Biology subjects

Cormier, K.

Publications and source records attributed to Cormier, K..

7 recordsLinked to original sources

bioRxiv2026

Radiation therapy synergizes with mRNA vaccination to overcome microglia-mediated suppression of dendritic cell migration and T cell priming in glioblastoma

Glioblastomas (GBMs) are uniformly fatal brain tumors resistant to immunotherapy, yet the mechanisms driving immune dysfunction remain poorly understood. Here we identify a tissue-specific mechanism of dendritic cell (DC) dysfunction contributing to GBM immune evasion. We demonstrate that while systemic immunity depends on type 1 conventional DCs (cDC1s), GBMs preferentially accumulate cDC2s with impaired antigen-presenting capacity. Further, microglia-derived GAS6 and PROS1 signaling through the AXL receptor on DCs suppresses DC activation and, critically, migration to tumor-draining lymph nodes. Pharmacologic AXL inhibition enhances DC migration and consequently anti-tumor immunity. Importantly, radiation therapy activates cDC1-mediated endogenous immune responses, which synergizes with mRNA vaccination to promote complete and durable immune-mediated tumor regression. These findings establish DC-mediated immunity as a therapeutic target in brain tumors and reveal a synergistic mechanism for combining radiation with personalized cancer vaccines.

cancer biology↗

bioRxiv2025

The Pdgfd-Pdgfrb axis orchestrates tumor-nerve crosstalk in pancreatic cancer

Nerves are an integral component of the tumor microenvironment, contributing to cancer progression, metastasis, morbidity, and mortality. In pancreatic ductal adenocarcinoma (PDAC), worse clinical outcomes are associated with perineural invasion (PNI), a process by which cancer cells surround and invade nerves. Here, we employed whole-transcriptome and single-cell spatial transcriptomics to identify candidate tumor-nerve interactions that promote PNI. We discovered that Pdgfd signaling promotes key features of nerve invasion. Mechanistically, Pdgfd stimulated cancer cell invasiveness, neurite outgrowth, and direct physical engagement with glia. Pharmacological blockade of this axis reduced each of these processes in vitro as well as PNI in vivo. Thus, Pdgfd-Pdgfrb signaling mediates PNI by coordinating multifaceted cancer-neuron-glia interactions and represents a promising therapeutic strategy aimed at disrupting harmful cancer-nerve crosstalk.

cancer biology↗

bioRxiv2025

Hyperglycemia worsens smooth muscle foam cell formation through PI3Kgamma-dependent defective autophagy

BackgroundDiabetes significantly increases the risk of cardiovascular complications, particularly through the mechanisms of atherosclerosis. In this context, uncontrolled hyperglycaemia is a key contributor to arterial dysfunctions. However, the specific effects of elevated glucose levels on smooth muscle cells (SMC)-derived foam cells formation remain poorly defined. MethodsUsing a wire injury-based accelerated atherosclerosis mouse model combined to lipid biochemistry and cellular lipid imaging approaches, we analysed molecular mechanisms involved in SMC derived foam cell formation. ResultsOur findings demonstrated that hyperglycaemia induced a specific lipid loading in SMC in an accelerated atherosclerosis mice model. In vitro, high glucose concentration negatively affected autophagic process independently of lipid uptake and efflux in human and mouse primary SMC. Consistently, treatment with autophagy activators successfully reduced lipid droplet formation. Mechanistically, we identified that PI3K{psi} activity impaired autophagy through TFEB phosphorylation promoting SMC foam cells formation in response to high glucose. ConclusionThese findings shed light on the mechanisms underlying SMC homeostasis disruption under hyperglycemic conditions and underscore the potential therapeutic window for PI3K{psi} inhibitor in managing cardiovascular diseases in diabetic patients.

cell biology↗

bioRxiv2024

Comparative analysis of dietary iron deprivation and supplementation in a murine model of colitis

Inflammatory bowel diseases are chronic inflammatory conditions with growing prevalence in western populations. Iron is an essential component of erythrocytes hemoglobin. Under the influence of elevated hepcidin production, iron is sequestered in cells during inflammation which, in turn, leads to iron restriction for red blood cells synthesis. As a consequence, iron deficiency and anemia of inflammation are the most prevalent extraintestinal complications in IBD patients. Patients are thus treated with oral iron supplements that have limited efficacy as iron absorption is blunted during intestinal inflammation. Moreover, iron supplementation can cause intestinal complications and previous studies have shown that iron supplementation worsens the inflammatory response. However, a comparative analysis of the effects of low, adequate and high dietary iron content matching iron the supplementation given to patients has not been performed in mice. We therefore tested the impact of dietary iron deprivation and supplementation in a murine model of colitis induced by dextran sodium sulfate. We found that both dietary iron deprivation and supplementation were accompanied by a more severe inflammation with earlier signs of gastrointestinal bleeding compared to mice fed an iron adequate diet. The manipulation of dietary iron led to a comparable oxidative stress and a pronounced dysbiosis in the colon of control mice that differed depending on the dietary iron content. Analysis of these dysbiosis is in line with a pronounced susceptibility to colonic inflammation thus questioning the benefit/risk balance of oral iron supplementation for IBD patients.

pathology↗

bioRxiv2023

The hepatokine FGL1 regulates hepcidin and iron metabolism during the recovery from hemorrhage-induced anemia in mice

As a functional component of erythrocyte hemoglobin, iron is essential for oxygen delivery to all tissues in the body. The liver-derived peptide hepcidin is the master regulator of iron homeostasis. During anemia, the erythroid hormone erythroferrone regulates hepcidin synthesis to ensure adequate supply of iron to the bone marrow for red blood cells production. However, mounting evidence suggested that another factor may exert a similar function. We identified the hepatokine FGL1 as a previously undescribed suppressor of hepcidin that is induced in the liver in response to hypoxia during the recovery from anemia and in thalassemic mice. We demonstrated that FGL1 is a potent suppressor of hepcidin in vitro and in vivo. Deletion of Fgl1 in mice results in a blunted repression of hepcidin after bleeding. FGL1 exerts its activity by direct binding to BMP6, thereby inhibiting the canonical BMP-SMAD signaling cascade that controls hepcidin transcription. Key points1/ FGL1 regulates iron metabolism during the recovery from anemia. 2/ FGL1 is an antagonist of the BMP/SMAD signaling pathway.

physiology↗

bioRxiv2022

Ablative radiotherapy improves survival in autochthonous cancer mouse models

Genetically engineered mouse models (GEMMs) of cancer are powerful tools to study mechanisms of disease progression and therapy response, yet little is known about how these models respond to multimodality therapy used for curative intent in patients. Radiation therapy (RT) is frequently used to treat localized cancers with curative intent, delay progression of oligometastases, and palliate symptoms of metastatic disease. RT can be combined with surgery, systemic therapy, and/or immunotherapy for definitive treatment of solid tumors. Here we report the development, testing, and validation of a murine platform that faithfully emulates human stereotactic ablative radiotherapy (SABR). We demonstrate that SABR regimens used in clinical practice can be effectively delivered in mouse models and establish the intestinal tract as the dose limiting organ for abdominopelvic radiation with notable, but transient, lymphodepletion. SABR alters tumor stroma and immune environment, improves survival in GEMMs of primary prostate and colorectal cancer, and synergizes with androgen deprivation in prostate cancer. While SABR is capable of fully ablating xenografts it is unable to completely eradicate disease in GEMMs. These data show that some GEMMs are resistant to curative therapy suggesting the existence of treatment-resistant persister cells in these models.

cancer biology↗

bioRxiv2018

STF-62247 blocks late stages of autophagy by disrupting lysosomal physiology

STF-62247 was previously identified as a promising compound able to selectively target the loss of the tumor suppressor gene von Hippel-Lindau (VHL) in renal cell carcinomas. This present work investigates the effect of STF-62247 on the autophagic flux. Our investigations show that STF-62247 blocks late stages of autophagy through lysosomal disruption. Indeed, STF-62247 localizes at lysosomes and causes unregulated swelling of these acidic compartments in VHL-mutated cells, linking a potential role for VHL in lysosomal integrity. Knock-outs of BECN1 and ATG5 were able to rescue the viability of VHL-mutated cells in response to STF-62247 but did not rescue the lysosomal swelling. In fact, neutralizing the lysosomal pH by inhibiting the vacuolar H+-ATPase completely rescued this phenotype. Moreover, we show that STF-62247 disrupts endocytic routes and causes cathepsin D trafficking defects. This mechanistic study is the first to characterize STF-62447 as a novel lysosomotropic compound. Importantly, our study re-classifies STF-62247 as a blocker of later stages of autophagy and highlights its potential usage as a powerful new tool for endocytic and autophagy-related research.

cancer biology↗