Biology subjects

Theurillat, J.-P.

Publications and source records attributed to Theurillat, J.-P..

6 recordsLinked to original sources

bioRxiv2026

An integrated, transcript-resolution atlas of prostate cancer progression unmasks associations with oncogenic pathways

Most genes produce multiple non-coding and coding RNA transcripts with potentially divergent biological functions, yet their contribution to cancer remains largely unexplored. Here, we built an integrated, transcript-resolution RNA sequencing atlas of prostate cancer spanning 1,140 clinical samples from 10 independent studies, covering the full range of disease progression from normal tissue to primary, hormone-sensitive, and castration-resistant disease. Cross-study integration removes technical batch effects while retaining the biological heterogeneity that distinguishes these disease states, a property we validate against long-read sequencing and leverage to place newly incorporated external cohorts within this disease-progression context. We describe transcript patterns of oncogenic and tumor-suppressive long non-coding RNAs along disease progression and identify 41 protein-coding genes with significant isoform switches in cancer-relevant pathways, including WNT2B, RNF43, RELA, BRCA1, ROCK2, and TRIM11. Finally, we provide the Prostate Cancer Atlas (www.prostatecanceratlas.org), an interactive web resource that lets researchers contextualize their own transcriptomic data against this atlas.

cancer biology↗

bioRxiv2026

A modular patient-derived organoid-xenograft platform reveals molecular and clinical trajectories of prostate cancer progression

Patient-derived organoids (PDOs) are becoming increasingly important in prostate cancer (PCa) translational research. However, direct proof-of-concept studies demonstrating their ability to model disease evolution, identify relevant biomarkers, and accurately predict treatment response in PCa patients, remain scarce. Here, we report the establishment of serially transplantable xenografts series derived from two advanced PCa PDO lines, which can be further re-cultured as organoids. Newly-generated model series maintain key phenotypic, genomic, and functional characteristics of the original patient tumors, and emulate relevant molecular subtypes of advanced PCa. Single-cell RNA sequencing (scRNA-seq) analysis uncovers transcriptomic differences between xenograft and organoid models, as well as signaling pathways which are largely preserved and can be targeted ex vivo. Functional drug profiles correlate with molecular and clinical attributes, as exemplified by response to androgen receptor (AR) pathway inhibitors and glucocorticoid-mediated AR signaling activation. Longitudinal scRNA-seq analysis of perturbed PDOs identifies a rare PROX1+/ALDH1A1+ cell population, which pre-exist in the treatment-naive setting and is significantly enriched upon androgen deprivation. Notably, this cell population is similarly enriched in post-treatment samples of the original patient and is associated with aggressive AR-negative PCa molecular subtypes, suggesting a potential link with PCa progression. Our study provides proof-of-concept evidence that organoids can mirror PCa patient-specific drug sensitivity profiles and molecular paths of disease progression, uncovering pertinent biomarkers. Ultimately, our organoid-xenograft model series provide a modular and scalable platform that can readily be used for mechanistic and translational studies.

cancer biology↗

bioRxiv2025

Targeting FOXA1 and FOXA2 Disrupts the Lineage-Specific Oncogenic Output Program in Prostate Cancer

Activation of the androgen receptor (AR) is the key lineage-specific oncogenic pathway and the primary therapeutic target in prostate cancer. While AR signaling is enabled by the pioneer transcription factor FOXA1, its homolog FOXA2 is specifically expressed in advanced lineage plasticity prostate cancers that have lost the AR signaling axis. However, their roles and utility as drug targets remain incompletely characterized. Here, we show an unexpected collaboration of FOXA1 and FOXA2 in mediating AR-independent cell proliferation in different lineage plasticity cancer subtypes. Conversely, joint loss-of-function or pharmacologic disruption of FOXA1 and FOXA2 leads to the collapse of lineage-specific oncogenic transcription factors followed by cell cycle arrest. In summary, our findings uncover a druggable dependency for AR-positive and - negative prostate cancers.

cancer biology↗

bioRxiv2025

TRIM24 Degradation Counteracts Adaptation to Androgen Receptor Inhibition in Prostate Cancer

The androgen receptor (AR) is the primary therapeutic target in prostate cancer. While androgen deprivation therapy (ADT) and androgen receptor signaling inhibitors (ARSi) are effective, the disease eventually progresses to fatal castration-resistant prostate cancer (CRPC). That said, little is known about the mechanisms in residual disease that initiates tumor relapse upon ADT/ARSi. Here, we discover a crucial role for TRIM24 in supporting the survival of residual cell clusters primed for tumor relapse in vivo. Consequently, reducing TRIM24 with bifunctional degraders (dTRIM24) significantly delays or even prevents the emergence of CRPC in the context of AR reactivation and lineage plasticity. dTRIM24 not only inhibits AR signaling but also counteracts adaptive pathways engaged by AR inhibition itself, such as STAT3 activation and EMT. Our findings underscore the potential of TRIM24 as an effective and druggable target for preventing prostate cancer progression under AR inhibition. SignificanceDespite advances in targeting AR signaling in prostate cancer, tumor relapse remains a major concern. Here, we provide evidence that more durable responses can be achieved by pharmacologically degrading TRIM24. At the molecular level, TRIM24 degradation inhibits both AR signaling and adaptive pathways that enable tumor relapse.

cancer biology↗

bioRxiv2023

JUN mediates senescence and immune cell recruitment to prevent prostate cancer progression

BackgroundProstate cancer develops through malignant transformation of the prostate epithelium in a stepwise, mutation-driven process. Although activator protein-1 transcription factors such as JUN have been implicated as potential oncogenic drivers, the molecular programs contributing to prostate cancer progression are not fully understood. MethodsWe analyzed JUN expression in clinical prostate cancer samples across different stages and investigated its functional role in a Pten-deficient mouse model. We performed histopathological examinations, transcriptomic analyses and explored the senescence-associated secretory phenotype in the tumor microenvironment. ResultsElevated JUN levels characterized early-stage prostate cancer and predicted improved survival in human and murine samples. Immune-phenotyping of Pten-deficient prostates revealed high accumulation of tumor-infiltrating leukocytes, particularly innate immune cells, neutrophils and macrophages as well as high levels of STAT3 activation and IL-1{beta} production. Jun depletion in a Pten-deficient background prevented immune cell attraction which was accompanied by significant reduction of active STAT3 and IL-1{beta} and accelerated prostate tumor growth. Comparative transcriptome profiling of prostate epithelial cells revealed a senescence-associated gene signature, upregulation of pro-inflammatory processes involved in immune cell attraction and of chemokines such as IL-1{beta}, CCL3 and CCL8 in Pten-deficient prostates. Strikingly, JUN depletion reversed both, senescence and senescence-associated immune cell infiltration and consequently accelerated tumor growth. ConclusionsOur results suggest that JUN acts as tumor-suppressor and decelerates the progression of prostate cancer by transcriptional regulation of senescence- and inflammation-associated genes. This study opens avenues for novel treatment strategies that could impede disease progression and improve patient outcomes.

cancer biology↗

bioRxiv2020

Patient-derived xenografts and organoids model therapy response in prostate cancer

Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe a novel androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naive, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbours BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modelled in vivo. Comparison of the treatment-naive PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds.

cancer biology↗