Biology subjects

Maenosono, R.

Publications and source records attributed to Maenosono, R..

3 recordsLinked to original sources

bioRxiv2026

NECTIN4 defines a subtype-dependent tumor state coupling enfortumab vedotin targetability to antitumor immunity in bladder cancer

NECTIN4 is the target of enfortumab vedotin (EV), but its biological role in bladder cancer (BC) and its relationship to EV plus PD-1 blockade remain unclear. Integrating clinical multi-omics, spatial and single-cell immune profiling, and experimental models, we identify NECTIN4 as a subtype-dependent determinant of tumor state and antitumor immunity. In basal BC cells, NECTIN4 suppressed inflammatory and mesenchymal programs. Consistently, NECTIN4-high basal/squamous muscle-invasive BCs showed favorable survival, higher checkpoint inhibitor response rates, and a coordinated CD8+ T cell-inflamed microenvironment with no comparable associations in luminal papillary tumors. In orthotopic models, murine Nectin4 promoted CD8+ T cell-dependent tumor control, whereas human NECTIN4 conferred EV sensitivity. EV also attenuated NECTIN4-dependent TIGIT binding. Conversely, NECTIN4-low models were preferentially sensitive to HDAC inhibition. NECTIN4 therefore couples antibody-drug conjugate targetability to a subtype-specific tumor-immune state permissive for checkpoint blockade, whereas the NECTIN4-low state defines a distinct inflammatory-mesenchymal state with an alternative therapeutic vulnerability.

cancer biology↗

bioRxiv2026

A positional and combinatorial regulatory code for alternative splicing

Alternative pre-mRNA splicing generates extensive transcript diversity, yet the regulatory code that determines how splicing decisions are encoded across the transcriptome remains poorly defined. Splicing outcomes are controlled by combinatorial RNA-binding protein (RBP) interactions and positional context, but how these features are integrated at the transcriptome scale remains unclear. CLIP-based approaches have mapped RBP binding, but directly comparable endogenous maps across multiple RBPs are lacking, limiting inference of global regulatory principles. Here we introduce SCALE-CLIP, an endogenous CLIP framework that integrates CRISPR-Cas9-mediated epitope tagging with long-read-guided read attribution to generate directly comparable RBP binding maps across splicing-regulatory factors. Applied to 23 RBPs, SCALE-CLIP expanded endogenous RBP coverage and, across benchmarked shared factors, increased peak recovery by a median of 12.2-fold relative to ENCODE eCLIP while preserving specificity and reproducibility. We define a transcriptome-wide positional and combinatorial code for alternative splicing, in which binding position is a primary determinant of regulatory outcome: SRSF binding within alternative exons promotes inclusion, whereas binding on flanking exons drives exon skipping. Higher-order SRSF occupancy further tunes this code, buffering exon inclusion when centered on alternative exons but reinforcing repression when distributed across flanking exons. We also show that m6A provides an epitranscriptomic layer that locally enhances SRSF binding and is associated with increased exon inclusion. Together, these results establish a multi-layered RNA-binding logic in which binding position, combinatorial RBP architecture and RNA modification jointly shape splicing outcomes, providing a framework for rational interpretation and modulation of alternative splicing.

molecular biology↗

bioRxiv2021

Restored TDCA and Valine Levels Imitate the Effects of Bariatric Surgery

Obesity is widespread and linked to various co-morbidities. Bariatric surgery has been identified as the only effective treatment, promoting sustained weight loss and the remission of co-morbidities. We performed sleeve-gastrectomies (SGx) in a pre-clinical mouse model of diet-induced obesity (DIO), delineating the effects on long-term remission from obesity. SGx resulted in sustained weight loss and improved glucose tolerance. Mass-spectrometric metabolomic profiling revealed significantly reduced systemic levels of taurodeoxycholic acid (TDCA) and L-valine in DIO mice. Notably, TDCA and L-Valine levels were restored after SGx in both human and mice to levels comparable with lean controls. Strikingly, combined systemic treatment with TDCA and valine induced a profound weight loss in DIO mice analogous to effects observed after SGx. Utilizing indirect calorimetry, we confirmed reduced food intake as causal for TDCA/valine-mediated weight loss via a central inhibition of the melanin-concentrating hormone. In summary, we identified restored TDCA/valine levels as an underlying mechanism of SGx-derived effects on weight loss. Of translational relevance, TDCA and L-valine are presented as novel agents promoting weight loss while reversing obesity-associated metabolic disorders.

cell biology↗