Biology subjects

Stubben, C. J.

Publications and source records attributed to Stubben, C. J..

5 recordsLinked to original sources

bioRxiv2026

SWI/SNF Alterations Define a Chromatin-Dependent Subtype of Urothelial Carcinoma

PurposeSWI/SNF (BAF) chromatin remodeling complex alterations are common in urothelial carcinoma, yet no biomarker-directed therapeutic strategies have been established for this population. We investigated whether BAF alterations delineate a biologically distinct, therapeutically actionable urothelial carcinoma subtype. Experimental DesignWe performed integrative genomic and transcriptomic analyses of 792 urothelial carcinoma tumors from the Oncology Research Information Exchange Network (ORIEN) and validated findings in the TCGA-BLCA cohort. Mechanistic studies incorporated RNA sequencing and ATAC-seq following histone deacetylase (HDAC) inhibition. Functional dependencies were assessed using patient-derived xenograft organoids and cell line models. Clinical relevance was explored in a biomarker-enriched investigator-initiated trial. ResultsApproximately half of urothelial carcinoma tumors exhibited BAF alterations, defining a previously unrecognized chromatin-altered molecular subtype characterized by activation of proliferative programs, loss of lineage identity, and altered metabolic signaling. This subtype was enriched for transcriptomic programs associated with HDAC inhibitor sensitivity and depleted of HDAC inhibitor resistance signatures. Mechanistically, HDAC inhibition induced widespread chromatin remodeling with reduced accessibility at AP-1 and TEAD-associated regions, and downregulation of E2F- and MYC-driven transcriptional networks. Functional studies confirmed enhanced HDAC inhibition sensitivity in ARID1A-mutated cell lines and a patient-derived organoid model. Early clinical observations demonstrated a durable responder treated with HDAC inhibitors and immunotherapy. ConclusionsBAF alterations define a chromatin-dependent tumor state in urothelial carcinoma that is selectively vulnerable to HDAC inhibition. Integrating genomic, epigenomic, functional, and early clinical evidence, these findings provide a rationale for biomarker-enriched clinical trials and HDAC inhibitor-based combination strategies in urothelial carcinoma.

cancer biology↗

bioRxiv2026

Integrative Clinical-Molecular Modeling Identifies LRRN4CL as a Determinant of Structural and Functional Myocardial Improvement

BackgroundMechanical ventricular unloading and systemic circulatory support with left ventricular assist devices (LVADs) enable myocardial recovery in a subset of advanced heart failure (HF) patients, but predictors and mechanisms of recovery are not well understood. Integrating clinical and molecular data may improve identification of patients most likely to recover and uncover biologically relevant targets in HF. MethodsWe collected and analyzed left ventricular apical myocardial tissue and clinical data from 208 patients undergoing LVAD implantation across five centers. Pre-implant transcriptomic profiles (22,373 mRNA transcripts) were integrated with 59 clinical variables using supervised machine learning with repeated cross-validation to identify and prioritize features associated with myocardial recovery, defined as a binary outcome based on improvement in left ventricular ejection fraction (LVEF [≥]40%) and left ventricular end-diastolic diameter (LVEDD [≤]5.9 cm). We also modeled functional (LVEF) and structural (LVEDD) improvement as a continuous outcome without any predefined LVEF and LVEDD pathological thresholds. Feature prioritization was followed by validation in human myocardial tissue and mechanistic interrogation in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). ResultsIntegrative models achieved modest discrimination for myocardial recovery as a binary categorical outcome (maximum mean cross-validated area under the curve 0.73{+/-}0.15), identifying clinical features such as HF duration, LVEDD, HF pharmacologic therapy, and device configuration. Leucine-rich repeat neuronal 4C-like (LRRN4CL), measured in human myocardium, consistently emerged as a top transcriptomic predictor across both binary and continuous metric models (functional and structural). Higher pre-LVAD LRRN4CL expression was associated with reduced likelihood of myocardial recovery and localized primarily to cardiomyocytes. In iPSC-CMs, LRRN4CL overexpression localized to the sarcoplasmic reticulum, induced transcriptional remodeling characterized by suppression of contractile pathways and activation of stress programs, impaired calcium handling, impaired contraction-relaxation kinetics, and diminished mitochondrial respiratory reserve capacity. ConclusionsIntegration of clinical and myocardial transcriptomic data identifies LRRN4CL as a novel marker associated with impaired myocardial recovery following LVAD-mediated ventricular unloading and systemic circulatory support. These findings move beyond predictive modeling, linking integrative computational discovery to cardiomyocyte dysfunction and providing a translational framework for biologically informed risk stratification and therapeutic targeting for myocardial recovery. CLINICAL PERSPECTIVEO_ST_ABSWhat Is New?C_ST_ABSO_LIIntegrative clinical and myocardial transcriptomic modeling identifies LRRN4CL as a novel molecular determinant of structural and functional changes after LVAD-mediated ventricular unloading and enhanced systemic circulatory support. C_LIO_LIElevated LRRN4CL expression is associated with adverse remodeling signatures, impaired calcium handling, and stress responses in human iPSC-derived cardiomyocytes. C_LIO_LIExperimental overexpression of LRRN4CL directly disrupts calcium cycling, contractile performance, and mitochondrial respiration linking molecular signature to functional phenotype. C_LI What Are the Clinical Implications?O_LIIdentification of LRRN4CL as a marker associated with impaired myocardial recovery supports future efforts toward biologically informed risk stratification for patients undergoing LVAD therapy. C_LIO_LILRRN4CL as a marker of cardiac improvement potential may extend beyond advanced HF to earlier stage disease patients and inform prognosis, risk stratification, and response to medical therapies. C_LIO_LIThese findings highlight LRRN4CL-associated pathways as potential therapeutic targets and demonstrate how integrative clinical-transcriptomic approaches can move beyond clinical prediction toward identification of new biologically precise therapeutic targets in HF following a bedside to bench and back approach. C_LI

bioinformatics↗

bioRxiv2026

Excessive Ca2+-dependent ER-mitochondrial contact stabilization by EFHD1 drives liver injury

Metabolic-associated steatohepatitis (MASH) involves hepatocyte damage that cannot be explained solely by lipid accumulation. Here, to discover injury-specific pathways, we focused on a gene of uncertain function, EF-Hand Domain Family Member D1 (EFHD1), identified in human genome-wide association studies of liver injury but not liver fat. We show that EFHD1, a Ca2+-dependent actin crosslinker, stabilizes endoplasmic reticulum-mitochondria contact sites (ERMCS), detecting spatiotemporal coincidence of inter-organellar proximity and ER Ca2+ release. During MASH, EFHD1 upregulation drives pathological mitochondrial fragmentation via excessive contact persistence. This structural failure promotes mitochondrial double-stranded RNA escape and activation of a maladaptive antiviral PKR-dependent stress response, a causal relationship also supported by Mendelian randomization in humans. Consequently, inhibiting EFHD1 in human and mouse models blunts hepatocyte damage. These findings identify EFHD1 as a Ca2+-dependent ERMCS stabilizer, reveal a hepatocyte-intrinsic injury pathway, and suggest EFHD1 inhibition as a therapeutic strategy.

cell biology↗

bioRxiv2025

RNA splicing is required for timely completion of abscission and is modulated by the abscission checkpoint

The abscission checkpoint pauses the progression of cytokinetic abscission at the intercellular bridge when various checkpoint-sustaining errors are sensed. A unique cytoplasmic organelle, the abscission checkpoint body (ACB), forms when the abscission checkpoint is active. This organelle houses proteins involved in abscission and RNA splicing factors. Here, we investigate the role of RNA splicing factors in abscission checkpoint maintenance. A specific subset of RNA splicing factors localizes to ACBs, while others move back into the nucleus. The key RNA splicing factor SF3b1 is aberrantly localized in the cytoplasm and its catalytic activity limited when ACBs are present. Efficient abscission was found to rely on RNA splicing, and we have identified patterns in gene expression and RNA splicing that occur at this time in cell division. Finally, we found a unique RNA landscape associated with the formation of ACBs due to a specific set of changes in RNA expression and alternative splicing, revealing a previously unrecognized level of regulation imparted by abscission checkpoint activity.

cell biology↗

bioRxiv2022

Senescence-Induced Immune Remodeling Facilitates Metastatic Adrenal Cancer in a Sex-Dimorphic Manner

Aging is a carcinogen that markedly increases cancer risk, yet we have limited mechanistic understanding of cancer initiation in aged cells. Here, we demonstrate induction of the hallmark aging process cellular senescence, triggered by loss of Wnt inhibitor ZNRF3, remodels the tissue microenvironment and ultimately permits metastatic adrenal cancer. Detailed characterization reveals a striking sexual dimorphism. Males exhibit earlier senescence activation and a greater innate immune response. This results in high myeloid cell accumulation and lower incidence of malignancy. Conversely, females present a dampened immune response and are more prone to metastatic cancer. Senescence-recruited myeloid cells become increasingly depleted with advanced tumor progression, which is recapitulated in patients where a low myeloid signature is associated with worse outcome. Collectively, our study reveals a novel role for myeloid cells in restraining adrenal cancer progression with significant prognostic value, and provides a model for interrogating pleiotropic effects of cellular senescence in cancer. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=67 SRC="FIGDIR/small/488426v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@bddf22org.highwire.dtl.DTLVardef@18434a3org.highwire.dtl.DTLVardef@9bc772org.highwire.dtl.DTLVardef@1430fbb_HPS_FORMAT_FIGEXP M_FIG Graphical abstract created with BioRender.com C_FIG

cancer biology↗