Description of a Large Family with Periodic Fever Carrying a Variant in RXFP1 Gene: A Possible Novel Modulator of Inflammation in Autoinflammatory Diseases Marianna Buttarelli, Giulia Rapari, Melania Riccio, Raffaele Manna, Donato Rigante, et al. International Journal of Molecular Sciences, 2026 Autoinflammatory diseases involve recurrent systemic inflammation caused by dysregulated innate immunity, arising from genetic or multifactorial mechanisms, as seen in periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome. About 10% of PFAPA patients show autosomal dominant inheritance. We describe a three-generation family with a PFAPA-like recurrent fever syndrome displaying clear autosomal dominant transmission. All affected individuals tested negative on a diagnostic panel of 13 known autoinflammatory genes. Whole-exome sequencing was performed in two distantly related affected members, followed by variant filtering, segregation analysis, and phenotype-based prioritization. A single heterozygous missense variant in RXFP1, c.154G>A p.(Asp52Asn), co-segregated with disease in all affected relatives. This variant is extremely rare in population databases, absent from ClinVar, present in COSMIC, and predicted as damaging by REVEL and CADD. RXFP1, not previously implicated in autoinflammatory or innate immune disorders, encodes the relaxin family peptide receptor 1, a G protein–coupled receptor involved in extracellular matrix regulation, anti-fibrotic pathways, and modulation of inflammatory cytokine production. Protein network analysis showed interactions with RLXN1-3, inflammatory mediators, PTGDR, ADORA2B, and C1QTNF8, supporting an immunomodulatory function. This is the first report linking RXFP1 variation to a hereditary recurrent fever syndrome, identifying relaxin signalling as a potential immune regulatory pathway.
Decoding tumor evolution in advanced ovarian cancer: Proteogenomic insights before and after neoadjuvant chemotherapy. Valentina Iacobelli, Marianna Buttarelli, Enrica Martinelli, Alessia Piermattei, Giuseppina Raspaglio, et al. Journal of Clinical Oncology, 2025 e17582 Background: Platinum-based neoadjuvant chemotherapy (NACT) is a cornerstone in advanced ovarian cancer (OC) treatment. However, biomarkers predictive of response and the mechanisms underlying chemoresistance remain poorly defined. The PROGENITOR study aimed to (1) identify biomarkers associated with treatment response, as measured by Chemotherapy Response Score (CRS) and platinum-free interval (PFI), and (2) elucidate pathways driving chemoresistance and tumor adaptation. Methods: Tumor samples from 39 OC patients were analyzed pre- (T0) and post-NACT (T1) using RNA sequencing and liquid chromatography-mass spectrometry. Differentially expressed genes (DEGs) and proteins (DEPs) were identified, and transcriptomic-proteomic integration was performed. Deconvolution analysis, using xCell tool, evaluated tumor microenvironment dynamics, stratified by CRS and PFI. Genomic alterations were also correlated with transcriptomic and proteomic changes. Results: Longitudinal analysis revealed significant downregulation of PKMYT1, CDK1, and UBE2C at T1, suggesting impaired cell cycle progression and the potential induction of a quiescent state, contributing to chemoresistance mechanisms, as observed in CCNE1-amplified tumors. Deconvolution analysis revealed notable shifts in the tumor microenvironment post-NACT. Cancer-associated fibroblasts (CAFs) and stromal scores increased significantly in OC patients with suboptimal response (CRS 1–2), highlighting their role in chemoresistance through extracellular matrix remodeling. Additionally, immune cell populations showed significant alterations, including reduced T-cell and natural killer cell composition, along with a decline in dendritic cells, suggesting impaired antitumor immunity. These immune-stromal alterations were more pronounced in patients with poor PFI (<6 months). Conclusions: This study suggests dependency on PKMYT1 for CDK1 inhibition and a role in chemoresistance, particularly in CCNE1-amplified tumors. The integration of multi-omics and deconvolution analysis underscores the critical roles of cell cycle dysregulation, stromal activation, and immune suppression in shaping tumor evolution under NACT. These findings provide a foundation for biomarker-driven therapeutic strategies targeting cell-cycle machinery.
Dual inhibition of CDK12 and CDK13 uncovers actionable vulnerabilities in patient-derived ovarian cancer organoids Eleonora Cesari, Alessandra Ciucci, Marco Pieraccioli, Cinzia Caggiano, Camilla Nero, et al. Journal of Experimental and Clinical Cancer Research, 2023 Background High grade serous ovarian cancer (HGSOC) is highly lethal, partly due to chemotherapy resistance and limited availability of targeted approaches. Cyclin dependent kinases 12 and 13 (CDK12/13) are promising therapeutic targets in human cancers, including HGSOC. Nevertheless, the effects of their inhibition in HGSOC and the potential synergy with other drugs are poorly known. Methods We analyzed the effects of the CDK12/13 inhibitor THZ531 in HGSOC cells and patient-derived organoids (PDOs). RNA sequencing and quantitative PCR analyses were performed to identify the genome-wide effects of short-term CDK12/13 inhibition on the transcriptome of HGSOC cells. Viability assays with HGSOC cells and PDOs were performed to assess the efficacy of THZ531 as single agent or in combination with clinically relevant drugs. Results The CDK12 and CDK13 genes are deregulated in HGSOC and their concomitant up-regulation with the oncogene MYC predicts poor prognosis. HGSOC cells and PDOs display high sensitivity to CDK12/13 inhibition, which synergizes with drugs in clinical use for HGSOC. Transcriptome analyses revealed cancer-relevant genes whose expression is repressed by dual CDK12/13 inhibition through impaired splicing. Combined treatment with THZ531 and inhibitors of pathways regulated by these cancer relevant genes (EGFR, RPTOR, ATRIP) exerted synergic effects on HGSOC PDO viability. Conclusions CDK12 and CDK13 represent valuable therapeutic targets for HGSOC. We uncovered a wide spectrum of CDK12/13 targets as potential therapeutic vulnerabilities for HGSOC. Moreover, our study indicates that CDK12/13 inhibition enhances the efficacy of approved drugs that are already in use for HGSOC or other human cancers.
Exploring the Control of PARP1 Levels in High-Grade Serous Ovarian Cancer Giuseppina Raspaglio, Marianna Buttarelli, Natalia Cappoli, Alessandra Ciucci, Anna Fagotti, et al. Cancers, 2023 High-grade serous ovarian cancer (HGSOC) is a leading cause of mortality from gynecologic malignancies worldwide. Although a transformative improvement has been shown with the introduction of PARP (poly(ADP-ribose) polymerase) inhibitors, the emergence of resistance to these drugs represents a therapeutic challenge. Hence, expanding our understanding of mechanisms behind the control of PARP1 expression can provide strategic guidance for the translation of novel therapeutic strategies. The Signal Transducer and Activator of Transcription (STAT) family of proteins consists of transcription factors critically involved in the regulation of important cellular functions. Notably, we recently demonstrated that, in cervical cancer cells, STAT1 controls PARP1 levels through multiple mechanisms, possibly involving also STAT3. Here, we tested the hypothesis that a similar mechanism might be operative in HGSOC. To this end, the impact of STAT1/STAT3 modulation on PARP1 expression was assessed in established and primary HGSOC cells, and molecular biology studies proved that STAT1 might act at both transcriptional and post-transcriptional levels to modulate the PARP1 level. Notably, bioinformatics analysis of TCGA databases demonstrated that increased STAT1 mRNA expression levels are associated with a favorable prognosis and with response to chemotherapy in HGSOC patients. Our findings suggest an alternative strategy for targeting HGSOC cells based on their dependency on PARP1.
The interaction of β-arrestin1 with talin1 driven by endothelin A receptor as a feature of α5β1 integrin activation in high-grade serous ovarian cancer Ilenia Masi, Flavia Ottavi, Danila Del Rio, Valentina Caprara, Cristina Vastarelli, et al. Cell Death and Disease, 2023 Dissemination of high-grade serous ovarian cancer (HG-SOC) in the omentum and intercalation into a mesothelial cell (MC) monolayer depends on functional α5β1 integrin (Intα5β1) activity. Although the binding of Intα5β1 to fibronectin drives these processes, other molecular mechanisms linked to integrin inside-out signaling might support metastatic dissemination. Here, we report a novel interactive signaling that contributes to Intα5β1 activation and accelerates tumor cells toward invasive disease, involving the protein β-arrestin1 (β-arr1) and the activation of the endothelin A receptor (ETAR) by endothelin-1 (ET-1). As demonstrated in primary HG-SOC cells and SOC cell lines, ET-1 increased Intβ1 and downstream FAK/paxillin activation. Mechanistically, β-arr1 directly interacts with talin1 and Intβ1, promoting talin1 phosphorylation and its recruitment to Intβ1, thus fueling integrin inside-out activation. In 3D spheroids and organotypic models mimicking the omentum, ETAR/β-arr1-driven Intα5β1 signaling promotes the survival of cell clusters, with mesothelium-intercalation capacity and invasive behavior. The treatment with the antagonist of ETAR, Ambrisentan (AMB), and of Intα5β1, ATN161, inhibits ET-1-driven Intα5β1 activity in vitro, and tumor cell adhesion and spreading to intraperitoneal organs and Intβ1 activity in vivo. As a prognostic factor, high EDNRA/ITGB1 expression correlates with poor HG-SOC clinical outcomes. These findings highlight a new role of ETAR/β-arr1 operating an inside-out integrin activation to modulate the metastatic process and suggest that in the new integrin-targeting programs might be considered that ETAR/β-arr1 regulates Intα5β1 functional pathway.
