Biology subjects

Formaggio, N.

Publications and source records attributed to Formaggio, N..

3 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↗

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↗