Biology subjects

Floris, G.

Publications and source records attributed to Floris, G..

9 recordsLinked to original sources

bioRxiv2026

Enhancing cGMP signaling with psilocybin reduces head twitch and restructures the synaptic proteome while maintaining antidepressant response

Psilocybin has antidepressant effects, but its 5-HT2AR-mediated perceptual effects limit tolerability. We combined psilocybin with a phosphodiesterase-9 inhibitor (PDE9i) and observed suppression of head-twitch response, but maintenance of antidepressant-like behavior. Proteomics showed that PDE9i-psilocybin reduced 5-HT2AR-mediated pathways while enhancing synaptogenesis. These results suggest that PDE9i-psilocybin represents a promising therapeutic strategy.

neuroscience↗

bioRxiv2024

Psilocybin reduces heroin seeking behavior and modulates inflammatory gene expression in the nucleus accumbens and prefrontal cortex of male rats

Preclinical and human studies indicate psilocybin may reduce perseverant maladaptive behaviors, including nicotine and alcohol seeking. Such studies in the opioid field are lacking, though opioids are involved in more >50% of overdose deaths. Psilocybin is an agonist at the serotonin 2A receptor (5-HT2AR), a well-documented target for modulation of drug seeking, and evidence suggests 5-HT2AR agonists may dampen motivation for opioids. We sought to investigate the therapeutic efficacy of psilocybin in mediating cessation of opioid use and maintenance of long-lasting abstinence from opioid seeking behavior in a rat model of heroin self-administration (SA). Psilocybin or 5-HT2AR antagonists ketanserin and volinanserin were administered systemically to rats prior to SA of 0.075 mg/kg/infusion of heroin, or relapse following forced abstinence. Psilocybin did not alter heroin taking, but a single exposure to 3.0 mg/kg psilocybin 4-24 hours prior to a relapse test blunted cue-induced heroin seeking. Conversely, 5-HT2AR antagonists exacerbated heroin relapse. To begin to elucidate mechanisms of psilocybin, drug-naive rats received psilocybin and/or ketanserin, and tissue was collected from the prefrontal cortex (PFC), a region critical for drug seeking and responsive to psilocybin, 24 hours later for RNA-sequencing. 3.0 mg/kg psilocybin regulated [~]2-fold more genes in the PFC than 1.0 mg/kg, including genes involved in the cytoskeleton and cytokine signaling. Ketanserin blocked >90% of psilocybin-regulated genes, including the IL-17a cytokine receptor, Il17ra. Psychedelic compounds have reported anti-inflammatory properties, and therefore we performed a gene expression array to measure chemokine/cytokine molecules in the PFC of animals that displayed psilocybin-mediated inhibition of heroin seeking. Psilocybin regulated 4 genes, including Il17a, and a subset of genes correlated with relapse behavior. Selective inhibition of PFC IL-17a was sufficient to reduce heroin relapse. We conclude that psilocybin reduces heroin relapse and highlight IL-17a signaling as a potential downstream pathway of psilocybin that also reduces heroin seeking.

neuroscience↗

bioRxiv2024

Prefrontal 5α-reductase 2 mediates male-specific acute stress response

A key response to acute stress is the increased brain synthesis of the neurosteroid allopregnanolone (AP). While the rate-limiting step of this reaction is catalyzed by 5-reductase (5R), the role of its two primary isoenzymes, 5R1 and 5R2, in stress reactivity remains unclear. Here, we found that acute stress led to increased levels of 5R2, but not 5R1, in the medial prefrontal cortex (mPFC) of male, but not female, rats. Downregulation of 5R2 in the mPFC significantly reduced stress response in males, and similar sexual dimorphic effects were observed in a novel line of 5R2 knockout rats. Notably, 5R1 regulated baseline AP synthesis, while 5R2 enabled AP production under stress. Acute AP administration restored stress response in 5R2 knockdown rats. Single-nucleus transcriptomics showed that 5R2 enabled stress-induced protein translation in neurons and glia. These results highlight the crucial role of 5R2 in mediating sex-specific differences in acute stress reactivity.

neuroscience↗

bioRxiv2022

A palmitate-rich metastatic niche enables metastasis growth via p65 acetylation

Cancer cells outgrowing in distant organs of metastasis rewire their metabolism to fuel on the available nutrients. While this is often considered an adaptive pressure limiting metastasis formation, some nutrients available at the metastatic site naturally or through changes in organ physiology may inherently promote metastatic growth. We find that the lung, a frequent site of metastasis, is a lipid-rich environment. Moreover, we observe that pathological conditions such as pre-metastatic niche formation and obesity further increase the availability of the fatty acid palmitate in the lung. We find that targeting palmitate processing inhibits spheroid growth in vitro and metastasis formation in lean and obese mice. Mechanistically, we discover that breast cancer cells use palmitate to synthesize acetyl-CoA in a carnitine palmitoyltransferase 1a (CPT1a)-dependent manner. Lysine acetyltransferase 2a (KAT2a), whose expression is promoted by palmitate availability, relies on the available acetyl-CoA to acetylate the NF-{kappa}B subunit p65. This favors nuclear location of p65 and activates a pro-metastatic transcriptional program. Accordingly, deletion of KAT2a phenocopies CPT1a silencing in vitro as well as in vivo and patients with breast cancer show co-expression of both proteins in metastases across palmitate-rich metastatic sites. In conclusion, we find that palmitate-rich environments foster metastasis growth by increasing p65 acetylation resulting in elevated NF-{kappa}B signaling.

cancer biology↗

bioRxiv2022

In vivo CRISPR screen defines Slc25a37 as an organ-specific regulator of antioxidant metabolism in metastasis

Withdrawal StatementThe authors have withdrawn their manuscript owing to the detection of inaccurate data analysis in some figure panels that leads in some but not all cases to a different interpretation of the data after corrected analysis. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.

cancer biology↗

bioRxiv2021

Anticancer immunotherapies transition postcapillary venules into high-endothelial venules that generate TCF1+ T lymphocyte niches through a feed-forward loop

The lack of T-cell infiltrates is a major obstacle to effective immunotherapy in cancer. Conversely, the formation of tumor-associated tertiary-lymphoid-like structures (TA-TLS), which are the local site of humoral and cellular immune responses against cancers, are associated with good prognosis and have recently been detected in Immune Checkpoint Blockade (ICB)-responding patients. However, how these lymphoid aggregates develop remains poorly understood. By employing scRNA sequencing, endothelial fate mapping, and functional multiplex immune profiling, we demonstrate that antiangiogenic immune-modulating therapies evoke the transition of postcapillary venules into inflamed high endothelial venules (HEVs), which generate permissive TA-TLS-like lymphocyte niches with PD1neg and PD1+TCF1+CD8 T cell progenitors that differentiate into GrzB+TCF1neg TIM3+ PD1+ CD8 T effector cells. Tumor-HEVs require continuous CD8 and NK cell-derived lymphotoxin signals revealing that tumor-HEV maintenance is actively sculpted by the adaptive immune system through a feed-forward loop. In BriefHua & Vella et al. reveal that effective antiangiogenic immunotherapy transitions postcapillary venules into inflamed high-endothelial venules (HEV), sustained by CD8 T and NK cell-derived signals through a feed-forward loop. Thereby, tumoral HEVs establish perivascular niches in which TCF1+ PD1+ lymphocytes expand and produce cytolytic PD1+ TIM3+ CD8 T cells that facilitate anti-tumoral immunity. HighlightsO_LIHigh endothelial venule induction by anticancer immunotherapies generates perivascular immune niches permissive for TCF1+ PD1+ CD8 progenitor T cell expansion and production of TCF1neg PD1+ TIM3+ CD8 effector T cells C_LIO_LITumoral high-endothelial venules exhibit characteristics of inflamed lymph node HEVs and postcapillary venules C_LIO_LIPostcapillary venules dynamically transdifferentiate into high-endothelial venules in tumors, which requires continuous signals from surrounding immune cells C_LIO_LICD8 and NK cells drive tumoral high-endothelial venule formation during antiangiogenic immunotherapies in a feed-forward loop via lymphotoxin beta receptor signaling C_LI

cancer biology↗

bioRxiv2020

The 5α-reductase inhibitor finasteride reduces opioid self-administration

Opioid use disorder (OUD) has become a leading cause of death in the US, yet current therapeutic strategies remain highly inadequate. To identify novel potential treatments for OUD, we screened a targeted selection of over 100 drugs, using a recently developed opioid self-administration assay in zebrafish. This paradigm showed that finasteride, a steroidogenesis inhibitor approved for the treatment of benign prostatic hyperplasia and androgenetic alopecia, reduced self-administration of multiple opioids without affecting locomotion or feeding behavior. These findings were confirmed in rats; furthermore, finasteride did not interfere with the antinociceptive effect of opioids in rat models of neuropathic pain. Steroidomic analyses of the brains of fish treated with finasteride revealed a significant increase in dehydroepiandrosterone sulfate (DHEAS). Treatment with precursors of DHEAS reduced opioid self-administration in zebrafish, in a fashion akin to the effects of finasteride. Our results highlight the importance of steroidogenic pathways as a rich source of therapeutic targets for OUD and point to the potential of finasteride as a new option for this disorder.

neuroscience↗

bioRxiv2020

The pleiotropic effects of the MNK1/2-eIF4E axis support immune suppression and metastasis in a model of postpartum breast cancer.

PurposeBreast cancer diagnosed within 10 years following childbirth is defined as postpartum breast cancer (PPBC) and is highly metastatic. Interactions between immune cells and other stromal cells within the involuting mammary gland are fundamental in facilitating an aggressive tumor phenotype. The MNK1/2-eIF4E axis promotes the translation of pro-metastatic mRNAs in tumor cells, but its role in modulating the function of non-tumor cells in the PPBC microenvironment, and in particular its activity in human PPBC, has not been explored. Experimental designWe used a combination of in vivo PPBC models and in vitro assays to study the effects of phospho-eIF4E deficiency on the pro-tumor function of select cells of the TME. Furthermore, we employed Imaging Mass Cytometry on PPBC and non-PPBC patient samples, to chart the expression of the MNK1/2-eIF4E axis components in the TME. ResultsHere, we show that phospho-eIF4E deficient (eIF4ES209A) PPBC mice are protected against lung metastasis and reveal differences in the lung immune microenvironment of the WT and eIF4ES209A mice. Moreover, we show that the expression of fibroblast-derived IL-33, an alarmin known to induce invasion, was repressed upon MNK1/2-eIF4E axis inhibition. Imaging Mass Cytometry results indicated that human PPBC contain phospho-eIF4E high-expressing tumor cells and CD8+ T cells displaying an activated dysfunctional phenotype. Finally, we block lung metastasis in PPBC mice, using combined MNK1/2 inhibition and anti-PD-1 therapy. ConclusionsThese findings implicate the involvement of the MNK1/2-eIF4E axis during PPBC metastasis and suggest a promising immunomodulatory route to enhance the efficacy of immunotherapy by blocking phospho-eIF4E. Translational relevancePostpartum breast cancer (PPBC) is highly aggressive. It is hypothesized that involution-induced changes in the postpartum breast microenvironment, which include an influx of inflammatory immune cells and activation of resident fibroblasts, facilitate the invasiveness of an existing neoplasm. We used imaging mass cytometry to do an in-depth profiling of the MNK1-eIF4E axis in the TME of a unique cohort of PPBC and non-PPBC patients. We observed patterns of phospho-eIF4E in non-tumor cells that were specific to the TME of PPBC. We also noted that the CD8+ T cells present in PPBC express an activated dysfunctional phenotype characterized by the co-expression of HLA-DR and PD-1. This study represents a first look at the expression of the MNK1-eIF4E axis in the stromal cells of metastatic breast cancer and has therapeutic implications as we show, in an animal model of PPBC, that MNK1/2 inhibition can be used to sensitize tumors to anti-PD1 immunotherapy.

cancer biology↗

bioRxiv2020

A Pan-Cancer Blueprint of the Heterogeneous Tumour Microenvironment Revealed by Single-Cell Profiling

AO_SCPLOWBSTRACTC_SCPLOWThe stromal compartment of the tumour microenvironment consists of a heterogeneous set of tissue-resident and tumour-infiltrating cells, which are profoundly moulded by cancer cells. An outstanding question is to what extent this heterogeneity is similar between cancers affecting different organs. Here, we profile 233,591 single cells from patients with lung, colorectal, ovary and breast cancer (n=36) and construct a pan-cancer blueprint of stromal cell heterogeneity using different single-cell RNA and protein-based technologies. We identify 68 stromal cell populations, of which 46 are shared between cancer types and 22 are unique. We also characterise each population phenotypically by highlighting its marker genes, transcription factors, metabolic activities and tissue-specific expression differences. Resident cell types are characterised by substantial tissue specificity, while tumour-infiltrating cell types are largely shared across cancer types. Finally, by applying the blueprint to melanoma tumours treated with checkpoint immunotherapy and identifying a naive CD4+ T-cell phenotype predictive of response to checkpoint immunotherapy, we illustrate how it can serve as a guide to interpret scRNA-seq data. In conclusion, by providing a comprehensive blueprint through an interactive web server, we generate a first panoramic view on the shared complexity of stromal cells in different cancers.

cancer biology↗