Biology subjects

Benelli, M.

Publications and source records attributed to Benelli, M..

5 recordsLinked to original sources

bioRxiv2026

ASPARAGINE-RICH METASTATIC NICHES DRIVE PROSTATE CANCER ORGANOTROPISM BY ENABLING TRANSLATIONAL REWIRING TOWARD N-GLYCOSYLATED PROTEINS

Metastatic disease is the leading cause of mortality in prostate cancer (PC), with bone as the preferential site of dissemination and the lung frequently affected secondarily. Metabolic interactions between disseminated tumor cells and tissue-specific microenvironments play a key role in shaping site-specific metastatic patterns. In particular, the availability of certain metabolites before, during, and after the establishment of overt metastases represents a critical determinant of colonization. Here we show that asparagine (Asn) is selectively enriched in bone and lung microenvironments and supports PC metastatic colonization. Dietary Asn restriction selectively impairs bone and lung metastases in vivo, without affecting metastatic burden in other organs. Mechanistically, disseminated PC cells arriving at Asn-rich niches rely on extracellular Asn due to decreased asparagine synthetase (ASNS) expression enabling the activation of mTORC1-dependent translational program. Elevated Asn availability selectively promotes the synthesis of Asn-rich proteins enriched in N-glycosylation motifs (Asn-X-Ser/Thr), leading to enhanced global protein N-glycosylation during early metastatic colonization. This metabolic adaptation facilitates cell-cell interactions and promotes adhesion to bone- and lung-specific extracellular matrices. Among the N-glycosylated proteins induced by Asn, CD44 emerges as a central effector of PC bone metastases. Extracellular Asn shortening, genetic or pharmacological disruption N-glycosylation, or silencing of CD44 abolish the pro-metastatic advantage conferred by Asn. Together, these findings identify environmental Asn as a niche-specific metabolic cue that drives PC organotropism by rewiring translation toward proteins enriched in N-glycosylation sites, thereby enhancing adhesive interactions and revealing metabolic vulnerabilities that could be therapeutically exploited to interfere with earliest steps of metastatic colonization in PC.

cancer biology↗

bioRxiv2024

Sensitive tumor detection, accurate quantification, and cancer subtype classification using low-pass whole methylome sequencing of plasma DNA

The analysis of circulating tumor DNA (ctDNA) is increasingly used for monitoring disease in patients with metastatic cancer. Here, we introduce a robust and reproducible strategy combining low-pass whole methylome sequencing of plasma DNA with METER, a novel computational tool. Engaging prediction models trained on independent available datasets, METER enables the detection and quantification of tumor content (TC) and performs molecular cancer subtyping. Applied to plasma methylomes from early metastatic breast cancer patients, our method demonstrated reliable quantification, sensitive tumor detection below 3% of TC, and the ability to perform accurate Estrogen Receptor (ER) subtyping. METER provided clinically relevant predictions, underscored by associations with relevant prognostic factors, robust correlation with matched circulating tumor cells, and highly correlated with patients outcomes in challenging scenarios as TC<3%. Our strategy provides comprehensive and sensitive analysis of plasma samples, serving as a valuable yet cost-effective precision oncology tool.

cancer biology↗

bioRxiv2020

Cancer methylomes characterization enabled by Rocker-meth

Differentially DNA methylated regions (DMRs) inform on the role of epigenetic changes in cancer. We present Rocker-meth, a computational method exploiting a heterogeneous hidden Markov model to detect DMRs across multiple experimental platforms. Its application to more than 6,000 methylation profiles across 14 tumor types provides a comprehensive catalog of tumor type-specific and shared DMRs, also amenable to single-cell DNA-methylation data. In depth integrative analysis including orthogonal omics shows the enhanced ability of Rocker-meth in recapitulating known associations, further uncovering the pan-cancer relationship between DNA hypermethylation and transcription factor deregulation depending on the baseline chromatin state.

cancer biology↗

bioRxiv2020

CHD8 Suppression Impacts on Histone H3 Lysine 36 Trimethylation and Alters RNA Alternative Splicing.

Disruptive mutations in the chromodomain helicase DNA binding protein 8 (CHD8) have been recurrently associated with Autism Spectrum Disorders (ASD). In normal cellular physiology, CHD8 co-purifies with MLL1 and MOF transcriptional activation complex, with elongating RNAPII and directly binds to DNA promoters and enhancers regions, thus a regulatory role in transcriptional initiation and elongation could be postulated. Here we investigated how chromatin landscape reacts to CHD8 suppression by analyzing a panel of histone modifications in induced pluripotent stem cell-derived neural progenitors. We interrogated transcriptionally active and repressed regions, as well as active and poised enhancers. CHD8 suppression led to significant reduction (47.82%) in histone H3K36me3 peaks at gene bodies, particularly impacting on transcriptional elongation chromatin states. H3K36me3 reduction specifically affects highly expressed, CHD8-bound genes. Histone H3K36me3 reduction associated to CHD8-suppression does not functionally impact on global transcriptional levels, but correlated with altered alternative splicing patterns of [~] 2000 protein coding genes implicated in "RNA splicing", "mitotic cell cycle phase transition" and "mRNA processing", especially affecting alternative first exon and exon skipping events. In summary, our results point toward broad molecular consequences of CHD8 suppression, implicating altered histone deposition/maintenance and RNA processing regulation as important regulatory processes in ASD.

genetics↗

bioRxiv2020

Role of Specialized mSWI/SNF Complexes in Prostate Cancer Lineage Plasticity

Advanced prostate cancer initially responds to hormonal treatment, but ultimately becomes resistant and requires more potent therapies. One mechanism of resistance observed in [~]10% of these patients is through lineage plasticity, which manifests in a partial or complete small cell or neuroendocrine prostate cancer (NEPC) phenotype. Here, we investigate the role of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex in NEPC. Using large patient datasets, patient-derived organoids and cancer cell lines, we identify mSWI/SNF subunits that are deregulated in NEPC and demonstrate that SMARCA4 (BRG1) overexpression is associated with aggressive disease. We also show that SWI/SNF complexes interact with different lineage-specific factors in NEPC compared to prostate adenocarcinoma. These data suggest a role for mSWI/SNF complexes in therapy-related lineage plasticity, which may be relevant for other solid tumors.

cancer biology↗