Biology subjects

Berber, M.

Publications and source records attributed to Berber, M..

3 recordsLinked to original sources

bioRxiv2025

Rho-ROCK signaling and α-Catenin mediate β-Catenin-driven hyperplasia in the adrenal via adherens junctions

How {beta}-Catenin ({beta}Cat) mediates tissue hyperplasia is poorly understood. To explore this, we employed the adrenal cortex as a model system given its stereotypical spatial organization and the important role {beta}Cat plays in homeostasis and disease. For example, excessive production of aldosterone by the adrenal cortex (primary aldosteronism, PA) constitutes a significant cause of cardiovascular morbidity, which has been associated with {beta}Cat gain-of-function ({beta}Cat-GOF). Adherens junctions (AJs) connect the actin cytoskeletons of adjacent zona Glomerulosa (zG) cells via a cadherin/{beta}Cat/-Catenin (Cat) complex and mediate aldosterone production. Whether {beta}Cat-GOF drives zG hyperplasia, a key feature of PA, via AJs is unknown. Here, we show that aldosterone secretagogues (K+, AngII) and {beta}Cat-GOF mediate AJ enrichment via Rho-ROCK-actomyosin signaling. In addition, Rho-ROCK inhibition leads to altered zG rosette morphology and decreased aldosterone production. Mice with zG-specific {beta}Cat-GOF demonstrate increased AJ formation and zG hyperplasia, which was blunted by Rho-ROCK inhibition and deletion of Cat. Further, analysis of human aldosterone-producing adenomas (APAs) revealed high levels of {beta}Cat expression were associated with increased membranous expression of K-Cadherin. Together, our findings identify Rho-ROCK signaling and Cat as key mediators of AJ enrichment and {beta}-Catenin-driven hyperplasia. One Sentence SummaryThis study demonstrates that {beta}-Catenin-driven hyperplasia in the adrenal cortex, a key feature of primary aldosteronism, is mediated through Rho-ROCK signaling and -Catenin-dependent stabilization of adherens junctions, with significant implications for patients with primary aldosteronism. HighlightsO_LIRho-ROCK signaling drives AJ enrichment in the adrenal C_LIO_LIROCK inhibition via fasudil blunts aldosterone production C_LIO_LI{beta}Cat drives adrenal hyperplasia via enhanced AJ enrichment C_LIO_LIROCK inhibition or [a]Cat deletion block zG hyperplasia C_LI

cell biology↗

bioRxiv2025

Glutamine antagonism suppresses tumor growth in adrenocortical carcinoma through inhibition of de novo nucleotide biosynthesis

Dysregulation of cellular metabolism is a hallmark of cancer, which remains poorly understood in adrenocortical carcinoma (ACC). Here, we dissected ACC metabolism by integrating transcriptional profiling from human and mouse ACC, targeted tissue metabolomics from a mouse ACC model, and untargeted serum metabolomics from a large patient cohort, providing cross-species validation of metabolic rewiring in ACC. This study revealed global metabolic dysregulation, involving glutamine-dependent pathways such as non-essential amino-acid and hexosamine biosynthesis, nucleotide metabolism, and glutathione biosynthesis, suggesting glutamine catabolism is a critical metabolic vulnerability in ACC. Treatment with glutamine antagonists 6-Diazo-5-Oxo-L-Norleucine (DON) and JHU-083 elicited robust anti-tumor responses. Mechanistic studies revealed DONs anti-tumor effect was primarily driven by selective inhibition of glutamine-fueled de novo nucleotide biosynthesis. Additionally, DON led to DNA damage, which yielded potent synergism with inhibition of the DNA damage response pathway. Collectively, this work highlights glutamine metabolism as a central metabolic dependency and therapeutic target in ACC. HighlightsO_LIMouse and human ACC share conserved transcriptional-metabolic programs, revealing Gln metabolism as a central, targetable vulnerability. C_LIO_LITargeted tissue metabolomic analysis in a mouse model of ACC validates dysregulation in Gln-dependent metabolic pathways. C_LIO_LITargeting of Gln metabolism with JHU-083 (6-diazo-5-oxo-L-norleucine (DON) pro-drug) achieves marked inhibition of tumor growth in vivo. C_LIO_LIHigh expression of Gln-metabolizing genes mediating de novo nucleotide biosynthesis is associated with poor prognosis in ACC. C_LIO_LIDON drives nucleotide depletion and DNA damage, leading to potent synergy with inhibition of the DNA damage response. C_LIO_LIUntargeted serum metabolomic analysis in a large cohort of patients with adrenal tumors demonstrates dysregulation of Gln and nucleotide metabolism in ACC. C_LI

cancer biology↗

bioRxiv2024

Non-canonical Wnt signaling triggered by WNT2B drives adrenal aldosterone production

The steroid hormone aldosterone, produced by the zona glomerulosa (zG) of the adrenal gland, is a master regulator of plasma electrolytes and blood pressure. While aldosterone control by the renin-angiotensin system is well understood, other key regulatory factors have remained elusive. Here, we replicated a prior association between a non-coding variant in WNT2B and an increased risk of primary aldosteronism, a prevalent and debilitating disease caused by excessive aldosterone production. We further show that in both mice and humans, WNT2B is expressed in the mesenchymal capsule surrounding the adrenal cortex, in close proximity to the zG. Global loss of Wnt2b in the mouse results in a dysmorphic and hypocellular zG, with impaired aldosterone production. Similarly, humans harboring WNT2B loss-of-function mutations develop a novel form of Familial Hyperreninemic Hypoaldosteronism, designated here as Type 4. Additionally, we demonstrate that WNT2B signals by activating the non-canonical Wnt/planar cell polarity pathway. Our findings identify WNT2B as a key regulator of zG function and aldosterone production with important clinical implications. HighlightsO_LIWNT2B variant is associated with increased risk for primary aldosteronism C_LIO_LIWnt2b knock-out mice show defects in adrenal morphology C_LIO_LIWnt2b knock-out mice have hyperreninemic hypoaldosteronism C_LIO_LIWNT2B activates non-canonical Wnt/planar cell polarity signaling C_LIO_LIWNT2B deficiency causes a new form of familial hyperreninemic hypoaldosteronism C_LI

genetics↗