Biology subjects

Korbonits, M.

Publications and source records attributed to Korbonits, M..

4 recordsLinked to original sources

bioRxiv2025

Disruption of the Wnt-antagonist Apc in the pituitary stem cells drives the development of adamantinomatous craniopharyngioma.

Adamantinomatous craniopharyngiomas (aCPs) are complex intracranial neoplasms that generally arise in the sellar and suprasellar region of the brain which affect the endocrine and nervous systems causing severe sequelae. Activating mutations resulting in degradation-resistant forms of {beta}-catenin (CTNNB1) have been shown to be the main driver for many of these neoplasms. However, the underlying genetic driver for a proportion of these tumours is still unknown. Using murine transgenic models, we show that genetic disruption of the Wnt-antagonist and tumour suppressor, adenomatous polyposis coli (Apc), within the pituitary progenitors/stem cells, leads to pituitary tumours that closely resemble human aCPs. These tumours present classic histopathological hallmarks of aCPs, such as large deposits of wet keratin, stellar-reticular-like cells, large cystic components and clusters of accumulating nucleo-cytoplasmic {beta}-catenin that are slow-dividing and exhibit a secretory phenotype. We show that a hypomorphic allele of Apc is sufficient for tumour development, indicating that disruption of Apc function can lead to aCP formation. Moreover, we identify that bi-allelic loss of Apc in the Sox2+ve pituitary stem cells is sufficient to initiate tumour formation, indicating that Sox2+ve stem cells are the cell origin of these Apc-driven aCPs. Transcriptomic analyses of early tumour-initiating cells revealed that Apc-driven clusters of accumulating {beta}-catenin undergo senescence-associated secretory phenotype (SASP), which is p21-mediated and results in secretion of inflammasome, angiosome and developmental growth factors. Our data unequivocally show a causal role for the disruption of the tumour suppressor Apc as a primary driver of aCPs independent of mutations in {beta}-catenin. We provide murine models representing a novel genetic subtype of human aCPs offering insights into aCP pathogenesis. Our work reinforces the importance of genetic testing for mutations in APC in patients with aCPs and identifies a potential need to screen patients with familial adenomatous polyposis (FAP) or spectrum of APC-pathogenic syndromes for aCPs in early life.

cancer biology↗

bioRxiv2025

Chaperone AIP Couples mTORC1 Activation and Catabolic Metabolism During Neonatal Development

To grow and divide cells must tightly coordinate anabolic programs with the availability of nutrients and growth factors. This balance is especially critical during postnatal development, when biosynthetic and energetic demands are high, and nutrient supply and neonates have to adapt to periods of fasting. These conditions place acute stress on the proteostasis network, making autophagy essential for nutrient recycling. We found that the chaperone aryl hydrocarbon receptor-interacting protein (AIP) supports both arms of this metabolic balance: promoting anabolic PI3K-AKT signaling for mTORC1 activation and enabling catabolic processes such as proteasomal degradation and autophagy. Loss of AIP causes a severe neonatal metabolic disorder, where affected infants fail to thrive postnatally. Our findings establish AIP as a central regulator of neonatal metabolic adaptation and cellular homeostasis. One Sentence SummaryAIP integrates nutrient sensing and protein recycling to sustain neonatal survival.

developmental biology↗

bioRxiv2024

Biallelic Loss of Molecular Chaperone Molecule AIP Results in a Novel Severe Multisystem Disease Defined by Defective Proteostasis

Children born with deleterious biallelic variants of the chaperone aryl hydrocarbon receptor interacting protein (AIP) have a novel pediatric metabolic disease presenting a severe, complex clinical phenotype characterized by failure to develop following birth. Analysis of Aip knockout mouse embryonic fibroblasts and patient-derived dermal fibroblasts revealed that AIP was required to support proteostasis; including proteasome activity, induction of autophagy and lysosome function. aip knockout zebrafish, recapitulated the phenotype of the children; dying at an early stage of development when autophagy is required to adapt to periods of starvation. Our results demonstrate that AIP plays a crucial role in initiating autophagy and maintaining proteostasis in vitro and in vivo. One Sentence SummaryHomozygous loss of the chaperone AIP results in a novel pediatric disease exhibiting multiple features of a lysosomal storage disease.

molecular biology↗

bioRxiv2020

Male-biased islet β cell dysfunction is caused by the MODY MAFA S64F variant inducing premature aging and senescence

A heterozygous missense mutation producing a variant of the islet {beta}-cell-enriched MAFA transcription factor (Ser(S)64Phe(F) MAFA) was identified in humans who developed adult-onset, {beta}-cell dysfunction (diabetes or insulinomatosis), with men more prone to diabetes. This mutation engenders increased stability to the normally unstable MAFA protein. To obtain insight into how this variant impacts {beta} cell function, we developed a mouse model expressing S64F MafA and found sex-dependent phenotypes, with heterozygous mutant males displaying impaired glucose tolerance while females were slightly hypoglycemic with improved blood glucose clearance. Only heterozygous males showed transiently higher MafA protein levels preceding the onset of glucose intolerance and sex-dependent, differential expression of genes involved in calcium signaling, DNA damage, aging, and senescence. Functional changes in islet calcium handling and signs of islet aging and senescence processes were uniquely observed in male animals. In addition, S64F MAFA expression in human, male EndoC-{beta}H2 {beta} cells accelerated cellular senescence and increased production of senescence-associated secretory proteins compared to cells expressing wild-type MAFA. Together, these results implicate a conserved mechanism of accelerated islet aging and senescence in promoting diabetes in S64F MAFA carriers in a sex-dependent manner.

molecular biology↗