Cancer epithelia-derived mitochondrial DNA is a targetable initiator of a paracrine signaling loop that confers taxane resistance.

Stromal-epithelial interactions dictate cancer progression and therapeutic response. Prostate cancer (PCa) cells were identified to secrete greater concentration of mitochondrial DNA (mtDNA) compared to noncancer epithelia. Based on the recognized coevolution of cancer-associated fibroblasts (CAF) with tumor progression, we tested the role of cancer-derived mtDNA in a mechanism of paracrine signaling. We found that prostatic CAF expressed DEC205, which was not expressed by normal tissue-associated fibroblasts. DEC205 is a transmembrane protein that bound mtDNA and contributed to pattern recognition by Toll-like receptor 9 (TLR9). Complement C3 was the dominant gene targeted by TLR9-induced NF-κB signaling in CAF. The subsequent maturation complement C3 maturation to anaphylatoxin C3a was dependent on PCa epithelial inhibition of catalase in CAF. In a syngeneic tissue recombination model of PCa and associated fibroblast, the antagonism of the C3a receptor and the fibroblastic knockout of TLR9 similarly resulted in immune suppression with a significant reduction in tumor progression, compared to saline-treated tumors associated with wild-type prostatic fibroblasts. Interestingly, docetaxel, a common therapy for advanced PCa, further promoted mtDNA secretion in cultured epithelia, mice, and PCa patients. The antiapoptotic signaling downstream of anaphylatoxin C3a signaling in tumor cells contributed to docetaxel resistance. The inhibition of C3a receptor sensitized PCa epithelia to docetaxel in a synergistic manner. Tumor models of human PCa epithelia with CAF expanded similarly in mice in the presence or absence of docetaxel. The combination therapy of docetaxel and C3 receptor antagonist disrupted the mtDNA/C3a paracrine loop and restored docetaxel sensitivity

Heterogeneous cancer-associated fibroblast population potentiates neuroendocrine differentiation and castrate resistance in a CD105-dependent manner.

Heterogeneous prostatic carcinoma-associated fibroblasts (CAF) contribute to tumor progression and resistance to androgen signaling deprivation therapy (ADT). CAF subjected to extended passaging, compared to low passage CAF, were found to lose tumor expansion potential and heterogeneity. Cell surface endoglin (CD105), known to be expressed on proliferative endothelia and mesenchymal stem cells, was diminished in high passage CAF. RNA-sequencing revealed SFRP1 to be distinctly expressed by tumor-inductive CAF, which was further demonstrated to occur in a CD105-dependent manner. Moreover, ADT resulted in further expansion of the CD105+ fibroblastic population and downstream SFRP1 in 3-dimensional cultures and patient-derived xenograft tissues. In patients, CD105+ fibroblasts were found to circumscribe epithelia with neuroendocrine differentiation. CAF-derived SFRP1, driven by CD105 signaling, was necessary and sufficient to induce prostate cancer neuroendocrine differentiation in a paracrine manner. A partially humanized CD105 neutralizing antibody, TRC105, inhibited fibroblastic SFRP1 expression and epithelial neuroendocrine differentiation. In a novel synthetic lethality paradigm, we found that simultaneously targeting the epithelia and its microenvironment with ADT and TRC105, respectively, reduced castrate-resistant tumor progression, in a model where either ADT or TRC105 alone had little effect

Caractérisation in vitro et in vivo d'un mutant "Gain de Fonction" du récepteur AT1a de l'angiotensine II

L'Angiotensine II (AngII) est le principal effecteur du Système-Rénine-Angiotensine-Aldostérone (SRAA) et participe à la régulation de la pression artérielle (PA) et de l'équilibre hydroélectrolytique. L AngII agit sur ses tissus cibles par l'intermédiaire de récepteurs couplés aux protéines G comme le récepteur AT1. Le but de ce travail était de caractériser le phénotype in vitro et in vivo d un mutant gain de fonction du récepteur AT1A de l AngII. Le mutant choisi associait une mutation constitutivement activatrice et une délétion qui altère la désensibilisation du récepteur. L expression de ce mutant chez la souris conduit à une hypertension artérielle modérée, une absence de désensibilisation à l AngII, une modification du SRAA et une altération de la fonction cardiaque. Ce nouveau modèle de souris transgéniques ouvre des perspectives pour l étude des mécanismes régulant la PA et pour le rôle direct de l AngII à travers le récepteur AT1A sur les organes cibles du SRAA.PARIS5-BU-Necker : Fermée (751152101) / SudocSudocFranceF

Le rôle de la matrice extracellulaire dans la régénération des nerfs moteurs

International audienceThe motor neurons (MN) form the ultimate route to convey the commands from the central nervous system to muscles. During development, MN extend axons that follow stereotyped trajectories to their muscle targets, guided by various attractive and repulsive molecular cues. Extracellular matrix (ECM) is a major source of guidance cues, but its role in axonal development and regeneration remains poorly documented. Regenerating axons are able to return to their synaptic target following their original trajectory. The same guidance cues could be thus involved in motor nerve regeneration. Zebrafish has become a popular model system in understanding the development of the peripheral nervous system. Thanks to the generation of fluorescent transgenic lines and the optical transparency of embryos and larvae, it allows direct visualization of axonogenesis. Additionally, and contrary to humans, its remarkable capacity to regenerate makes it well suited for the study of nerve regeneration. A laser method to ablate nerves in living zebrafish larvae has been developed in our laboratory that, combined with the use of the fluorescent mnx1:gfp zebrafish transgenic line, allows the follow up of the dynamics of the nerve regeneration process. To study the role of ECM proteins present in the axonal path, mutant lines for different ECM proteins (already available in our laboratory or generated in mnx1:gfp fish using CRISPR-Cas9 method) will be used to analyze their role during the regeneration process. These mutant lines for ECM will be crossed with existing fluorescent transgenic lines to visualize different cell types involved in the nerve regeneration, such as macrophages ( mfap4:mcherry ), neutrophils ( mpx:gfp ) or even Schwann cells ( sox10:mrfp ). Overall, this study will depict the role of ECM in nerve regeneration and will provide essential knowledge for the development of new biomaterials to promote the regeneration of injured motor nerves

Antagonizing Glutamine Bioavailability Promotes Radiation Sensitivity in Prostate Cancer

Nearly half of localized prostate cancer (PCa) patients given radiation therapy develop recurrence. Here, we identified glutamine as a key player in mediating the radio-sensitivity of PCa. Glutamine transporters and glutaminase are upregulated by radiation therapy of PCa cells, but respective inhibitors were ineffective in radio-sensitization. However, targeting glutamine bioavailability by L-asparaginase (L-ASP) led to a significant reduction in clonogenicity when combined with irradiation. L-ASP reduced extracellular asparagine and glutamine, but the sensitization effects were driven through its depletion of glutamine. L-ASP led to G2/M cell cycle checkpoint blockade. As evidence, there was a respective delay in DNA repair associated with RAD51 downregulation and upregulation of CHOP, contributing to radiation-induced cell death. A radio-resistant PCa cell line was developed, was found to bypass radiation-induced mitotic catastrophe, and was sensitive to L-ASP/radiation combination treatment. Previously, PCa-associated fibroblasts were reported as a glutamine source supporting tumor progression. As such, glutamine-free media were not effective in promoting radiation-induced PCa cell death when co-cultured with associated primary fibroblasts. However, the administration L-ASP catalyzed glutamine depletion with irradiated co-cultures and catalyzed tumor volume reduction in a mouse model. The clinical history of L-ASP for leukemia patients supports the viability for its repurposing as a radio-sensitizer for PCa patients

Evaluation des fermetures spatio-temporelles mises en oeuvre à partir du 1er janvier 2020 pour la pêche au chalut en mer Méditerranée

L’examen des captures de juvéniles de merlu réalisées en 2020 montre une diminution de 55% par rapport à la moyenne sur la période 2015-2017 (223 tonnes contre 500 tonnes), tandis que la zone de fermeture concernée, quelles que soient les composantes de stocks concernés (merlu et rouget, juvéniles et adultes), contribue entre 15 à 20 % aux captures, et entre 30 et 40 % aux abondances estimées par la campagne MEDITS. En outre, la zone de fermeture englobe également des zones sensibles du point de vue des peuplements benthiques. En l’état des connaissances actuelles, la zone de fermeture mise en place au 1er Janvier 2020 semble montrer une bonne efficacité au regard des critères mis en avant par la Commission européenne et le CSTEP. Cette forte baisse pour le merlu est la conséquence de la mise en place des fermetures spatio-temporelles décidées par la France, mais également, pour partie, de la réduction d’effort des chalutiers de 10% conformément au plan de gestion, l’effet de la pandémie COVID-19 étant estimé négligeable. En revanche, pour le rouget, les augmentations de captures, consécutives aux bons recrutements récents, ne permettent pas de statuer sur l’efficacité de ces mesures sur cette espèce

ARID1A Deficiency Regulates Anti-Tumor Immune Response in Esophageal Adenocarcinoma

ARID1A, a member of the chromatin remodeling SWI/SNF complex, is frequently lost in many cancer types, including esophageal adenocarcinoma (EAC). Here, we study the impact of ARID1A deficiency on the anti-tumor immune response in EAC. We find that EAC tumors with ARID1A mutations are associated with enhanced tumor-infiltrating CD8+ T cell levels. ARID1A-deficient EAC cells exhibit heightened IFN response signaling and promote CD8+ T cell recruitment and cytolytic activity. Moreover, we demonstrate that ARID1A regulates fatty acid metabolism genes in EAC, showing that fatty acid metabolism could also regulate CD8+ T cell recruitment and CD8+ T cell cytolytic activity in EAC cells. These results suggest that ARID1A deficiency shapes both tumor immunity and lipid metabolism in EAC, with significant implications for immune checkpoint blockade therapy in EAC

Bone marrow mesenchymal stem cells interact with head and neck squamous cell carcinoma cells to promote cancer progression and drug resistance.

Head and neck cancers are often diagnosed at later stages with poor outcomes. Mesenchymal stem cells (MSC) are recruited to primary tumor sites where they can have pro- and antitumorigenic influence. In trying to better understand the dynamics between MSC and cancer cells, we found that head and neck cancer-MSC exposure resulted in mesenchymal features, elevated proliferation rate, and were more motile, like the same cells that fused with MSC. We orthotopically grafted the parental head and neck cancer cells, those fused with MSC, or those exposed to MSC into the tongues of mice. The cancer cells originally incubated with MSC developed larger more aggressive tumors compared to the parental cell line. RNA sequencing analysis revealed the expression of genes associated with drug resistance in the cancer cells exposed to MSC compared to parental cancer cells. Strikingly, MSC exposed cancer cell lines developed paclitaxel resistance that could be maintained up to 30 d after the initial co-incubation period. The secretory profile of the MSC suggested IL-6 to be a potential mediator of epigenetic imprinting on the head and neck cancer cells. When the MSC-imprinted cancer cells were exposed to the demethylation agent, 5-aza-2'deoxycytidine, it restored the expression of the drug resistance genes to that of parental cells. This study demonstrated that the recognized recruitment of MSC to tumors could impart multiple protumorigenic properties including chemotherapy resistance like that observed in the relatively rare event of cancer/MSC cell fusion