelsk
Tidsskrift	Hepatology
ISSN	0270-9139
DOI	https://doi.org/10.1097/HEP.0000000000001259
Status	Accepteret/In press - 2025

Bibliografisk note

Adgang til dokumentet

10.1097/HEP.0000000000001259

Citationsformater

Olaizola, P., Olaizola, I., Fernandez de Ara, M., Lapitz, A., Val, B., Izquierdo-Sanchez, L., Fernandez-Barrena, M. G., Alvarez, L., O'Rourke, C. J., Lee-Law, P. Y., Davies, K., Gradinaru, A., Jimenez-Agüero, R., La Casta, A., Riaño, I., Macias, R. I. R., Marin, J. J. G., Martinez-Chantar, M. L., Avila, M. A., ... Banales, J. M. (Accepteret/In press). Targeting protein hyperSUMOylation halts cholangiocarcinoma progression by impairing cancer cell viability and tumor-stroma crosstalk. Hepatology. https://doi.org/10.1097/HEP.0000000000001259

Olaizola, P, Olaizola, I, Fernandez de Ara, M, Lapitz, A, Val, B, Izquierdo-Sanchez, L, Fernandez-Barrena, MG, Alvarez, L, O'Rourke, CJ, Lee-Law, PY, Davies, K, Gradinaru, A, Jimenez-Agüero, R, La Casta, A, Riaño, I, Macias, RIR, Marin, JJG, Martinez-Chantar, ML, Avila, MA, Aspichueta, P, Andersen, JB, Boulter, L, Bujanda, L, Rodrigues, PM, Perugorria, MJ & Banales, JM 2025, 'Targeting protein hyperSUMOylation halts cholangiocarcinoma progression by impairing cancer cell viability and tumor-stroma crosstalk', Hepatology. https://doi.org/10.1097/HEP.0000000000001259

@article{6c71218dcd86449e932f4d99ef379133,

title = "Targeting protein hyperSUMOylation halts cholangiocarcinoma progression by impairing cancer cell viability and tumor-stroma crosstalk",

abstract = "BACKGROUND AND RATIONALE: Cholangiocarcinoma (CCA) includes a diverse group of biliary malignancies with poor prognosis. Alterations in post-translational modifications contribute to disrupted protein dynamics, cellular disturbances, and disease. This study investigates the role of protein SUMOylation in cholangiocarcinogenesis and its potential as a therapeutic target.APPROACH AND RESULTS: Analysis of CCA tumors from four patient cohorts and CCA cell lines, revealed increased expression of the SUMOylation machinery genes SAE1 and UBE2I , regardless of the tumor's molecular profile, resulting in elevated levels of SUMO1-conjugated proteins. Higher SAE1 and UBE2I levels were both indicative of unfavorable clinical outcomes. Deregulated SUMOylated proteins in CCA, mostly linked to cell proliferation, survival, and homeostasis, were identified through immunoprecipitation and mass spectrometry. Genetic ( UBE2I -knockdown) and pharmacological (ML792 and SAMe) inhibition of SUMOylation effectively suppressed tumorigenesis in subcutaneous and oncogene-driven CCA models, reducing the presence of cancer-associated fibroblasts (CAFs) and increasing the recruitment of anti-tumor immune cells. In vitro , targeting SUMOylation induced CCA cell death and reduced cell proliferation, colony formation, and spheroid growth. Importantly, ML792 and SAMe did not adversely affect normal human cholangiocytes. Moreover, co-culture of wild-type or UBE2I -knockdown CCA cells with CAFs revealed that depleting SUMOylation in CCA cells impaired CAF cell growth and altered their protein secretome, ultimately disrupting CCA growth through a regulatory feedback loop.CONCLUSION: Aberrant SUMOylation drives CCA progression by enhancing cell survival, proliferation, and shaping the tumor microenvironment. Targeting SUMOylation shows potential in inhibiting CCA growth, representing a promising therapeutic strategy.",

author = "Paula Olaizola and Irene Olaizola and {Fernandez de Ara}, Marta and Ainhoa Lapitz and Beatriz Val and Laura Izquierdo-Sanchez and Fernandez-Barrena, {Maite G} and Laura Alvarez and O'Rourke, {Colm J.} and Lee-Law, {Pui Y} and Kyle Davies and Andreea Gradinaru and Raul Jimenez-Ag{\"u}ero and {La Casta}, Adelaida and Ioana Ria{\~n}o and Macias, {Rocio I. R.} and Marin, {Jose J. G.} and Martinez-Chantar, {Maria L} and Avila, {Matias A.} and Patricia Aspichueta and Andersen, {Jesper B.} and Luke Boulter and Luis Bujanda and Rodrigues, {Pedro M} and Perugorria, {Maria J.} and Banales, {Jesus M}",

note = "Copyright {\textcopyright} 2025 The Author(s). Published by Wolters Kluwer Health, Inc.",

year = "2025",

doi = "10.1097/HEP.0000000000001259",

language = "English",

journal = "Hepatology",

issn = "0270-9139",

publisher = "JohnWiley & Sons, Inc.",

}

TY - JOUR

T1 - Targeting protein hyperSUMOylation halts cholangiocarcinoma progression by impairing cancer cell viability and tumor-stroma crosstalk

AU - Olaizola, Paula

AU - Olaizola, Irene

AU - Fernandez de Ara, Marta

AU - Lapitz, Ainhoa

AU - Val, Beatriz

AU - Izquierdo-Sanchez, Laura

AU - Fernandez-Barrena, Maite G

AU - Alvarez, Laura

AU - O'Rourke, Colm J.

AU - Lee-Law, Pui Y

AU - Davies, Kyle

AU - Gradinaru, Andreea

AU - Jimenez-Agüero, Raul

AU - La Casta, Adelaida

AU - Riaño, Ioana

AU - Macias, Rocio I. R.

AU - Marin, Jose J. G.

AU - Martinez-Chantar, Maria L

AU - Avila, Matias A.

AU - Aspichueta, Patricia

AU - Andersen, Jesper B.

AU - Boulter, Luke

AU - Bujanda, Luis

AU - Rodrigues, Pedro M

AU - Perugorria, Maria J.

AU - Banales, Jesus M

PY - 2025

Y1 - 2025

N2 - BACKGROUND AND RATIONALE: Cholangiocarcinoma (CCA) includes a diverse group of biliary malignancies with poor prognosis. Alterations in post-translational modifications contribute to disrupted protein dynamics, cellular disturbances, and disease. This study investigates the role of protein SUMOylation in cholangiocarcinogenesis and its potential as a therapeutic target.APPROACH AND RESULTS: Analysis of CCA tumors from four patient cohorts and CCA cell lines, revealed increased expression of the SUMOylation machinery genes SAE1 and UBE2I , regardless of the tumor's molecular profile, resulting in elevated levels of SUMO1-conjugated proteins. Higher SAE1 and UBE2I levels were both indicative of unfavorable clinical outcomes. Deregulated SUMOylated proteins in CCA, mostly linked to cell proliferation, survival, and homeostasis, were identified through immunoprecipitation and mass spectrometry. Genetic ( UBE2I -knockdown) and pharmacological (ML792 and SAMe) inhibition of SUMOylation effectively suppressed tumorigenesis in subcutaneous and oncogene-driven CCA models, reducing the presence of cancer-associated fibroblasts (CAFs) and increasing the recruitment of anti-tumor immune cells. In vitro , targeting SUMOylation induced CCA cell death and reduced cell proliferation, colony formation, and spheroid growth. Importantly, ML792 and SAMe did not adversely affect normal human cholangiocytes. Moreover, co-culture of wild-type or UBE2I -knockdown CCA cells with CAFs revealed that depleting SUMOylation in CCA cells impaired CAF cell growth and altered their protein secretome, ultimately disrupting CCA growth through a regulatory feedback loop.CONCLUSION: Aberrant SUMOylation drives CCA progression by enhancing cell survival, proliferation, and shaping the tumor microenvironment. Targeting SUMOylation shows potential in inhibiting CCA growth, representing a promising therapeutic strategy.

AB - BACKGROUND AND RATIONALE: Cholangiocarcinoma (CCA) includes a diverse group of biliary malignancies with poor prognosis. Alterations in post-translational modifications contribute to disrupted protein dynamics, cellular disturbances, and disease. This study investigates the role of protein SUMOylation in cholangiocarcinogenesis and its potential as a therapeutic target.APPROACH AND RESULTS: Analysis of CCA tumors from four patient cohorts and CCA cell lines, revealed increased expression of the SUMOylation machinery genes SAE1 and UBE2I , regardless of the tumor's molecular profile, resulting in elevated levels of SUMO1-conjugated proteins. Higher SAE1 and UBE2I levels were both indicative of unfavorable clinical outcomes. Deregulated SUMOylated proteins in CCA, mostly linked to cell proliferation, survival, and homeostasis, were identified through immunoprecipitation and mass spectrometry. Genetic ( UBE2I -knockdown) and pharmacological (ML792 and SAMe) inhibition of SUMOylation effectively suppressed tumorigenesis in subcutaneous and oncogene-driven CCA models, reducing the presence of cancer-associated fibroblasts (CAFs) and increasing the recruitment of anti-tumor immune cells. In vitro , targeting SUMOylation induced CCA cell death and reduced cell proliferation, colony formation, and spheroid growth. Importantly, ML792 and SAMe did not adversely affect normal human cholangiocytes. Moreover, co-culture of wild-type or UBE2I -knockdown CCA cells with CAFs revealed that depleting SUMOylation in CCA cells impaired CAF cell growth and altered their protein secretome, ultimately disrupting CCA growth through a regulatory feedback loop.CONCLUSION: Aberrant SUMOylation drives CCA progression by enhancing cell survival, proliferation, and shaping the tumor microenvironment. Targeting SUMOylation shows potential in inhibiting CCA growth, representing a promising therapeutic strategy.

U2 - 10.1097/HEP.0000000000001259

DO - 10.1097/HEP.0000000000001259

M3 - Journal article

C2 - 39932259

SN - 0270-9139

JO - Hepatology

JF - Hepatology

ER -