Biology subjects

German, B.

Publications and source records attributed to German, B..

3 recordsLinked to original sources

bioRxiv2025

EZH2-TTP-mTORC1 Axis Drives Phenotypic Plasticity and Therapeutic Vulnerability in Lethal Prostate Cancer

Phenotypic plasticity is a recognized mechanism of therapeutic resistance in prostate cancer (PCa), however current knowledge of driver mechanisms and therapeutic interventions are limited. Using genetically engineered mouse models (GEMMs) devoid of Pten and Rb1, we previously demonstrated the chromatin reprogramming factor enhancer of zeste homolog 2 (EZH2) as an important regulator of alternative transcription programs promoting phenotypic plasticity. Here, using a multi-omics approach we demonstrate that EZH2 regulates multilineage cell states dependent on the RNA binding protein Tristetraprolin (TTP) that mediates RNA stability and activation of translation. Combined chemical inhibition of EZH2 and PI3K/mTORC1 resulted in superior anti-tumor activity in murine and human phenotypic plastic models and was most significant when this combination was used with castration or enzalutamide. Together, these data indicate phenotypic plasticity dependence on coordination between EZH2, TTP and mTORC1 signaling that represent novel therapeutic dependencies for this lethal PCa phenotype. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC="FIGDIR/small/669104v1_ufig1.gif" ALT="Figure 1"> View larger version (66K): org.highwire.dtl.DTLVardef@5ef713org.highwire.dtl.DTLVardef@af402forg.highwire.dtl.DTLVardef@19eedcforg.highwire.dtl.DTLVardef@10ee421_HPS_FORMAT_FIGEXP M_FIG C_FIG Significance StatementEZH2 plays a key role in driving cell state transitions in neuroendocrine prostate cancer (NEPC), guiding cancer cells towards a more aggressive, therapy-resistant cell type. This transformation creates a specific vulnerability, as NEPC cells become highly reliant on both EZH2 and PI3K/mTORC1-translation signaling. Targeting this dependency, we demonstrate that combining EZH2 with PI3K/mTORC1 inhibition provides effective suppression of NEPC cell growth, offering a promising therapeutic strategy for treating this challenging and aggressive prostate cancer subtype.

cancer biology↗

bioRxiv2024

MYBL2 drives prostate cancer plasticity and identifies CDK2 as a therapeutic vulnerability in RB1-loss and neuroendocrine prostate cancer

Phenotypic plasticity is a recognized mechanism driving therapeutic resistance in prostate cancer (PCa) patients. While underlying molecular causations driving phenotypic plasticity have been identified, therapeutic success is yet to be achieved. To identify putative master regulator transcription factors (MR-TF) driving phenotypic plasticity in PCa, this work utilized a multiomic approach using genetically engineered mouse models of prostate cancer combined with patient data to identify MYBL2 as a significantly enriched transcription factor in PCa exhibiting phenotypic plasticity. Genetic inhibition of Mybl2 using independent murine PCa cell lines representing phenotypic plasticity demonstrated Mybl2 loss significantly decreased in vivo growth as well as cell fitness and repressed gene expression signatures involved in pluripotency and stemness. Because MYBL2 is currently not druggable, a MYBL2 gene signature was employed to identify cyclin-dependent kinase-2 (CDK2) as a potential therapeutic target. CDK2 inhibition phenocopied genetic loss of Mybl2 and significantly decreased in vivo tumor growth associated with enrichment of DNA damage. Together, this work demonstrates MYBL2 as an important MR-TF driving phenotypic plasticity in PCa. Further, high MYBL2 activity identifies PCa that would be responsive to CDK2 inhibition. SignificancePCa that escapes therapy targeting the androgen receptor signaling pathways via phenotypic plasticity are currently untreatable. Our study identifies MYBL2 as a MR-TF in phenotypic plastic PCa and implicates CDK2 inhibition as novel therapeutic target for this most lethal subtype of PCa.

cancer biology↗

bioRxiv2018

Word stress representations are language specific: evidence from event-related brain potentials

Understanding speech at the basic levels entails the simultaneous and independent processing of phonemic and prosodic features. While it is well-established that phoneme perception relies on language-specific long-term traces, it is unclear if the processing of prosodic features similarly involves language-specific representations. In the present study, we investigated the processing of a specific prosodic feature, word stress, using the method of event-related brain potentials (ERPs) employing a cross-linguistic approach. Hungarian participants heard disyllabic pseudowords stressed either on the first (legal stress) or on the second (illegal stress) syllable, pronounced either by a Hungarian or a German speaker. Results obtained using a data-driven ERP analysis methodology showed that all pseudowords in the deviant position elicited an Early Differentiating Negativity (EDN) and a Mismatch Negativity (MMN) component, except for the Hungarian pseudowords stressed on the first syllable. This suggests that Hungarian listeners did not process the native legal stress pattern as deviant, but the same stress pattern with a non-native accent was processed as deviant. This implies that the processing of word stress was based on language-specific long-term memory traces.

neuroscience↗