Cytidine Deaminase Resolves Replicative Stress and Protects Pancreatic Cancer from DNA-Targeting Drugs

Author:

Lumeau Audrey1ORCID,Bery Nicolas1ORCID,Francès Audrey1ORCID,Gayral Marion1ORCID,Labrousse Guillaume1ORCID,Ribeyre Cyril2ORCID,Lopez Charlene1ORCID,Nevot Adele1ORCID,El Kaoutari Abdessamad3ORCID,Hanoun Naima1ORCID,Sarot Emeline1ORCID,Perrier Marion1ORCID,Pont Frederic1ORCID,Cerapio Juan-Pablo1ORCID,Fournié Jean-Jacques1ORCID,Lopez Frederic1ORCID,Madrid-Mencia Miguel1ORCID,Pancaldi Vera14ORCID,Pillaire Marie-Jeanne5ORCID,Bergoglio Valerie6ORCID,Torrisani Jerome1ORCID,Dusetti Nelson3ORCID,Hoffmann Jean-Sebastien7ORCID,Buscail Louis18ORCID,Lutzmann Malik2ORCID,Cordelier Pierre1ORCID

Affiliation:

1. 1Centre de Recherches en Cancérologie de Toulouse, CRCT, Université de Toulouse, Inserm, CNRS, Toulouse, France.

2. 2Institut de Génétique Humaine, CNRS, Université de Montpellier, Montpellier, France.

3. 3Centre de Recherche en Cancérologie de Marseille, CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Université Aix-Marseille, Marseille, France.

4. 4Barcelona Supercomputing Center, Barcelona, Spain.

5. 5Institut de Pharmacologie et de Biologie Structurale, IPBS, Toulouse, France.

6. 6Centre de Biologie Intégrée, CBI, Toulouse, France.

7. 7Laboratoire d'Excellence Toulouse Cancer (TOUCAN), Laboratoire de pathologie, Institut Universitaire du Cancer-Toulouse, Toulouse, France.

8. 8Service de gastroentérologie et d'hépatologie, CHU Rangueil, Université de Toulouse, Toulouse, France.

Abstract

Abstract Cytidine deaminase (CDA) functions in the pyrimidine salvage pathway for DNA and RNA syntheses and has been shown to protect cancer cells from deoxycytidine-based chemotherapies. In this study, we observed that CDA was overexpressed in pancreatic adenocarcinoma from patients at baseline and was essential for experimental tumor growth. Mechanistic investigations revealed that CDA localized to replication forks where it increased replication speed, improved replication fork restart efficiency, reduced endogenous replication stress, minimized DNA breaks, and regulated genetic stability during DNA replication. In cellular pancreatic cancer models, high CDA expression correlated with resistance to DNA-damaging agents. Silencing CDA in patient-derived primary cultures in vitro and in orthotopic xenografts in vivo increased replication stress and sensitized pancreatic adenocarcinoma cells to oxaliplatin. This study sheds light on the role of CDA in pancreatic adenocarcinoma, offering insights into how this tumor type modulates replication stress. These findings suggest that CDA expression could potentially predict therapeutic efficacy and that targeting CDA induces intolerable levels of replication stress in cancer cells, particularly when combined with DNA-targeted therapies. Significance: Cytidine deaminase reduces replication stress and regulates DNA replication to confer resistance to DNA-damaging drugs in pancreatic cancer, unveiling a molecular vulnerability that could enhance treatment response.

Funder

Fondation Toulouse Cancer Santé

Region Occitanie

Institut National de la Santé et de la Recherche Médicale

Universite Paul Sabatier Toulouse III

Fondation de France

Ligue Contre le Cancer

Inserm Transfert

Publisher

American Association for Cancer Research (AACR)

Cited by 3 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3