Garcia-Alvarez, A. | bioRxiv Science

bioRxiv2026

From Splicing to Survival: Understanding the Molecular Basis of Prognostic Differences in advanced Small Intestine Neuroendocrine Tumors

Small intestine neuroendocrine tumors (SI-NETs) represent a challenging neoplasm due to their high rate of metastasis and the limited availability of effective therapies. Recent evidence has unveiled altered splicing as an influential player in tumor progression, linked to patient prognosis, which provides a powerful source of novel biomarkers and therapeutic targets in cancer. Here, we conducted a comprehensive analysis regarding the possible connection of the spliceosomic landscape of metastatic SI-NETs with patient survival. Initial analyses revealed a distinctive pattern of splicing events between the two conditions, short (< 5 years, n = 17 patients), vs. long survival ([≥] 5 years, n = 26 patients), with strong discrimination capacity. Furthermore, numerous key splicing events were associated with relevant clinical parameters in SI-NETs. The observed impairments in spliceosomic parameters led us to interrogate the integrity of the splicing machinery. This revealed striking changes in the expression of a high proportion of core spliceosome components and splicing factors between short vs. longsurvival groups, suggesting a possible mechanistic link with the distinct profile of splicing events observed. Among them, CPSF2, a core component of the CPSF complex, stands out as its higher expression is associated with worse survival and vascular and perineural invasion. Interestingly, the shifts potentially generated by this factor supported a possible role in tumor plasticity oriented to higher tumor aggressiveness and treatment resistance. In sum, this study offers the first detailed snapshot of the status of the spliceosomic landscape in SI-NETs and its molecular linkage to patient survival, thus offering a new window towards identification of novel candidate biomarkers and/or therapeutic targets.

cancer biology↗

bioRxiv2026

Endothelial β3-Adrenergic Receptor activation prevents pulmonary hypertension

BackgroundPulmonary hypertension (PH) is a progressive vascular disease characterized by endothelial dysfunction, vascular remodeling and increased pulmonary vascular resistance. The {beta}3-adrenergic receptor ({beta}3-AR) has been implicated in cardiovascular regulation and cardioprotective mechanisms; however, its role in pulmonary vascular disease remains poorly understood. We investigated whether activation of {beta}3-AR protects pulmonary endothelial function and prevents the development of pre-capillary PH. Methods{beta}3-AR expression was evaluated in pulmonary endothelium from patients with Chronic Obstructive Pulmonary Disease (COPD) and in murine models of hypoxia-induced PH. Genetic mouse models including {beta}3-AR knockout (KO) and conditional {beta}3-AR overexpression in endothelial cells (EC) or in smooth muscle cells (SMC), were used to determine cell-specific roles. Pharmacological activation of {beta}3-AR was achieved using the selective {beta}3-agonist mirabegron in hypoxia-induced PH mice and monocrotaline-induced PH rats. Pulmonary vascular reactivity and vasodilatory responses to {beta}3-AR stimulation were evaluated by wire myography in isolated pulmonary arteries. Mechanistic studies were performed in human pulmonary artery endothelial cells (HPAEC) under hypoxic conditions, in human pulmonary arterial smooth muscle cells (HPASMC) and in endothelial nitric oxide synthase (NOS3) KO mice. Results{beta}3-AR was upregulated in pulmonary endothelium of COPD patients and mice exposed to chronic hypoxia. Genetic deletion of {beta}3-AR aggravated PH, whereas endothelial-specific overexpression attenuated the disease phenotype, reducing right ventricular systolic pressure (RVSP), vascular remodeling and right ventricular (RV) hypertrophy. Activation of {beta}3-AR with mirabegron improved pulmonary hemodynamics, reduced vascular remodeling and preserved RV function. {beta}3-AR activation promoted endothelial nitric oxide synthase (eNOS)-dependent NO production, indirectly inhibiting SMC proliferation. Additionally, {beta}3-AR activation improved mitochondrial fitness in endothelial cells by increasing uncoupling protein 2 (UCP2) expression, reducing reactive oxygen species (ROS) generation and preventing mitochondrial fragmentation. ConclusionsThese findings identify endothelial {beta}3-AR as a previously unrecognized regulator of pulmonary vascular homeostasis and provide a strong translational rationale for targeting the {beta}3-adrenergic pathway in PH. Given that mirabegron is already approved for clinical use, our results support its repurposing as a therapeutic strategy for pre-capillary forms of PH.

pharmacology and toxicology↗