Biology subjects

Cusso, L.

Publications and source records attributed to Cusso, L..

4 recordsLinked to original sources

bioRxiv2025

Disrupted astrocyte-endothelial crosstalk drives hemangioblastoma lesions in VHL disease

Hemangioblastomas (HBs) are highly vascularized central nervous system (CNS) tumours that can become life-threatening, especially in the context of Von Hippel-Lindau (VHL) disease, caused by the loss of VHL function. The limited pharmacological options targeting VHL-HBs stem from an incomplete understanding of their cellular origin, development, and molecular pathogenesis. Here we use advanced mouse genetics to show that mosaic deletion of Vhl in Apln+ cells leads to the formation of precursor tumour-like lesions, composed by clusters of Vhl-knockout (VhlKO) astrocytes and surrounding Vhl-wild-type (VhlWT) vessels that become malformed, resembling early-stage HBs linked to VHL disease. VhlKO astrocytes morphologically and transcriptomically resembled the reactive astrocytes characteristic of ischemic CNS injury. They exhibited metabolic rewirement towards glycolysis and upregulation of cell growth pathways. They also expressed several secreted proangiogenic molecules that activate and prevent the normal maturation of neighbouring vessels, leading to VHL-HBs. Temporal conditional genetic analysis revealed that Vhl loss need to happen during postnatal development for HBs to form, and that lesions become quiescent in early adulthood. HIF-2 deletion, or MTORC1 inhibition with rapamycin, efficiently inhibited VHL-HBs growth and the associated vascular malformations. Our work shows that the loss of Vhl in single astrocytes induces their growth and pathogenic crosstalk with neighbouring endothelial cells, driving hemangioblastoma development in VHL disease. Our new somatic mosaic mouse models will also enable testing of novel drugs against this disease.

cancer biology↗

bioRxiv2025

Loss of the alternative calcineurin variant CnAβ1 enhances brown adipocyte differentiation and drives metabolic overactivation through FoxO1 activation

The alternative calcineurin A variant CnA{beta}1 has a unique C-terminal domain that provides it with distinct subcellular localization and mechanism of action different from other calcineurin isoforms. Here, we used mice lacking CnA{beta}1s C-terminal domain (CnA{beta}1{Delta}i12) to show that the absence of this specific isoform strongly reprograms metabolism. CnA{beta}1{Delta}i12 mice on a high-fat diet showed reduced body weight, white adipose tissue (WAT) mass, and circulating triglycerides, together with enhanced insulin sensitivity. In brown adipose tissue (BAT), CnA{beta}1 deficiency increased mitochondrial content and upregulated fatty acid oxidation and thermogenic proteins, improving cold resistance. Conversely, under starvation, CnA{beta}1{Delta}i12 mice experienced rapid fat depletion and hypothermia. Importantly, BAT-specific FoxO1 knockout in CnA{beta}1{Delta}i12 mice reduced catabolism-related gene expression and partially reversed the metabolic phenotypes, increasing body weight and WAT mass. Our findings reveal a relevant role for CnA{beta}1 in orchestrating BAT metabolism, highlighting its potential as a therapeutic target for obesity and metabolic syndrome.

physiology↗

bioRxiv2024

Broad therapeutic benefit of myosin inhibition in hypertrophic cardiomyopathy

Myosin inhibitor mavacamten is the only targeted treatment available for hypertrophic cardiomyopathy (HCM), a disease caused by hundreds of genetic variants that affect mainly sarcomeric myosin and its negative regulator cardiac myosin-binding protein C (cMyBP-C, encoded by MYBPC3). Here, we have examined whether the reported limited efficacy of mavacamten in a fraction of HCM patients can result from dissimilar HCM pathomechanisms triggered by different genetic variants, a scenario particularly relevant for MYBPC3-associated HCM. To this aim, we have generated knock-in mice including missense pathogenic variant cMyBP-C p.R502W, which, different from patients who carry truncations in the protein, develop progressive pathogenic myocardial remodeling in the absence of alterations of cMyBP-C levels and localization. Mechanistically, we find that mutation R502W reduces the binding affinity of cMyBP-C for myosin without inducing a shift towards more active myosin conformations as observed when cMyBP-C levels are reduced. Despite these diverging molecular alterations, we show that mavacamten blunts myocardial remodeling both in R502W and cMyBP-C-deficient, knock-out hearts. These beneficial effects are accompanied by improved tolerance to exercise only in R502W animals. Hence, our results indicate that myosin inhibition is effective to treat HCM caused by both truncating and missense variants in MYBPC3 regardless of the primary pathomechanisms they elicit.

physiology↗

bioRxiv2020

A drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent local relapse and treat established brain metastasis

Exclusion of brain metastases from clinical trials is a major cause of the limited therapeutic options for this growing population of cancer patients. Here, we report a medium-throughput drug-screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to brain metastasis, we identified several hits from a library of FDA approved inhibitors and others being tested in clinical trials. A blood-brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to organotypic cultures with metastases treated with the chaperone inhibitor revealed novel biomarkers in human brain metastasis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples. We envision that METPlatform could be established as a clinically relevant strategy to personalize the management of metastatic disease in the brain and elsewhere. SummarySystemic spread of cancer continues to be the key aspect associated with lethality. In this publication, Zhu et al. describes a drug-screening platform specifically designed to study vulnerabilities of metastasis when colonizing secondary organs and demonstrates its value in difficult-to-treat brain metastasis using new models and patient-derived samples.

cancer biology↗