TY - JOUR
T1 - Control of replication stress and mitosis in colorectal cancer stem cells through the interplay of PARP1, MRE11 and RAD51
AU - Manic, Gwenola
AU - Musella, Martina
AU - Corradi, Francesca
AU - Sistigu, Antonella
AU - Vitale, Sara
AU - Soliman Abdel Rehim, Sara
AU - Mattiello, Luca
AU - Malacaria, Eva
AU - Galassi, Claudia
AU - Signore, Michele
AU - Pallocca, Matteo
AU - Scalera, Stefano
AU - Goeman, Frauke
AU - De Nicola, Francesca
AU - Guarracino, Andrea
AU - Pennisi, Rosa
AU - Antonangeli, Fabrizio
AU - Sperati, Francesca
AU - Baiocchi, Marta
AU - Biffoni, Mauro
AU - Fanciulli, Maurizio
AU - Maugeri-Saccà, Marcello
AU - Franchitto, Annapaola
AU - Pichierri, Pietro
AU - De Maria, Ruggero
AU - Vitale, Ilio
N1 - Funding Information:
Funding This work was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC, IG 2017 grant number 20417 to IV; AIRC 5 × 1000 grant number 9979 to RDM; Start-Up 2016 grant number 18418 to AS), Ministero Italiano della Salute (grant number RF_GR-2011-02351355 to IV; RF-2018-12367044 to RDM; RF_GR-2013-02357273 to AS; RF-2016-02362022 to PP). IV is also supported by a startup grant from the Italian Institute for Genomic Medicine (Can-diolo, Turin, Italy) and Compagnia di San Paolo (Turin, Italy).
Publisher Copyright:
© 2021, The Author(s).
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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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U2 - 10.1038/s41418-020-00733-4
DO - 10.1038/s41418-020-00733-4
M3 - Article
AN - SCOPUS:85100306227
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
SN - 1350-9047
ER -