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THERAPEUTIC POTENTIAL OF TARGETING PROTEIN HYPER-SUMOYLATION IN CHOLANGIOCARCINOMA

Paula Olaizola 1,2, Irene Olaizola 1, Marta Fernandez de Ara 1, Maite G. Fernandez-Barrena 2,3,4, Laura Alvarez 3, Mikel Azkargorta 2,5, Colm J. O'Rourke 6, Pui-Yuen Lee-Law 1,7, Luiz M. Nova-Camacho 8, Jose Juan Marin 2,9, Maria L. Martinez-Chantar 2,10, Matias A. Avila 2,3,4, Patricia Aspichueta 2,11,12, Felix Elortza 2,5, Jesper B. Andersen 6, Luis Bujanda Fernández de Piérola 1,2, Pedro M. Rodrigues 1,2,13, María Jesús Perugorria 1,2,14, Jesús M. Bañales 1,2,13

Affiliations

1 Biodonostia Health Research Institute - Donostia University Hospital, San Sebastian, Spain

2 National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, “Instituto de Salud Carlos III”), Madrid, Spain

3 Hepatology Program, CIMA, University of Navarra, Pamplona, Spain

4 Instituto de Investigaciones Sanitarias de Navarra (Idi

5 Proteomics Platform, CIC bioGUNE, CIBERehd, ProteoRed-ISCIII, Bizkaia Science and Technology Park, Derio, Spain

6 Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

7 Radboud University Nijmegen Medical Center, Nijmegen, Netherlands

8 Osakidetza Basque Health Service, Donostialdea IHO, Donostia University Hospital, Department of Pathology, San Sebastian, Spain

9 Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, Institute of Biomedical Research of Salamanca (IBSAL), Unive

10 Liver Disease Laboratory, CIC bioGUNE, Basque Research and Technology Alliance (BRTA), Bilbao, Spain

11 Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain

12 Biocruces Bizkaia Health Resea

13 IKERBASQUE, Basque Foundation

14 Faculty of Medicine and Nursi

Summary

AI Generated

Aberrant SUMOylation machinery is overexpressed in cholangiocarcinoma and correlates with poor prognosis, while genetic and pharmacological SUMOylation inhibition halts tumor growth in preclinical models.

The SUMOylation machinery was overexpressed and overactivated in human cholangiocarcinoma cells and tumors, correlating with poor prognosis
Genetic inhibition using CRISPR/Cas9 against UBE2I and pharmacological inhibition with S-adenosylmethionine or ML792 reduced cholangiocarcinoma cell proliferation, impeded colony formation in vitro, and induced apoptotic cell death
SUMOylation depletion halted tumorigenesis in subcutaneous cholangiocarcinoma models in vivo
SUMOylation deficiency in cholangiocarcinoma cells reduced cancer-associated fibroblast and endothelial cell proliferation and impaired macrophage polarization towards an anti-inflammatory M2-like phenotype
The findings suggest that impaired SUMOylation may represent a potential new therapeutic strategy for patients with cholangiocarcinoma

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This summary was generated by an AI large language model based on the content transcript. It is for informational purposes only and should not be considered a substitute for clinical judgment. Always rely on your professional expertise and the full clinical context when making clinical decisions.

Abstract

Introduction

Cholangiocarcinoma (CCA) comprises a heterogeneous group of malignant tumors with dismal prognosis. Alterations in post-translational modifications (PTMs), including SUMOylation, result in abnormal protein dynamics, cell disturbances and disease. Here, we investigate the role of SUMOylation in CCA development and progression.

Aims & Methods

Levels and function of SUMOylation, together with response to S-adenosylmethionine (SAMe) and ML792 (SUMOylation inhibitors) or CRISPR/Cas9 against UBE2I were evaluated in vitro, in vivo and/or in patients with CCA. The impact of SUMOylation in CCA cells on tumor-stroma crosstalk was assessed performing co-culture experiments with CCA-derived cancer-associated fibroblasts (CAFs), human endothelial cells and monocytes. Proteomic analyses were carried out by mass spectrometry.

Results

The SUMOylation machinery was found overexpressed and overactivated in human CCA cells and tumors, correlating with poor prognosis. Most SUMOylated proteins found upregulated in CCA cells, after SUMO1-immunoprecipitation and further proteomics, participate in cell proliferation, survival or cell homeostasis. Genetic (CRISPR/Cas9-UBE2I) and pharmacological (SAMe and ML792) inhibition of SUMOylation reduced CCA cell proliferation and impeded colony formation in vitro. Moreover, both SAMe and ML792 induced apoptotic cell death in CCA cells in vitro. SUMOylation depletion (SAMe, ML792 or CRISPR/Cas9-UBE2I) halted tumorigenesis in subcutaneous models of CCA in vivo. Furthermore, SUMOylation deficiency in CCA cells reduced cancer-associated fibroblast and endothelial cell proliferation and impaired macrophage polarization towards an anti-inflammatory M2-like phenotype.

Conclusion

Aberrant protein SUMOylation contributes to cholangiocarcinogenesis by promoting cell survival and proliferation. Moreover, SUMOylation impacts the CCA-stroma crosstalk. Impaired SUMOylation halts CCA growth and, thus, may represent a potential new therapeutic strategy for patients with CCA.

Conference

UEG Week Copenhagen 2023

Topics

Hepatobiliary

Submission format

Abstract

Session

PP 07 Liver & biliary (Posters)

Citation

United European Gastroenterology Journal 2023; 11 (Supplement 8)

Published

2023

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SCAVENGER RECEPTOR MARCO IS ASSOCIATED WITH AN IMMUNOSUPPRESSIVE MICROENVIRONMENT AND TUMOR PROGRESSION IN INTRAHEPATIC CHOLANGIOCARCINOMA

Aloña Agirre Lizaso 1, Maider Huici-Izagirre 1, Colm J. O'Rourke 2, Ekaterina Zhuravleva 2, Ana Korosec 3, Mikel Azkargorta 4,5, Felix Elortza 4,5, Sumera I. Ilyas 6, Gregory J. Gores 6, Jesper B. Andersen 2, Gernot Schabbauer 3, Luis Bujanda Fernández de Piérola 1,4, Pedro M. Rodrigues 4,1,7, Omar Sharif 3, Jesús M. Bañales 1,4,7,8, María Jesús Perugorria 1,4,9

Affiliations

1 Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain

2 Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

3 Institute for Vascular Biology, Centre for Physiology and Pharmacology, Medical University Vienna, Christian Doppler Laboratory for Arginine Metabolism in Rheumatoid Arthritis and Multiple Sclerosis, Vienna, Austria

4 CIBERehd, Instituto de Salud Carlos III (ISCIII), Madrid, Spain

5 Proteomics Platform, CIC bioGUNE, ProteoRed-ISCIII, Bizkaia Science and Technology Park, Derio, Spain

6 Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, United States

7 IKERBASQUE, Basque Foundation for Science, Bilbao, Spain

8 University of Navarra, Pamplona,

9 Faculty of Medicine and Nursing, University of the Basque Country (UPV/EHU), Leioa, Spain