Biology subjects

Borges, K. S.

Publications and source records attributed to Borges, K. S..

4 recordsLinked to original sources

bioRxiv2026

EGFR INHIBITION PROMOTES ENTEROENDOCRINE CELL DIFFERENTIATION CONTRIBUTING TO TREATMENT-ASSOCIATED DIARRHEA

Enteroendocrine cells (EECs) are specialized sensors of the gastrointestinal (GI) epithelium that regulate gut function and systemic metabolism through hormone secretion. The molecular pathways directing intestinal stem cell (ISC) differentiation into EECs are incompletely understood due, in part, to their rarity. We sought to identify novel regulators of human EEC differentiation using a high-throughput screen of FDA-approved drugs and human duodenal organoids. Two epidermal growth factor receptor inhibitors (EGFRi) commonly used in cancer therapy and known to cause GI side effects, erlotinib and lapatinib, emerged as strong inducers of EEC differentiation, dramatically increasing chromogranin A (CHGA) expression compared to controls, while maintaining ISC function and organoid growth. EGFRi-treated organoids revealed robust and broad upregulation of EEC hormones, including serotonin (5HT), motilin (MLN), and somatostatin (SST), among others. In agreement with these findings, analysis of a patient cohort with lung cancer revealed an association with erlotinib use and increased circulating levels of the above EEC hormones compared to matched controls. Supporting a direct effect of EGFRi on EEC differentiation, mice treated with erlotinib demonstrated increased EEC numbers and hormones and showed EGFRi-associated diarrhea (EAD), a limiting side effect of these medications. Mechanistically, EGFRi induced upregulation of interferon (IFN) signaling targets during early ISC-to-EEC differentiation. Consistent with this, inhibition of Signal Transducer and Activator of Transcription 1 (STAT1) attenuated EGFRi-induced EEC differentiation. These findings provide important insight into EEC differentiation that could inform treatment strategies for EAD, metabolic diseases, and GI diseases. Brief SummaryInhibition of EGFR signaling promotes human ISC-to-EEC differentiation through activation of STAT1 signaling.

cell biology↗

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↗

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↗

bioRxiv2022

β-catenin programs a tissue-specific epigenetic vulnerability in aggressive adrenocortical carcinoma

Adrenocortical carcinoma (ACC) is a rare cancer in which tissue-specific differentiation is paradoxically associated with dismal outcomes. The differentiated ACC subtype CIMP-high is prevalent, incurable, and routinely fatal. CIMP-high ACC possess abnormal DNA methylation and frequent {beta}-catenin activating mutations. Here, we demonstrate that ACC differentiation is maintained by a balance between nuclear, tissue-specific {beta}-catenin-containing complexes and the epigenome. On chromatin, {beta}-catenin binds master adrenal transcription factor SF1 and hijacks the adrenocortical super-enhancer landscape to maintain differentiation. Off chromatin, {beta}-catenin binds histone methyltransferase EZH2, which is redistributed by the CIMP-high DNA methylation signature. SF1/{beta}-catenin and EZH2/{beta}-catenin complexes exist in normal adrenals and are selected for through all phases of ACC evolution. Pharmacologic EZH2 inhibition in CIMP-high ACC favors EZH2/{beta}-catenin assembly and purges SF1/{beta}-catenin from chromatin, erasing differentiation and restraining cancer growth in vitro and in vivo. Our studies illustrate how tissue-specific programs shape oncogene selection, surreptitiously encoding targetable therapeutic vulnerabilities.

cancer biology↗