Biology subjects

Reale, M.

Publications and source records attributed to Reale, M..

4 recordsLinked to original sources

bioRxiv2025

A K27-linked Ubiquitin Checkpoint Controls NOTCH Homeostasis

Cell surface receptors such as NOTCH1 must be tightly regulated to ensure developmental fidelity and prevent pathological activation. Although the proteolytic steps culminating in nuclear NOTCH1 signaling are established, how cells prevent excessive or uncontrolled activation has remained unresolved. Here we identify the autophagy-related protein UVRAG as a negative regulator of NOTCH1. Upon receptor activation, UVRAG, acting independently of autophagy, recruits and activates the E3-ligase ITCH to catalyze K27-linked ubiquitination of membrane-tethered NOTCH1, thereby licensing ESCRT-dependent lysosomal degradation. Disruption of the UVRAG-ITCH-ESCRT axis stabilizes activated NOTCH1 intermediates and amplifies oncogenic signaling. In T-cell leukemia models driven by constitutive NOTCH1 activity, restoring UVRAG expression reinstates receptor turnover, suppresses disease progression, and improves therapeutic response. These findings define a ubiquitin-directed safeguard circuit that enforces NOTCH1 signaling homeostasis and reveals a tunable axis for intervention in NOTCH1-driven cancers.

molecular biology↗

bioRxiv2025

Taxonomy-free fecal microbiome profiles enable robust prediction of immunotherapy response and toxicity in melanoma

The gut microbiome has been causally linked to the efficacy of immune-checkpoint inhibitor therapy (ICI), prompting numerous clinical trials of microbiome-targeting strategies. Yet, mechanisms by which gut microbiota shape immune responses remain elusive as taxonomic biomarkers have failed to generalize across multiple cohorts. In this study, we develop a taxonomy-agnostic framework to identify microbial biomarkers of ICI response and immune-related adverse event (irAE) occurrence from metagenomic sequencing. Applying this approach to four independent melanoma cohorts from clinical centers across the United States, we uncover gut microbial proteins produced by diverse bacterial taxa that consistently predict ICI response. Notably, we uncover a previously uncharacterized operon involved in cellular redox homeostasis that is encoded by different bacteria and reliably predicts irAE occurrence. We further validated the predictive power of this operon in a prospectively sequenced melanoma cohort. Our results demonstrate that taxa-agnostic microbial protein biomarkers are robust, generalizable, and provide a path towards pretreatment risk stratification for melanoma patients initiating ICI therapy.

cancer biology↗

bioRxiv2025

Clonal dynamics shaped by diverse drug-tolerant persister states in melanoma resistance

Most advanced melanomas initially respond to targeted therapy but eventually relapse. Rather than acquiring new mutations, resistance is driven by drug-tolerant persister cells that enter a reversible drug-refractory state. We developed MeRLin, a high-resolution lineage tracing platform integrating cellular barcoding, single-cell transcriptomics, RNA fluorescence in situ hybridization (FISH), and computational analyses to track clonal and transcriptional dynamics in patient-derived melanoma models during prolonged therapy. Clonal dynamics revealed that persister subpopulations first responded to treatment but persisted and expanded during minimal residual disease, ultimately leading to tumor recurrence. Pre-treatment melanoma populations diversified into four conserved persister states characterized by stress-like, lipid metabolism, PI3K signaling, and extracellular matrix remodeling programs associated with adaptive resistance. Spatial transcriptomics showed the organization of these adaptive programs and a complex signaling network of autocrine and paracrine interactions among persister subpopulations. Barcoded RNA-FISH enabled spatial mapping of clonal identity and gene expression, revealing in situ co-localization of a dominant resistant clone with SLC2A1 expression. MeRLin provides a robust framework for dissecting cancer heterogeneity and identifying vulnerabilities in persister populations.

cancer biology↗

bioRxiv2022

The role of Absorbing Markov Chains in childhood cancer

Absorbing Markov Chains are an important mathematical tool used for different applications in science. On the other hand, cancer and its metastases in children have a significant impact on health due to their degree of lethality. Therefore, the aim of this work is to model the metastatic pathways of the main childhood cancers worldwide. The probabilities of generating metastases, from a primary site to secondary and tertiary sites, were characterized by constructing a directed graph and the associated transition matrix. In addition, the time of absorption and the probabilities of absorption by each absorbing state were calculated.

cancer biology↗