Biology subjects

Bellmunt, J.

Publications and source records attributed to Bellmunt, J..

7 recordsLinked to original sources

bioRxiv2026

A tumor-cell MHC-II program is associated with checkpoint-blockade outcomes across stages of bladder cancer

Purpose: A minority of patients with bladder cancer derive lasting benefit from immunotherapy, and current biomarkers capture only part of the biology. We evaluated whether tumor-cell MHC class II defines an immune state associated with outcome across disease stages and after PD-1/PD-L1 blockade. Experimental Design: We localized differential MHC-II activity to malignant epithelial cells by single-nucleus and single-cell RNA sequencing and confirmed HLA-DR expression by immunohistochemistry in 122 specimens. Chromatin profiling and IFN-{gamma} stimulation of cell lines and primary tumors supported derivation of an 11-gene tumor-cell program. Associations were tested in 434 patients with non-muscle-invasive disease, 82 receiving neoadjuvant pembrolizumab, and 288 receiving atezolizumab for metastatic disease. Results: Tumor-cell MHC-II was present in approximately one third of bladder cancers, and malignant cells accounted for the differential signal between MHC-II-high and MHC-II-low tumors. The program was inducible by IFN-{gamma} through JAK/STAT signaling. Within luminal non-muscle-invasive disease, MHC-II-low status was associated with progression (HR 3.31, 95% CI 1.37 to 7.99). In PURE-01, the 11-gene program was associated with pathological complete response (52% versus 24%, p = 0.018) and recurrence-free survival (p = 0.0054), retaining an independent association in models including tumor mutational burden and PD-L1. In bladder-primary metastatic disease, program-high status was associated with overall survival in unadjusted analysis (HR 0.62, 95% CI 0.44 to 0.89); the association did not extend to upper tract tumors (interaction p = 0.0018). Conclusions: Tumor-cell MHC-II defines an inducible state associated with outcomes across bladder cancer stages and after checkpoint blockade, supporting prospective evaluation by RNA and immunohistochemistry.

cancer biology↗

bioRxiv2026

Integrated inference of cancer gene expression from cell-free plasma chromatin

Gene expression is a defining determinant of tumor identity, behavior, and therapeutic response, yet remains challenging to measure noninvasively. Here, we introduce APEX (Associating Plasma Epigenomic features with eXpression), a framework for inferring expression from circulating cell-free chromatin. Trained on [~]270,000 gene-sample pairs from matched tumor RNA-seq and plasma cfChIP-seq across multiple cancers and validated on >15 unseen cancer subtypes, APEX accurately infers cancer gene expression across a range of tumor fractions and outperforms existing plasma-based approaches by integrating positional histone mark and DNA fragmentation patterns across promoters and gene bodies. Using plasma alone, APEX enables classification of prognostically relevant basal and classical pancreatic cancer subtypes and identifies plasma-inferred NECTIN4 expression as a biomarker of response to enfortumab vedotin in metastatic bladder cancer. Together, these findings establish APEX as a biopsy-free approach for profiling tumor transcriptional states and extend liquid biopsy beyond genomic alterations to clinically relevant gene expression programs.

genomics↗

bioRxiv2025

Tumor-myeloid crosstalk drives therapy resistance in localized bladder cancer

Neoadjuvant cisplatin-based chemotherapy results in pathologic complete response for only a minority of patients with muscle-invasive bladder cancer (MIBC), and mechanisms of resistance and the effects of chemotherapy on the MIBC microenvironment remain incompletely understood. Here, we defined the single-cell and spatial transcriptomes of cancer and immune cells from MIBC patients with resistance to cisplatin-based chemotherapy. Tumors with persistent MIBC after chemotherapy harbored cancer cells expressing epithelial-to-mesenchymal programs that were associated with worse overall survival in independent cisplatin-treated bladder cancer cohorts. These cisplatin-resistant tumor cells were infiltrated by macrophages that upregulated tumor permissive programs defined by increased PARP14 expression in spatially resolved multicellular niches. Macrophage reprogramming through PARP14 inhibition sensitized tumors to cisplatin via downregulation of tumor cell pathways implicated in resistance. Our results demonstrate that cancer cells and macrophages cooperate to promote cisplatin resistance and identify macrophage-directed PARP14 inhibition as a novel therapeutic strategy to sensitize MIBC to cisplatin.

cancer biology↗

bioRxiv2025

Epigenetic Subtypes of High-Grade T1 Bladder Cancer Reveal Intra-Tumor Heterogeneity and Distinct Interactions with Tumor Microenvironment.

High-Grade T1 (HGT1) Non-Muscle Invasive Bladder Cancer (NMIBC) is a clinically heterogeneous disease, characterized by unpredictable treatment responses and limited tools for recurrence prediction. Although molecular classification efforts have been made, patient stratification still primarily relies on clinicopathological features, which offer limited clinical precision. In this study, we integrated chromatin profiling in bulk with single-nuclei(sn) RNA-seq, immunohistochemistry and spatial transcriptomics to define epigenetic subtypes of HGT1, characterize their heterogeneity, and investigate tumor-microenvironment interactions. Our findings reveal distinct chromatin profiles differentiating urothelial (URO) and micropapillary (MP) histological variants of high-risk HGT1. We identified three epigenetic states: two within the URO group, luminal-like inflammatory (LLI) and basal-like (BL), and a separate signature unique to MP tumors. Single-cell and spatial resolution approaches validated intratumoral heterogeneity and provided insight into subtype-specific microenvironmental contexts. Notably, [~]40% of URO tumors exhibited spatially distinct coexisting LLI and BL components. BL regions showed enrichment for angiogenesis and hypoxia pathways and were preferentially located near vascular stroma, while LLI regions showed to be located at the core of the tumor. MP tumors featured a markedly different microenvironment, characterized by diverse populations of cancer-associated fibroblasts (CAFs) and M2-polarized macrophages intermingled with tumor cells, suggesting a more immunosuppressive niche which could account for their worse clinical outcome. URO tumors, by comparison, showed a more immune-excluded phenotype. These findings provide a detailed molecular and spatial map of bladder cancer heterogeneity, highlighting how distinct epigenetic subtypes and histological variants are associated with tumor architecture and microenvironmental interactions. Our data underscore the need for subtype-specific therapeutic strategies to more effectively address the complexity already existing at HGT1 bladder cancer.

cancer biology↗

bioRxiv2024

Predicting immunotherapy response in advanced bladder cancer: a meta-analysis of six independent cohorts

Advanced bladder cancer patients show very variable responses to immune checkpoint inhibitors (ICIs) and effective strategies to predict response are still lacking. Here we integrate mutation and gene expression data from 707 advanced bladder cancer patients treated with anti-PD-1/anti-PD-L1 to build highly accurate predictive models. We find that, in addition to tumor mutational burden (TMB), enrichment in the APOBEC mutational signature, and the abundance of pro-inflammatory macrophages, are major factors associated with the response. Paradoxically, patients with high immune infiltration do not show an overall better response. We show that this can be explained by the activation of immune suppressive mechanisms in a large portion of these patients. In the case of non-immune-infiltrated cancer subtypes, we uncover specific variables likely to be involved in the response. Our findings provide novel information for advancing precision medicine in patients with advanced bladder cancer treated with immunotherapy.

cancer biology↗

bioRxiv2020

Subtype Heterogeneity and Epigenetic Convergence in Neuroendocrine Prostate Cancer

Neuroendocrine carcinomas (NEC) are tumors expressing markers of neuronal differentiation that can arise at different anatomic sites but have strong histological and clinical similarities. Here we report the chromatin landscapes of a range of human NECs and show convergence to the activation of a common epigenetic program. With a particular focus on treatment emergent neuroendocrine prostate cancer (NEPC), we analyzed cell lines, patient-derived xenograft (PDX) models and human clinical samples to show the existence of two distinct NEPC subtypes based on the expression of the neuronal transcription factors ASCL1 and NEUROD1. While in cell lines and PDX models these subtypes are mutually exclusive, single cell analysis of human clinical samples exhibit a more complex tumor structure with subtypes coexisting as separate sub-populations within the same tumor. These tumor sub-populations differ genetically and epigenetically contributing to intra- and inter-tumoral heterogeneity in human metastases. Overall our results provide a deeper understanding of the shared clinicopathological characteristics shown by NECs. Furthermore, the intratumoral heterogeneity of human NEPCs suggests the requirement of simultaneous targeting of coexisting tumor populations as a therapeutic strategy.

cancer biology↗

bioRxiv2018

The consensus molecular classification of muscle-invasive bladder cancer

Muscle-Invasive Bladder Cancer (MIBC) is a molecularly diverse disease with heterogeneous clinical outcomes. Several molecular classifications have been proposed, yielding diverse sets of subtypes, which hampers the clinical implications of such knowledge. Here, we report the results of a large international effort to reach a consensus on MIBC molecular subtypes. Using 1750 MIBC transcriptomes and a network-based analysis of six independent MIBC classification systems, we identified a consensus set of six molecular classes: Luminal Papillary (24%), Luminal Non-Specified (8%), Luminal Unstable (15%), Stroma-rich (15%), Basal/Squamous (35%), and Neuroendocrine-like (3%). These consensus classes differ regarding underlying oncogenic mechanisms, infiltration by immune and stromal cells, and histological and clinical characteristics. This consensus system offers a robust framework that will enable testing and validating predictive biomarkers in future clinical trials.

cancer biology↗