Biology subjects

Alvarez, J. R.

Publications and source records attributed to Alvarez, J. R..

3 recordsLinked to original sources

bioRxiv2026

p38α MAPK integrates opposing oncogenic APC/β-catenin/TCF and GUCY2C tumor-suppressor axes in colorectal cancer

Introduction: Sporadic colorectal cancers (CRCs) form following initiating APC mutations, inducing constitutive {beta}-catenin/TCF signaling. Similarly, the guanylyl cyclase C (GUCY2C) tumor suppressor axis is universally silenced in CRC. While the GUCY2C receptor is retained, loss of its paracrine hormones guanylin (GUCA2A) and uroguanylin (GUCA2B) is among the earliest events in transformation. Mutant APC/{beta}-catenin/TCF signaling driving CRC transcriptionally silences GUCY2C hormone expression while suppressing that oncogenic pathway reconstitutes hormone production opposing tumorigenesis. p38 opposes tumor initiation, and its loss promotes transformation in chemical and genetic mouse models of CRC. In healthy intestine, p38 supports a gradient of epithelial differentiation along the crypt-surface axis. Here, we reveal that p38 links regulation of oncogenic APC/{beta}-catenin/TCF signaling and GUCY2C hormone expression. Methods: Regulation of p38 by APC/{beta}-catenin/TCF signaling was defined in four genetically engineered human CRC cell lines with conditional oncogenic APC/{beta}-catenin/TCF signaling and healthy human colon organoids. Expression of p38 was eliminated from conditional human CRC cell lines by pharmacological inhibition, RNA knockdown, and CRISPR/Cas9 gene editing. Transcriptomic analysis of these cells by RNA sequencing defined the set of genes regulated by APC/{beta}-catenin/TCF signaling controlled through p38. Results: In CRC cell lines, APC/{beta}-catenin/TCF signaling suppressed p38 phosphorylation and activity, whereas inhibition of APC/{beta}-catenin/TCF restored p38 signaling. In the absence of APC/{beta}-catenin/TCF signaling, inhibiting p38 repressed GUCY2C hormone expression. Inhibiting APC/{beta}-catenin/TCF signaling enriched phosphorylated p38 at the GUCA2A promoter. In that context, analysis of the CPTAC proteomic database revealed that phosphorylation of p38 and its upstream kinases MKK3 and MKK4 was reduced in human CRC. Finally, transcriptomic analysis revealed that p38 is a critical signaling node controlling the expression of a substantial subset of APC/{beta}-catenin/TCF-regulated genes in human CRC cells and patient tumors. Conclusions: APC/{beta}-catenin/TCF signaling inhibits p38 phosphorylation and transcriptional activity, suppressing GUCA2A and GUCA2B expression and functionally silencing the retained GUCY2C receptor. These findings identify p38 as a signaling intermediary integrating oncogenic APC/{beta}-catenin/TCF activity to extinction of the GUCY2C tumor-suppressor axis and reveal a broader p38-dependent component of the APC/{beta}-catenin/TCF-regulated transcriptome.

cancer biology↗

bioRxiv2025

Spatial transcriptomics AI agent charts hPSC-pancreas maturation in vivo

Spatial transcriptomics has revolutionized our understanding of tissue organization by simultaneously capturing gene expression and spatial localization within intact tissues. However, analyzing these increasingly complex datasets requires specialized expertise across computational biology, statistics, and biological context. To address this challenge, we introduce the Spatial Transcriptomics AI Agent (STAgent), an autonomous multimodal agentic AI that integrates multimodal large language models (LLMs) with specialized computational tools to transform weeks-long analysis tasks into minutes of automated processing. Unlike conventional machine learning approaches that are limited to narrow, predefined tasks, STAgent leverages the emergent capabilities of multimodal LLMs - such as flexible reasoning, contextual understanding, and cross-modal integration - which allow it to adapt to novel data, execute multi-step analyses, and generate biologically meaningful insights with minimal human input. STAgent enables autonomous deep research through integrated capabilities, including dynamic code generation for complex analytical workflows, visual reasoning for interpreting spatial patterns, real-time retrieval of relevant peer-reviewd scientific literature, and synthesis of comprehensive, actionable reports. We applied STAgent to investigate the in vivo maturation of human stem cell-derived pancreatic cells (SC-pancreas) transplanted into immunodeficient mice. We generated single-cell spatial transcriptomics data spanning multiple developmental timepoints. STAgent autonomously (1) identified the maturation of initially scattered endocrine cells into well-defined islet-like structures, with predominantly peripheral -cells surrounding {beta}-cell cores supported by an expanding mesenchymal network; (2) revealed strengthening endocrine-endocrine cell interactions over time and, through context-aware gene set analysis, uncovered spatially resolved biological processes driving maturation; (3) unlike traditional analytical approaches, STAgent offers mechanistic explanations of spatial patterns, contextualizing findings with relevant literatures and developing cohesive insights into human pancreatic development. This agentic approach establishes a new paradigm in spatial transcriptomics analysis by substantially lowering the expertise barrier and reducing analysis time, accelerating biological and biomedical discovery.

genomics↗

bioRxiv2024

Integrated multiomic analysis identifies TRIP13 as a mediator of alveolar epithelial type II cell dysfunction in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a lethal progressive lung disease urgently needing new therapies. Current treatments only delay disease progression, leaving lung transplant as the sole remaining option. Recent studies support a model whereby IPF arises because alveolar epithelial type II (AT2) cells, which normally mediate distal lung regeneration, acquire airway and/or mesenchymal characteristics, preventing proper repair. Mechanisms driving this abnormal differentiation remain unclear. We performed integrated transcriptomic and epigenomic analysis of purified AT2 cells which revealed genome-wide alterations in IPF lungs. The most prominent epigenetic alteration was activation of an enhancer in thyroid receptor interactor 13 (TRIP13), coinciding with TRIP13 upregulation. TRIP13 is broadly implicated in epithelial-mesenchymal plasticity and transforming growth factor-{beta} signaling. In cultured human AT2 cells and lung slices, small molecule TRIP inhibitor DCZ0415 prevented acquisition of the mesenchymal gene signature characteristic of IPF, suggesting TRIP13 inhibition as a potential therapeutic approach to fibrotic disease.

bioinformatics↗