Maintenance of genome integrity during cell renewal is instrumental for preserving cell identity, functions and survival. Our team aims to determine how genetic alterations are transmitted during the earliest stages of tumorigenesis.
More specifically, our research focuses on DNA damage checkpoint signaling pathways, which coordinate DNA repair and prevent the propagation of genetic alterations to daughter cells. Increasing evidence indicates that these checkpoint pathways possess intrinsic functional limitations that remain poorly understood at the molecular level. Because the transmission of DNA damage is a rare event, our approach relies heavily on single-cell analyses to capture and characterize heterogeneous cell behaviors. In parallel, the team has developed a unique expertise in combining quantitative live-cell imaging with innovative kinase activity biosensors, enabling us to monitor checkpoint activation dynamics and regulatory mechanisms in real time across various stress conditions.
Axis 1 — Intrinsic limitations of DNA damage checkpoints, underlying mechanisms and consequences for genome integrity
Our current projects investigate the ATR/Chk1 and ATM/Chk2 DNA damage checkpoint pathways, which are activated in response to highly deleterious single-strand (SSBs) and double-strand DNA breaks (DSBs), respectively. These signaling pathways are essential guardians of genome stability and play a critical role in preventing tumor development. However, under conditions of persistent or irreparable DNA damage, checkpoint signaling can be bypassed through a process known as checkpoint adaptation. This phenomenon has been widely observed in several organisms and is associated with chromosomal instability as well as acquired resistance to genotoxic treatments
Our research seeks to address several fundamental questions:
By answering these questions, we aim to uncover how these mechanisms may fuel cancer progression and therapeutic resistance.
Axis 2 — DNA damage checkpoint signatures and therapeutic opportunities in ovarian cancers
Perturbed DNA replication leading to replication stress and chronic ATR/Chk1 activation are hallmarks of many precancerous and cancerous lesions, resulting from the activation of various oncogenes. In addition, some cancers, such as breast and ovarian cancers, frequently harbor BRCA mutations, leading to defects in double-strand DNA break repair controlled by ATM/Chk2 signaling.
How do tumor cells continue to proliferate despite sustained and recurrent DNA damage checkpoint activation? Using ovarian cancer as a model system, and in collaboration with the GM & PD teams, we are investigating whether tumor cell proliferation depends on:
These distinct scenarios may confer differential sensitivities to checkpoint inhibition–based therapeutic strategies currently under clinical trials.
Our objective is to improve the prediction of treatment responses by identifying checkpoint signaling signatures associated with specific genetic backgrounds and oncogenic driver mutations in ovarian tumors.
