2. Academic Validation
  3. Control of replication stress and mitosis in colorectal cancer stem cells through the interplay of PARP1, MRE11 and RAD51

Control of replication stress and mitosis in colorectal cancer stem cells through the interplay of PARP1, MRE11 and RAD51

  • Cell Death Differ. 2021 Jul;28(7):2060-2082. doi: 10.1038/s41418-020-00733-4.
Gwenola Manic 1 2,  Martina Musella  # 3,  Francesca Corradi  # 4,  Antonella Sistigu  # 3 5,  Sara Vitale 3,  Sara Soliman Abdel Rehim 6 4,  Luca Mattiello 6 7,  Eva Malacaria 8,  Claudia Galassi 3,  Michele Signore 9,  Matteo Pallocca 10,  Stefano Scalera 11,  Frauke Goeman 12,  Francesca De Nicola 11,  Andrea Guarracino 6 4,  Rosa Pennisi 13,  Fabrizio Antonangeli 14 15,  Francesca Sperati 16,  Marta Baiocchi 17,  Mauro Biffoni 17,  Maurizio Fanciulli 11,  Marcello Maugeri-Saccà 18,  Annapaola Franchitto 8,  Pietro Pichierri 8,  Ruggero De Maria 19 20,  Ilio Vitale 21 22
Affiliations

Affiliations

  • 1 IIGM - Italian Institute for Genomic Medicine, c/o IRCSS, Candiolo, Italy. gwenola.manic@gmail.com.
  • 2 Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Italy. gwenola.manic@gmail.com.
  • 3 Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy.
  • 4 Department of Biology, University of Rome "Tor Vergata", Rome, Italy.
  • 5 UOSD Immunology and Immunotherapy Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
  • 6 IIGM - Italian Institute for Genomic Medicine, c/o IRCSS, Candiolo, Italy.
  • 7 Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Italy.
  • 8 Mechanisms, Biomarkers and Models Unit, Department of Environment and Health, Istituto Superiore di Sanità, Rome, Italy.
  • 9 RPPA unit, Proteomics area, Core Facilities, Istituto Superiore di Sanità, Rome, Italy.
  • 10 UOSD Biostatistics, Bioinformatics and Clinical Trial Center, IRCSS Regina Elena National Cancer Institute, Rome, Italy.
  • 11 UOSD SAFU, Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
  • 12 Oncogenomic and Epigenetic Unit, Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, IRCCS Regina Elena National Cancer Institute, Rome, Italy.
  • 13 Department of Experimental Oncology, European Institute of Oncology (IEO), Milano, Italy.
  • 14 Department of Molecular Medicine, University "La Sapienza", Laboratory affiliated to Istituto Pasteur Italia, Rome, Italy.
  • 15 Institute of Molecular Biology and Pathology, National Research Council (CNR), Rome, Italy.
  • 16 UOSD Biostatistics, Bioinformatics and Clinical Trial Center, San Gallicano Dermatological Institute IRCCS, Rome, Italy.
  • 17 Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
  • 18 Division of Medical Oncology 2, IRCSS Regina Elena National Cancer Institute, Rome, Italy.
  • 19 Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy. ruggero.demaria@unicatt.it.
  • 20 Fondazione Policlinico Universitario "A. Gemelli" - IRCCS, Rome, Italy. ruggero.demaria@unicatt.it.
  • 21 IIGM - Italian Institute for Genomic Medicine, c/o IRCSS, Candiolo, Italy. iliovit@gmail.com.
  • 22 Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Italy. iliovit@gmail.com.
  • # Contributed equally.
PMID: 33531658 DOI: 10.1038/s41418-020-00733-4
Abstract

Cancer Stem Cells (CSCs) are tumor subpopulations driving disease development, progression, relapse and therapy resistance, and their targeting ensures tumor eradication. CSCs display heterogeneous replication stress (RS), but the functionality/relevance of the RS response (RSR) centered on the ATR-CHK1 axis is debated. Here, we show that the RSR is efficient in primary CSCs from colorectal Cancer (CRC-SCs), and describe unique roles for PARP1 and MRE11/RAD51. First, we demonstrated that PARP1 is upregulated in CRC-SCs resistant to several replication poisons and RSR inhibitors (RSRi). In these cells, PARP1 modulates replication fork speed resulting in low constitutive RS. Second, we showed that MRE11 and RAD51 cooperate in the genoprotection and mitosis execution of PARP1-upregulated CRC-SCs. These roles represent therapeutic vulnerabilities for CSCs. Indeed, PARP1i sensitized CRC-SCs to ATRi/CHK1i, inducing replication catastrophe, and prevented the development of resistance to CHK1i. Also, MRE11i + RAD51i selectively killed PARP1-upregulated CRC-SCs via mitotic catastrophe. These results provide the rationale for biomarker-driven clinical trials in CRC using distinct RSRi combinations.

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