Biology subjects

Krucker, C.

Publications and source records attributed to Krucker, C..

4 recordsLinked to original sources

bioRxiv2025

Deep Learning Bridges Histology and Transcriptomics to Predict Molecular Subtypes and Outcomes in Muscle-Invasive Bladder Cancer

Muscle-Invasive Bladder Cancer (MIBC) is a heterogeneous disease with distinct molecular subtypes influencing prognosis and therapeutic response. However, molecular profiling through RNA sequencing remains costly, time-consuming and complicated by intratumoral heterogeneity. We developed a Deep Learning (DL) approach to infer molecular subtypes from routine histopathological slides and to evaluate its prognostic value in patients treated with neoadjuvant chemotherapy (NAC). We developed an DL-model predicting the expression of 848 subtype-associated genes from histological images of transurethral resection of bladder tumor, enabling spatial molecular subtyping at tile level. The model was trained on 297 NAC-treated patients from the VESPER clinical trial and evaluated on three independent cohorts (COBLAnCE, n=224; Saint-Louis, n=30 and TCGA, n=315), covering diverse staining protocols and scanner types. Spatial transcriptomics from six VESPER patients confirmed the spatial consistency of the inferred expression profiles. Our approach achieved a ROC AUC of 0.94 for molecular subtype prediction, with 95% of genes significantly predicted, demonstrating its ability to capture transcriptomic dysregulations from histological morphology. Predicted expression maps revealed spatially coherent patterns and intratumoral molecular heterogeneity. Importantly, tumors predicted with basal/squamous features (pure or mixed), were associated with significantly worse progression-free and overall survival after NAC (log-rank p=0.014 and 0.037, respectively). This DL-based framework enables accurate and spatially resolved inference of gene expression and molecular subtypes in MIBC without sequencing. These findings could improve patient stratification in clinical practice and support the design of more targeted clinical trials. Further validation in larger cohorts is needed before routine clinical implementation.

cancer biology↗

bioRxiv2022

Integrated molecular and pharmacological characterization of patient-derived xenografts from bladder and ureteral cancers identifies new potential therapies.

BackgroundMuscle-invasive bladder cancer (MIBC) and upper urinary tract urothelial carcinoma (UTUC) are molecularly heterogeneous. Despite chemotherapies, immunotherapies or anti-FGFR treatments, these tumors are still of poor outcome. Our objective was to develop a bank of patient-derived xenografts (PDXs) recapitulating molecular heterogeneity of MIBC and UTUC, to facilitate preclinical identification of therapies. MethodsFresh tumors were obtained from patients and subcutaneously engrafted into immune-compromised mice. Patient tumors and matched PDXs were compared regarding histopathology, transcriptomic (microarrays) and genomic profiles (targeted-NGS). Several PDXs were treated with chemotherapy (cisplatin/gemcitabine) or targeted therapies (FGFR and EGFR inhibitors). Results31 PDXs were established from 1 non-MIBC, 25 MIBC, 5 upper urinary tract tumors, including 28 urothelial (UCC) and 3 squamous-cell carcinomas (SCC). Integrated genomic and transcriptomic profiling identified PDXs of 3 different consensus molecular subtypes (Basal/Squamous, Luminal papillary and Luminal unstable), and included FGFR3-mutated PDXs. High histological and genomic concordance was found between matched patient tumor/PDX. Discordance in molecular subtypes, such as a basal/squamous patient tumor giving rise to a luminal papillary PDX, was observed (n=5) at molecular and histological levels. Ten models were treated with cisplatin-based chemotherapy and we did not observe association between subtypes and response. Of the 3 basal/squamous models treated with anti-EGFR therapy, two models were sensitive and one model, of sarcomatoid variant, was resistant. Treatment of 3 FGFR3-mutant PDXs with combined FGFR/EGFR inhibitors was more efficient than anti-FGFR3 treatment alone. ConclusionsWe developed preclinical PDX models that recapitulate the molecular heterogeneity of MIBCs and UTUC, including actionable mutations, which will represent an essential tool in therapy development. Pharmacological characterization of the PDXs suggested that upper urinary tract and MIBCs, UCC but also SCC, with similar molecular characteristics could benefit from the same treatments including anti-FGFR for FGFR3-mutated tumors and anti-EGFR for basal ones and showed a benefit for combined FGFR/EGFR inhibition in FGFR3-mutant PDXs, compared to FGFR inhibition alone.

cancer biology↗

bioRxiv2022

Epigenomic mapping identifies a super-enhancer repertoire that regulates cell identity in bladder cancers through distinct transcription factor networks

Muscle-invasive bladder cancer (BLCA) is an aggressive disease. Consensus BLCA transcriptomic subtypes have been proposed, with two major Luminal and Basal subgroups, presenting distinct molecular and clinical characteristics. However, how these distinct subtypes are regulated remains unclear. We hypothesized that epigenetic activation of distinct super-enhancers could drive the transcriptional programs of BLCA subtypes. Through integrated RNA-sequencing and epigenomic profiling of histone marks in primary tumours, cancer cell lines, and normal human urothelia, we established the first integrated epigenetic map of BLCA and demonstrated the link between subtype and epigenetic control. We identified the repertoire of activated super-enhancers and highlighted Basal, Luminal and Normal-associated SEs. We revealed the super-enhancer-regulated networks of candidate master transcription factors for Luminal and Basal subgroups including FOXA1 and ZBED2 respectively. FOXA1 CRISPR-Cas9 mutation triggered a shift from Luminal to Basal phenotype, confirming its role in Luminal identity regulation and induced ZBED2 overexpression. In parallel, we showed that both FOXA1 and ZBED2 play concordant roles in preventing inflammatory response in cancer cells through STAT2 inhibition. Our study furthers the understanding of epigenetic regulation of muscle-invasive BLCA and identifies a co-regulated network of super-enhancers and associated transcription factors providing potential targets for the treatment of this aggressive disease.

cancer biology↗

bioRxiv2019

PPARG is a tumor suppressor in basal bladder tumors offering new potential therapeutic opportunities.

PPAR{gamma} activation is a critical event in luminal muscle-invasive bladder cancer (MIBC) tumorigenesis, favoring both tumor cell growth and microenvironment modulation toward tumor immune escape. Conversely, the down-regulation of PPAR{gamma} activity in basal MIBC suggests tumor suppressive effects in this subgroup. Here, we report genetic, epigenetic and functional evidence to support the tumor suppressor role for PPAR{gamma} in basal bladder tumors. We identified hemizygous deletions, DNA hyper-methylation and loss-of-function mutations of PPAR{gamma} in basal MIBC, associated with PPAR{gamma} under-expression and its decreased activity. Re-expression of PPAR{gamma} in basal tumor cells resulted in the activation of PPAR{gamma} -dependent transcription program that modulated fatty acid metabolism and cell differentiation and decreased cell growth, which could partly rely on EGFR down-regulation. Structure-function studies of two PPAR{gamma} mutant revealed a destabilization of a region important for coactivator recruitment and should help develop potent molecules to activate PPAR{gamma} as a therapeutic strategy for basal MIBC. The identification of this subtype-dependent dual role of PPAR{gamma} in MIBC strengthens the critical role of PPAR{gamma} in bladder tumorigenesis and reinforces the interest in stratified medicine based on tumor molecular subtyping. One sentence summaryGenetic, epigenetic and functional evidence of a tumor suppressor role for PPAR{gamma} in basal bladder tumors offer new therapeutic opportunities for this subgroup.

cancer biology↗