Biology subjects

Cordelier, P.

Publications and source records attributed to Cordelier, P..

10 recordsLinked to original sources

bioRxiv2026

A genome-wide CRIPR-Cas9 screen identifies TGN46 as a host determinant for H-1PV susceptibility in pancreatic adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal malignancy with limited response to current therapeutic strategies. Oncolytic viruses such as the rat protoparvovirus H-1PV represent promising alternatives; however, their clinical development is hindered by an incomplete understanding of virus-host interactions that determine tumor susceptibility. Here, we conducted a genome-scale CRISPR-Cas9 knockout screen in primary PDAC cultures to identify host determinants of viral infection and cytotoxicity. The screen confirmed the central role of the sialylation pathway in mediating susceptibility to H-1PV and uncovered several additional genes involved in vesicular trafficking and protein recycling. Among these candidates, TGOLN2, encoding the transmembrane protein TGN46, emerged as a critical host factor. Functional analyses demonstrate that TGN46 supports efficient H-1PV infection, replication, and virus-induced cytotoxicity in pancreatic cancer cells. TGN46 colocalizes with viral particles at the cell surface and facilitates their internalization through dynamin-dependent endocytosis. Molecular studies further indicate that the luminal N-terminal domain of TGN46 interacts with the viral capsid. In vivo, TGOLN2 expression in essential to H-1PV-mediated antitumor activity in experimental models. Collectively, these findings identify TGN46 as a membrane-associated entry factor required for optimal H-1PV infection in PDAC cells. This work refines the mechanistic understanding of H-1PV tropism and provides a rationale for exploring host determinants of viral susceptibility as candidate biomarkers to guide parvovirus-based virotherapy.

cancer biology↗

bioRxiv2025

SG33, a vaccine strain of myxoma virus with oncolytic potential, exploits macropinocytosis and clathrin-mediated endocytosis for entry into pancreatic cancer cells.

Oncolytic viruses are being investigated as therapeutic agents in cancer, yet their mechanisms of entry into tumor cells remain incompletely understood. We previously showed that SG33, a veterinary vaccinal strain derived from a pathogenous myxoma virus, displays oncolytic activity in preclinical models of pancreatic ductal adenocarcinoma (PDAC). Here, we investigated the entry pathways of SG33 into primary PDAC-derived cultures. We found that macropinocytosis, an endocytic process frequently upregulated in PDAC, contributes to SG33 uptake. Moreover, SG33 infection itself induced macropinocytosis in a subset of primary PDAC cultures. Mechanistic studies revealed that phosphatidylserine exposed on the viral envelope promotes SG33 internalization through apoptotic mimicry. In PDAC cultures lacking detectable macropinocytosis, SG33 employed clathrin-mediated endocytosis as an alternative entry route. These findings provide the first insights into the entry mechanisms of SG33 into PDAC-derived cells and indicate that this virus can utilize distinct endocytic pathways depending on the cellular context. ImportancePancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers, with limited therapeutic options. Oncolytic virotherapy is emerging as a promising strategy to overcome treatment resistance, yet the mechanisms by which candidate viruses enter cancer cells remain poorly defined. Here, we characterize the entry route of SG33, a derivative of myxoma virus with potent oncolytic activity in PDAC models. We show that SG33 exploits multiple endocytic pathways, including macropinocytosis (MPC), induces MPC through apoptotic mimicry, and also uses clathrin-mediated endocytosis (CME). These findings provide the first evidence that SG33 has evolved a flexible cell entry strategy, which could enhance its efficacy in the heterogeneous context of PDAC. Understanding the molecular determinants of viral entry is essential for the rational design of improved oncolytic virotherapies. Our study is aligned with this objective and highlights SG33 as a promising candidate to expand the toolbox of virotherapeutic agents against aggressive cancers.

cancer biology↗

bioRxiv2025

Monitoring the poroelastic response of collagen gels with embedded senescent fibroblasts reveals tissue softening associated with collagen network reorganization

The poroelastic properties of tissues regulate molecular transport and mechanical signaling, yet their evolution during aging remains poorly understood. In particular, senescent fibroblasts accumulate in aged tissues, contributing to extracellular matrix (ECM) remodeling, but their impact on tissue mechanics and permeability is unclear. In this study, we developed a microfluidic-based in vitro model to assess the poroelastic properties of collagen gels embedded with senescent fibroblasts over time. Our approach integrates periodic pressure actuation with real-time pressure monitoring in a sealed air cavity, enabling the detection of fluid permeation and solid matrix deformations. We analyze our data using analytical and numerical models based on a porohyperelastic framework. This framework combines compressible Neo-Hookean elasticity with the Kozeny-Carman permeability relationship. We demonstrate that senescent fibroblasts induce a progressive softening of the ECM without altering its permeability. Immunostaining reveals that this softening correlates with structural reorganization of the collagen network, characterized by increased branching and network remodeling. Our findings provide insights into the biomechanical effects of senescent fibroblasts on ECM homeostasis. We further argue that our platform offers a unique solution to investigate ECM remodeling not only in aging but also fibrosis, cancer progression, or regenerative medicine strategies.

biophysics↗

bioRxiv2023

The intrinsically disordered region of the E3 ubiquitin ligase TRIP12 induces the formation of chromatin condensates and interferes with DNA damage response.

Chromatin compaction is crucial for the faithful expression and integrity of the genome. Although largely studied, proteins and mechanisms that control the chromatin compaction are not entirely discovered. We previously showed that the nuclear HECT-type E3 ubiquitin ligase Thyroid hormone Receptor Interacting Protein 12 (TRIP12) is tightly associated to chromatin. As TRIP12 is overexpressed in several types of cancers, we explored herein the consequences of a TRIP12 overexpression on chromatin homeostasis. First, we established the TRIP12 proxisome and unveiled its pleiotropic role in chromatin regulation. Second, we demonstrated that TRIP12 overexpression leads to the formation of chromatin condensates enriched in heterochromatin marks via its intrinsically disordered region (IDR). We further discovered that the formation of TRIP12-mediated chromatin condensates is highly dynamic and driven by a mechanism of phase separation. Chromatin condensate formation depends on the TRIP12 concentration, the length of the TRIP12-IDR and relies on electrostatic interactions. We found that the formation of TRIP12 mediated-condensates alters cell cycle progression, genome accessibility, transcription as well as DNA damage response by inhibiting the accumulation of Mediator of DNA Damage Checkpoint 1 (MDC1). Altogether, this study reveals a novel dynamic role for TRIP12 in chromatin compaction independently of its ubiquitin ligase activity with important consequences on cellular homeostasis. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=155 SRC="FIGDIR/small/556486v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@13b3d90org.highwire.dtl.DTLVardef@46b991org.highwire.dtl.DTLVardef@1410bdeorg.highwire.dtl.DTLVardef@1722197_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

bioRxiv2023

Minute virus of mice is oncolytic for pancreatic cancer cells with mesenchymal phenotype

Pancreatic cancer will soon become the second cause of death by cancer in Western countries. The main barrier to increase the survival of patients with this disease requires the development of novel and efficient therapeutic strategies, that better consider tumor biology. Oncolytic viruses are quickly moving toward the forefront of medicines for the management of cancer. Among them, the fibrotropic minute virus of mice prototype (MVMp) preferentially infects migrating and undifferentiated cells, that highly resemble poorly differentiated, basal-like, pancreatic tumors showing the worst clinical outcome. Thus, we hypothesized that MVMp may specifically target the most aggressive subtype of pancreatic cancer cells. We report here that MVMp specifically infects, replicates in and kills pancreatic cancer cells from murine and human origin with a mesenchymal, basal-like profile, while sparing cancer cells with an epithelial phenotype. In vivo, MVMp shows oncolytic activity in experimental tumors with mesenchymal phenotype only, and shows increased antitumoral efficacy in immune competent models. Collectively, we demonstrate herein for the first time that MVMp is specific and oncolytic for pancreatic tumors with mesenchymal, basal-like profile, paving the way for precision medicine opportunities for the management of the most aggressive and lethal form of this disease.

cancer biology↗

bioRxiv2022

Preclinical development of non-viral gene therapy for patients with advanced pancreatic cancer

Pancreatic ductal adenocarcinoma remains one of the greatest challenges in oncology for which therapeutic intervention is urgently needed. We demonstrated that the intratumoral gene transfer of somatostatin receptor 2, to combat tumor aggressiveness, or of deoxycytidine kinase and uridylate monophosphate kinase, to sensitize to gemcitabine chemotherapy, has antitumoral potential. Here, we describe the development of CYL-02 non-viral gene-therapy product, that comprises a DNA-plasmid encoding for the three aforementioned genes complexed with PolyEthylEnimine (22 kDa). In this work, we performed preclinical toxicology, biodistribution and therapeutic activity studies of CYL-02 in experimental models of pancreatic cancer. We demonstrated the safety of CYL-02 and defined the maximal tolerated dose in two animal species. CYL-02 co-administrated with gemcitabine did not increase gemcitabine toxicity. Biodistribution studies revealed that CYL-02 is rapidly cleared from blood following intravenous administration, and sequestered in tumors following intratumoral injection. CYL-02 drives the expression of therapeutic genes in cancer cells and strongly sensitizes tumor cells to gemcitabine, with significant inhibition of tumor cells dissemination. This study was instrumental for the later use of CYL-02 in patients with advanced pancreatic cancer, demonstrating that rigorous and thorough preclinical investigations are informative for the clinical transfer of gene therapy against pancreatic cancer. GRAPHICAL ABSTRACT

cancer biology↗

bioRxiv2022

Cytidine deaminase regulates mitochondrial biogenesis in pancreatic cancer cells

Despite tremendous efforts from the scientific community, pancreatic ductal adenocarcinoma (PDAC) is still a deadly disease and will soon become the second cause of death by cancer worldwide1. When surgery is not possible, therapeutic options are few and ineffective2. Patients are most often treated with Folfirinox or gemcitabine chemotherapy, that extends survival in weeks to months. Cytidine deaminase (CDA) catalyzes the irreversible hydrolytic deamination of cytidine and deoxycytidine to uridine and deoxyuridine to fuel RNA and DNA synthesis3. CDA also deaminates and neutralizes deoxycytidine-based therapies, and as such, has been identified as a major contributor of tumor chemoresistance, especially to gemcitabine in PDAC3. We previously identified that CDA is elevated in PDAC tumors at diagnosis and that CDA exerts an unexpected role on DNA replication that can be exploited for therapeutic intervention4. Very recently, CDA was associated with cellular metabolism5. Here, we show that CDA promotes mitochondrial biogenesis and oxidative phosphorylation independently of its deaminase activity. This uncloaks novel therapeutic vulnerabilities in primary cancer cells that overexpress this protein. This study shines a new light on the tumoral potential of CDA in PDAC.

cancer biology↗

bioRxiv2021

Cytidine deaminase protects pancreatic cancer cells from replicative stress and drives resistance to DNA-targeting drugs

Chronic DNA replication stress and genome instability are two hallmarks of cancer that fuel oncogenesis and tumor diversity. Therapeutic approaches aimed to leverage tumor-specific replication stress to intolerable levels or to expose vulnerabilities for synthetic lethality purposes have recently gained momentum, especially for pancreatic cancer, a disease with no cure. However, the current knowledge regarding the molecular mechanisms involved in the replication stress response in pancreatic tumors is limited. Cytidine deaminase (CDA) is involved in the pyrimidine salvage pathway for DNA and RNA synthesis. Loss of CDA induces genomic instability in Bloom Syndrome, and CDA protects tumor cells from chemotherapy with pyrimidine analogs. Here, we show that CDA is overexpressed in genetically unstable pancreatic tumors, associates with a DNA replication signature, and is instrumental for experimental tumor growth. In cancer cells, CDA promotes DNA replication, increases replication fork speed, and controls replication stress and genomic stability levels. CDA expression is predictive of DNA-damaging drug efficacy and targeting CDA relieves resistance to chemotherapy in patients models, both in vitro and in vivo. Our findings shed new light on the mechanisms by which pancreatic cancer cells control replication stress, and highlight targeting of CDA as a potential therapeutic strategy to defeat tumor resistance to treatment.

cancer biology↗

bioRxiv2020

Pancreatic Cancer Intrinsic PI3Kα Activity accelerates Metastasis and rewires Macrophage Component

Pancreatic ductal adenocarcinoma (PDAC) patients frequently suffer from undetected micrometastatic disease. This clinical situation would greatly benefit from additional investigation. Therefore, we set out to identify key signalling events that drive metastatic evolution from the pancreas. We researched a gene signature that could discriminate localised PDAC from confirmed metastatic PDAC and devised a preclinical protocol using circulating cell-free DNA (cfDNA) as an early biomarker of micro-metastatic disease to validate the identification of key signalling events. Amongst actionable markers of disease progression, the PI3K pathway and a distinctive PI3K activation signature predict PDAC aggressiveness and prognosis. Pharmacological or tumour-restricted genetic PI3K-selective inhibition prevented macro-metastatic evolution by inhibiting tumoural cell migratory behaviour independently of genetic alterations. We found that PI3K inhibition altered the quantity and the species composition of the lipid second messenger PIP3 produced, with selective reduction of C36:2 PI-3,4,5-P3. PI3K inactivation prevented the accumulation of protumoural CD206-positive macrophages in the tumour-adjacent tissue. Tumour-cell intrinsic PI3K therefore promotes pro-metastatic features that could be pharmacologically targeted to delay macro-metastatic evolution. The paper explainedPROBLEM Pancreatic cancer is one of the most lethal solid cancers characterised by rapid progression after primary tumour detection by imaging. Key signalling events that specifically drives this rapid evolution into macro-metastatic disease are so far poorly understood. RESULT With two unbiased approaches to patient data analysis, higher PI3K pathway and more specifically higher PI3K activation signature can now be identified in the most aggressive pancreatic cancer primary tumours, that lead to earlier patient death. Our in vitro data showed that PI3K is a major positive regulator of tumour cell escape from the primary tumour: tumour-intrinsic PI3K activity enables actin cytoskeleton remodelling to escape the pancreatic tumour. We chose to use two preclinical models of pancreatic cancer to validate that PI3K is a target for delaying evolution of PDAC. The first one mimicked pancreatic patient micrometastatic disease that is undetected by echography and consisted in treating mice presenting echography detected primary tumours combined with increased circulating DNA as a blood biomarker of the most aggressive tumours. The second model consisted in studying the tumour cell implantation and their early proliferation in metastatic organ after injection in blood. We treated both preclinical models with a clinically relevant PI3K -selective inhibitor (BYL-719/Alpelisib), that is currently being tested in pancreatic cancer patients (without any patient selection). We found that PI3K activity drives evolution of micrometastatic disease towards macro-metastatic stage in both models: inhibition of PI3K delayed primary tumour and micro-metastasis evolution. Finally, PI3K activity increases protumoural characteristics in peritumoural immune cells via tumour cell-intrinsic cytokine production that could facilitate metastatic evolution. IMPACT Circulating tumour DNA represents a strong independent biomarker linked to relapse and poor survival in solid cancer patients. A clinical study in resected PDAC patients with micrometastatic disease characterised by high circulating tumoural DNA levels is needed to assess if PI3K-selective inhibitors significantly delay metastatic progression and death. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/307884v1_ufig1.gif" ALT="Figure 1"> View larger version (25K): org.highwire.dtl.DTLVardef@a5a8b4org.highwire.dtl.DTLVardef@1e6e18dorg.highwire.dtl.DTLVardef@e22859org.highwire.dtl.DTLVardef@1c7148b_HPS_FORMAT_FIGEXP M_FIG Pancreatic ductal adenocarcinoma requires tumour-intrinsic PI3K activity to accelerate inflammatory metastatic disease. Biorender illustration. C_FIG

cancer biology↗

bioRxiv2020

The antitumoral activity of TLR7 ligands is corrupted by the microenvironment of pancreatic tumors

Toll like receptors are key players in the innate immune system. Recent studies have suggested that they may impact the growth of pancreatic cancer, a disease with no cure. Among them, Toll like receptor-7 shows promise for therapy but may also promote tumor growth. Thus, we aimed to better understand the mechanism of action of Toll like receptor-7 ligands in pancreatic cancer, to open the door for clinical applications. In vitro, Toll like receptor-7 ligands strongly inhibit the proliferation and induce cell death by apoptosis of pancreatic cancer cells. In vivo, while Toll like receptor-7 agonists significantly delay the growth of aggressive tumors engrafted in immunodeficient mice, they instead surprisingly promote tumor growth and accelerate animal death in immunocompetent models. Molecular investigations revealed that Toll like receptor-7 agonists strongly increase the number of tumor-promoting macrophages to drive pancreatic tumorigenesis in immunocompetent mice. This is in stark contrast with Toll like receptor-7 ligands great potential to inhibit pancreatic cancer cell proliferation in vitro and tumor growth in vivo in immunosuppressed models. Collectively, our findings shine a light on the duality of action of Toll like receptor-7 agonists in experimental cancer models, and calls into question their use for pancreatic cancer therapy.

cancer biology↗