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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. [ABSTRACT FROM AUTHOR]

The article focuses on exploring a potential pro-immunogenic treatment for triple-negative breast cancers (TNBC) by combining the inhibition of alternative splicing with EZH2 activity, aiming to enhance tumor immunogenicity and potentially improve therapeutic outcomes for TNBC patients.

DNA is a danger signal sensed by cGAS to engage signaling through STING to activate innate immune functions. The best-studied downstream responses to STING activation include expression of type I interferon and inflammatory genes, but STING also activates other pathways, including apoptosis. Here, we report that STING-dependent induction of apoptosis in macrophages occurs through the intrinsic mitochondrial pathway and is mediated via IRF3 but acts independently of gene transcription. By intersecting four mass spectrometry datasets, we identify SAM68 as crucial for the induction of apoptosis downstream of STING activation. SAM68 is essential for the full activation of apoptosis. Still, it is not required for STING-mediated activation of IFN expression or activation of NF-κB. Mechanistic studies reveal that protein trafficking is required and involves SAM68 recruitment to STING upon activation, with the two proteins associating at the Golgi or a post-Golgi compartment. Collectively, our work identifies SAM68 as a STING-interacting protein enabling induction of apoptosis through this DNA-activated innate immune pathway. The signaling protein SAM68 mediates apoptosis in macrophages downstream of stimulator of interferon genes (STING) activation. [ABSTRACT FROM AUTHOR]

Neural Progenitor Cells (NPCs) are multipotent cells that are able to self‐renew and differentiate into neurons. The size of the initial pool of NPCs during the brain development strongly affects the number of neurons that compose cortical multi‐layer during development. Gonadal hormones can influence the balance between self‐renewal and differentiation processes. Herein, we investigated the role of dihydrotestosterone (DHT), the active metabolite of testosterone, in the regulation of NPC stemness and differentiation. First, we evaluated the expression of the androgen receptor (AR), the transcription factor activated by DHT that mediates the physiological effects of androgens, in NPCs. Western blot analysis showed that DHT‐mediated activation of AR induces mitogenic signaling pathways (PI3K/AKT and MAPK/ERK) in NPCs, whereas luciferase activity assays demonstrated the induction of AR transcriptional activity. AR activation mediated by DHT treatment strongly increased the proliferation of NPCs and reduced their propensity to differentiate into neurons. Furthermore, the effects of AR activation were mediated, at least in part, by increased expression of Aldehyde Dehydrogenase 1 Family Member A3 enzyme (ALDH1A3). Pharmacological inhibition of ALDH activity with N,N‐diethylaminobenzaldehyde (DEAB) reduced the effect of DHT on NPC proliferation in vitro. Furthermore, inhibition of AR activity by Enzalutamide reduced the NPC pool in the developing cortex of male C57/BL6 mouse embryos. These findings indicate that androgens engage an AR‐dependent signaling pathway that impact on neurogenesis by increasing the NPC pool in the developing mouse cortex. [ABSTRACT FROM AUTHOR]

Background: High grade serous ovarian cancer (HGSOC) is among the deadliest human cancers and its prognosis remains extremely poor. Tumor heterogeneity and rapid acquisition of resistance to conventional chemotherapeutic approaches strongly contribute to poor outcome of patients. The clinical landscape of HGSOC has been radically transformed since the advent of targeted therapies in the last decade. Nevertheless, the lack of predictive biomarkers informing on the differential clinical benefit in select subgroups, and allowing patient-centric approaches, currently limits the efficacy of these novel therapies. Thus, rational selection of the best possible treatment for each patient represents a clinical priority in order to improve outcome, while limiting undesirable effects. Main body: In this review, we describe the state of the art and the unmet needs in HGSOC management, illustrate the treatment options that are available and the biomarkers that are currently employed to orient clinical decisions. We also describe the ongoing clinical trials that are testing new therapeutic approaches for HGSOC. Next, we introduce the organoid technology as a promising, expanding strategy to study cancer and to develop personalized therapeutic approaches. In particular, we discuss recent studies that have characterized the translational potential of Patient's Derived Organoids (PDOs) to inform on drug sensitivity of HGSOC patients. Conclusions: PDOs can predict the response of patients to treatments and may therefore guide therapeutic decisions. Although preliminary results appear encouraging, organoids still need to be generated and expanded efficiently to enable drug screening in a clinically meaningful time window. A new generation of clinical trials based on the organoid technology should guarantee tailored approaches to ovarian cancer management, as it is now clear that the one-size-fits-all approach cannot lead to efficient and meaningful therapeutic advancements. [ABSTRACT FROM AUTHOR]

The balance between self-renewal and differentiation of neural progenitor cells (NPCs) dictates neurogenesis and proper brain development. We found that the RNA- binding protein Sam68 (Khdrbs1) is strongly expressed in neurogenic areas of the neocortex and supports the self- renewing potential of mouse NPCs. Knockout of Khdrbs1 constricted the pool of proliferating NPCs by accelerating their cell cycle exit and differentiation into post-mitotic neurons. Sam68 function was linked to regulation of Aldh1a3 pre-mRNA 3'-end processing. Binding of Sam68 to an intronic polyadenylation site prevents its recognition and premature transcript termination, favoring expression of a functional enzyme. The lower ALDH1A3 expression and activity in Khdrbs1-/- NPCs results in reduced glycolysis and clonogenicity, thus depleting the embryonic NPC pool and limiting cortical expansion. Our study identifies Sam68 as a key regulator of NPC self- renewal and establishes a novel link between modulation of ALDH1A3 expression and maintenance of high glycolytic metabolism in the developing cortex. [ABSTRACT FROM AUTHOR]

The article focuses on the identification of a subtype-specific splicing signature in pancreatic ductal adenocarcinoma (PDAC) associated with prognosis, with the splicing factor QKI playing a key role in promoting the aggressive basal-like subtype and its associated poor clinical.

Mounting evidence points to immune-mediated synaptopathy and impaired plasticity as early pathogenic events underlying cognitive decline (CD) in Multiple sclerosis (MS) and in the experimental autoimmune encephalomyelitis (EAE) mouse model of the disease. However, knowledge of the neurobiology of synaptic dysfunction is still incomplete. Splicing regulation represents a flexible and powerful mechanism involved in dynamic remodeling of the synapse, which allows the expression of synaptic protein variants that dynamically control the specificity of contacts between neurons. The pre-synaptic adhesion molecules neurexins (NRXNs) 1–3 play a relevant role in cognition and are alternatively spliced to yield variants that differentially cluster specific ligands in the postsynaptic compartment and modulate functional properties of the synaptic contact. Notably, mutations in these genes or disruption of their splicing program are associated with neuropsychiatric disorders. Herein, we have investigated how inflammatory changes imposed by EAE impact on alternative splicing of the Nrxn 1–3 mouse genes in the acute phase of disease. Due to its relevance in cognition, we focused on the prefrontal cortex (PFC) of SJL/J mice, in which EAE-induced inflammatory lesions extend to the rostral forebrain. We found that inclusion of the Nrxn 1–3 AS4 exon is significantly increased in the PFC of EAE mice and that splicing changes are correlated with local Il1β -expression levels. This correlation is sustained by the concomitant downregulation of SLM2, the main splicing factor involved in skipping of the AS4 exon, in EAE mice displaying high levels of Il1β- expression. We also observed that Il1β -expression levels correlate with changes in parvalbumin (PV)-positive interneuron connectivity. Moreover, exposure to environmental enrichment (EE), a condition known to stimulate neuronal connectivity and to improve cognitive functions in mice and humans, modified PFC phenotypes of EAE mice with respect to Il1β- , Slm2 -expression, Nrxn AS4 splicing and PV-expression, by limiting changes associated with high levels of inflammation. Our results reveal that local inflammation results in early splicing modulation of key synaptic proteins and in remodeling of GABAergic circuitry in the PFC of SJL/J mice. We also suggest EE as a tool to counteract these inflammation-associated events, thus highlighting potential therapeutic targets for limiting the progressive CD occurring in MS. • Acute inflammation deregulates alternative splicing of Nrxn 1–3 at AS4 in prefrontal cortex of EAE mice. • Inclusion of AS4 exon in Nrxn 1–3 genes positively correlates with local Il1β -expression levels. • Acute inflammation induces concomitant downregulation of the splicing factor SLM2. • Splicing deregulation is associated with changes in PV-expression in the PFC of EAE mice. • Environmental enrichment reverts alternative splicing deregulation and circuitry alterations induced by high levels of IL-1β in the PFC of EAE mice. [ABSTRACT FROM AUTHOR]