Biology subjects

Serio, S.

Publications and source records attributed to Serio, S..

4 recordsLinked to original sources

bioRxiv2026

A multilayered in silico analysis links UHRF1, DNA methylation and developmental chromatin memory to lineage-dependent prognosis in gastric, renal and adrenal cancers

Aberrant DNA methylation is a hallmark of cancer, but its clinical interpretation remains debated. UHRF1, a key epigenetic adaptor for DNA methylation maintenance and chromatin bivalency regulation in embryonic stem cells, is frequently overexpressed yet shows context-dependent prognostic behaviour. By integrating bulk and single-cell transcriptomics, CpG-resolution methylation, developmental chromatin states, immune profiling and clinical outcomes across gastric (STAD), clear-cell renal (KIRC) and adrenal (ACC) carcinomas, we identified a four-class UHRF1-embryonic morphogenesis (UHRF1-EM) framework resolving this paradox. This axis revealed an inverse prognostic pattern: whilst across all three tumours EM-low and EM-high states mark better or worse prognosis, respectively, UHRF1-high levels associate with favourable outcome in STAD (UH-EML), and unfavourable in KIRC and ACC (UH-EMH). The classification proved reproducible and independently prognostic after adjustment for stage and molecular subtypes, outperforming existing classifiers and exceeding pathological stage in KIRC and ACC. Multivariable models incorporating UHRF1-EM yielded uniformly positive {Delta}C-indices. Hypermethylation associated with the UHRF1-EM axis was enriched at ESC bivalent developmental loci (EM and oncofoetal genes), but not at housekeeping cell-cycle sites. In STAD, this pattern was related to oncofoetal gene downregulation and best prognosis, whereas in KIRC and ACC it matched with gene-body/enhancer methylation, higher EM expression, immunosuppressive microenvironments and worst prognosis. Together, these findings establish the UHRF1-EM axis as a clinically robust molecular classifier and support a mechanistic model in which tumour-specific epigenetic engagement of developmental loci may contribute to the prognostic inversion, providing a foundation for further mechanistic experimental validation.

cancer biology↗

bioRxiv2025

Adventitial leptin receptor-expressing fibroblasts are preferential contributors to fibrotic remodeling of the heart post infarction

BackgroundCardiac fibrosis, a hallmark of heart failure and an unmet clinical need, arises from pathological activation of pre-existing cardiac fibroblasts (CFs), but the contribution of CF heterogeneity to this process remains unclear. MethodsMurine models were used to lineage trace or deplete a specific sub-population of CFs at baseline and after myocardial infarction (MI). Transcriptional and epigenetic differences between fibroblast subsets were assessed using next-generation sequencing. Conservation in humans was evaluated through single-cell RNA-seq datasets and histological examination. ResultsIn mice, fibroblasts were the sole cardiac cell type expressing the signaling-capable isoform of the leptin receptor (LepR). LepR+ CFs emerged neonatally, occupied a defined niche in the coronary adventitia, exhibited enhanced hedgehog signaling, and responded to leptin. After MI, LepR-Cre+ CFs proliferated more than interstitial CFs, became a predominant fibroblast lineage in the scar, and their genetic ablation reduced fibrosis while improving function. LepR+ CFs were also detected in the human heart, where they were embedded in an adipocyte-rich niche. ConclusionsThese findings identify adventitial fibroblasts as key drivers of pathological remodeling and demonstrate that fibroblasts, rather than cardiomyocytes, are the principal responders to leptin in the heart, redefining how this major endocrine pathway influences cardiac remodeling and disease.

cell biology↗

bioRxiv2023

RORγ bridges cancer-driven lipid dysmetabolism and myeloid immunosuppression

Despite well-documented metabolic and hematopoietic alterations during tumor development1, the mechanisms underlying this crucial immunometabolic intersection have remained elusive. Of particular interest is the ligand-activated transcription factor retinoic acid-related orphan receptor 1 (RORC1/ROR{gamma}), whose activity is boosted by cholesterol metabolites2, acting as a modulator of cancer-related emergency myelopoiesis3, while hypercholesterolemia itself is associated with dysregulated myelopoiesis4,5. Here we show that both cancer growth and hypercholesterolemic diet can independently or cooperatively activate ROR{gamma}-dependent expansion of myeloid-derived suppressor cells (MDSCs) and M2 polarization of tumor-associated macrophages (TAMs), thereby supporting cancer spread. Moreover, we report that tumor development enhances the hepatic production of IL-1{beta} and IL-6, which in turn promote upregulation of hepatic proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, as we confirmed in models of fibrosarcoma, melanoma, colorectal (CRC), and lung cancer, as well as in CRC, non-small-cell lung cancer (NSCLC), breast (BRC), pancreatic ductal adenocarcinoma (PDAC), biliary tract carcinoma (BTC) and pancreatic neuroendocrine tumor (PNET) patients. Importantly, lowering cholesterol levels prevents MDSC expansion and M2 TAM accumulation in a ROR{gamma}-dependent manner, unleashing specific anti-tumor immunity and improving the efficacy of anti-PD-1 immunotherapy. Overall, we identify ROR{gamma} as a novel sensor of lipid disorders in cancer bearers, bridging hypercholesterolemia and pro-tumor myelopoiesis.

immunology↗

bioRxiv2022

Ablation of palladin in adult heart causes dilated cardiomyopathy associated with intercalated disc abnormalities

Palladin (PALLD) belongs to the PALLD/myopalladin (MYPN)/myotilin family of actin-associated immunoglobulin-containing proteins in the sarcomeric Z-line. PALLD is ubiquitously expressed in several isoforms and its longest 200 kDa isoform, predominantly expressed in striated muscle, shows high structural homology to MYPN. MYPN gene mutations are associated with human cardiomyopathies, whereas the role of PALLD in the heart has remained unknown, partly due to embryonic lethality of PALLD knockout mice. In a yeast two-hybrid screening, CARP/Ankrd1 and FHOD1 were identified as novel interaction partners of PALLDs N-terminal region. To study the role of PALLD in the heart, we generated conditional (cPKO) and inducible (cPKOi) cardiomyocyte-specific PALLD knockout mice. While cPKO mice exhibited no pathological phenotype, ablation of PALLD in adult cPKOi mice caused progressive cardiac dilation and systolic dysfunction, associated with reduced cardiomyocyte contractility, intercalated disc abnormalities, and fibrosis, demonstrating that PALLD is essential for normal cardiac function. Double cPKO and MYPN knockout mice exhibited a similar phenotype as MKO mice, suggesting that MYPN does not compensate for the loss of PALLD in cPKO mice. Transcript levels of MYPN and the PALLD long isoform were significantly increased in myocardial tissue from human dilated cardiomyopathy patients, suggesting a role of PALLD in cardiac disease.

molecular biology↗