CV Science

Jean Marc PASCUSSI PhD Cell Biology

Course and current status

Since 2010: Team "Signalling and Cancer", CNRS 5203 - INSERM U661 UM1&2. Institut de génomique fonctionnelle (Dir JP Pin, P MARIN, S GRANIER) , 141 rue de Navacelle, 34 Montpellier, France

2006-2010: Team "nuclear receptor and drug metabolism", INSERM U632, Dir P Maurel, 1919 route de Mende, 34 Montpellier, France.

2001-2006: Team "liver physiology", INSERM U128, Dir C Balny, 1919 route de Mende, 34 Montpellier, France.

2000-2001: Postdoctoral position National Institute of Health and Environmental Sciences (NIEHS), Triangle park research, Chapell Hill, NC- USA

Scientific summary

Jean-Marc Pascussi is an INSERM researcher at the Institute of Functional Genomics (IGF), University of Montpellier, CNRS and INSERM, whose research has focused for more than two decades on the molecular mechanisms controlling xenobiotic metabolism, nuclear receptor signaling, cancer progression and therapeutic resistance. His scientific career has been characterized by a progressive transition from fundamental studies of drug metabolism regulation toward translational oncology, with a particular emphasis on the Pregnane X Receptor (PXR/NR1I2) as a key molecular interface between environmental exposure, metabolism and cancer biology.

Nuclear receptors and regulation of xenobiotic metabolism (2001–2010)

At the beginning of his career, Jean-Marc Pascussi contributed to the understanding of how nuclear receptors regulate hepatic adaptation to chemical exposure and drug metabolism. His work focused particularly on the Pregnane X Receptor (PXR), a ligand-activated transcription factor acting as a central sensor of foreign compounds and a regulator of genes involved in detoxification pathways, including cytochromes P450 (CYP), conjugation enzymes and transporters.

One of his important contributions was the characterization of PXR-dependent regulation of metabolic pathways involved in drug response. His studies demonstrated that activation of PXR could strongly modify the expression of enzymes responsible for the metabolism of clinically important molecules. This work helped establish the concept that nuclear receptor-mediated adaptation to xenobiotics represents an important determinant of pharmacological variability and treatment outcome.

In collaboration with clinicians and molecular biologists, Pascussi also investigated the role of PXR in human diseases linked to altered metabolism. His studies contributed to identifying PXR-dependent mechanisms involved in drug-induced metabolic disorders, including the regulation of vitamin D metabolism through CYP24 expression.

PXR and cancer drug resistance (2010–2020)

A major turning point in Jean-Marc Pascussi’s research was the demonstration that PXR is not only a metabolic regulator but also a critical determinant of cancer cell adaptation and resistance to chemotherapy.

Working in colorectal cancer models, his team showed that PXR expression in tumor cells contributes to reduced sensitivity to irinotecan, one of the major chemotherapeutic agents used in colorectal cancer treatment. Mechanistically, PXR activation promoted the expression of metabolic pathways responsible for enhanced inactivation of SN-38, the active metabolite of irinotecan, thereby limiting therapeutic efficacy.

These findings introduced the concept that tumor-associated metabolic reprogramming is not merely a consequence of cancer progression but can actively participate in treatment failure. The work positioned PXR as a potential therapeutic target to overcome chemotherapy resistance.

During this period, Pascussi’s research expanded toward cancer stem cells and tumor relapse. His team investigated how metabolic adaptation pathways controlled by nuclear receptors influence tumor cell plasticity, survival after treatment and the emergence of drug-tolerant populations. This research contributed to the understanding that residual cancer cells surviving chemotherapy represent a major source of relapse and that targeting their adaptive mechanisms could improve long-term therapeutic outcomes.

Development of innovative therapeutic strategies targeting PXR (2020–)

Because classical PXR antagonists have shown limitations, Jean-Marc Pascussi moved toward the development of innovative molecular approaches aimed at directly eliminating PXR protein from cancer cells. This strategy led to the design of a new class of targeted protein degradation molecules: PXR-directed PROTACs (PROteolysis TArgeting Chimeras).

Through interdisciplinary collaborations involving medicinal chemistry, structural biology and cancer biology groups in Montpellier, his team developed the PROTAC molecule JMV7048, designed to induce selective degradation of human PXR through recruitment of the CRBN E3 ubiquitin ligase and activation of the 26S proteasome degradation pathway.

Published in 2025, this work demonstrated that pharmacological degradation of PXR reduced cancer cell stemness properties, impaired tumor initiation capacity and delayed colorectal cancer relapse in experimental models. Importantly, the study showed that targeting a metabolic regulator such as PXR could represent a novel therapeutic strategy complementary to conventional chemotherapy.

This research represents a significant conceptual advance: rather than blocking only the transcriptional activity of PXR, PROTAC technology allows elimination of the receptor itself, potentially overcoming limitations associated with conventional antagonists.