Biology subjects

Hanratty, B.

Publications and source records attributed to Hanratty, B..

4 recordsLinked to original sources

bioRxiv2025

Defined cellular reprogramming of androgen receptor-active prostate cancer to neuroendocrine prostate cancer

Neuroendocrine prostate cancer (NEPC) arises primarily through neuroendocrine transdifferentiation (NEtD) as an adaptive mechanism of therapeutic resistance. Models to define the functional effects of putative drivers of this process on androgen receptor (AR) signaling and NE cancer lineage programs are lacking. We adapted a genetically defined strategy from the field of cellular reprogramming to directly convert AR-active prostate cancer (ARPC) to AR-independent NEPC using candidate factors. We delineated critical roles of the pioneer factors ASCL1 and NeuroD1 in NEtD and uncovered their abilities to silence AR expression and signaling by remodeling chromatin at the somatically acquired AR enhancer and global AR binding sites with enhancer activity. We also elucidated the dynamic temporal changes in the transcriptomic and epigenomic landscapes of cells undergoing acute lineage conversion from ARPC to NEPC which should inform future therapeutic development. Further, we distinguished the activities of ASCL1 and NeuroD1 from the inactivation of RE-1 silencing transcription factor (REST), a master suppressor of a major neuronal gene program, in establishing a NEPC lineage state and in modulating the expression of genes associated with major histocompatibility complex class I (MHC I) antigen processing and presentation. These findings provide important, clinically relevant insights into the biological processes driving NEtD of prostate cancer.

cancer biology↗

bioRxiv2024

Molecular consequences of acute versus chronic CDK12 loss in prostate carcinoma nominates distinct therapeutic strategies

Genomic loss of the transcriptional kinase CDK12 occurs in [~]6% of metastatic castration-resistant prostate cancers (mCRPC) and correlates with poor patient outcomes. Prior studies demonstrate that acute CDK12 loss confers a homologous recombination (HR) deficiency (HRd) phenotype via premature intronic polyadenylation (IPA) of key HR pathway genes, including ATM. However, mCRPC patients have not demonstrated benefit from therapies that exploit HRd such as inhibitors of polyADP ribose polymerase (PARP). Based on this discordance, we sought to test the hypothesis that an HRd phenotype is primarily a consequence of acute CDK12 loss and the effect is greatly diminished in prostate cancers adapted to CDK12 loss. Analyses of whole genome sequences (WGS) and RNA sequences (RNAseq) of human mCRPCs determined that tumors with biallelic CDK12 alterations (CDK12BAL) lack genomic scar signatures indicative of HRd, despite carrying bi-allelic loss and the appearance of the hallmark tandem-duplicator phenotype (TDP). Experiments confirmed that acute CDK12 inhibition resulted in aberrant polyadenylation and downregulation of long genes (including BRCA1 and BRCA2) but such effects were modest or absent in tumors adapted to chronic CDK12BAL. One key exception was ATM, which did retain transcript shortening and reduced protein expression in the adapted CDK12BAL models. However, CDK12BALcells demonstrated intact HR as measured by RAD51 foci formation following irradiation. CDK12BAL cells showed a vulnerability to targeting of CDK13 by sgRNA or CDK12/13 inhibitors and in vivo treatment of prostate cancer xenograft lines showed that tumors with CDK12BALresponded to the CDK12/13 inhibitor SR4835, while CDK12-intact lines did not. Collectively, these studies show that aberrant polyadenylation and long HR gene downregulation is primarily a consequence of acute CDK12 deficiency, which is largely compensated for in cells that have adapted to CDK12 loss. These results provide an explanation for why PARPi monotherapy has thus far failed to consistently benefit patients with CDK12 alterations, though alternate therapies that target CDK13 or transcription are candidates for future research and testing.

cancer biology↗

bioRxiv2024

LSD1 inhibition suppresses ASCL1 and de-represses YAP1 to drive potent activity against neuroendocrine prostate cancer

Progression to lethal metastatic castration-resistant prostate cancer (mCRPC) is driven in part by epigenetic modulators such as LSD1 (KDM1A), a lysine-specific demethylase. Yet, mCRPC is increasingly recognized as a highly heterogeneous disease whose classification into subtypes is defined by the extent of androgen receptor (AR) and/or neuroendocrine (NE) characteristics. Meanwhile, the role of LSD1 in driving the different subtypes of mCRPC has remained unclear. Here, we assess the necessity of LSD1 in driving progression of mCRPC subtypes including AR+/NE- (ARPC), AR-/NE+ (NEPC), AR+/NE+ (amphicrine; AMPC), and AR-/NE- (double-negative; DNPC) through the use of LSD1 inhibitors in clinical development. LSD1 inhibition (LSD1i) was observed to be highly effective in restricting growth of NEPC, and efficacy was associated with TP53 loss-of-function. Mice bearing NEPC patient-derived xenografts treated with the LSD1 inhibitors, bomedemstat (MK-3543) or iadademstat (ORY-1001), exhibited suppression of the NE transcriptional profile, including ASCL1. LSD1i also induced expression and activity of YAP1, a non-NE transcription factor canonically silenced in NEPC (YAPOFF cancer), thereby switching NEPC from a YAPOFF to a YAPON cancer class. Therapeutically-induced YAPON NEPC tumors exhibited cell cycle arrest and repression of proliferative transcriptional programs. Importantly, the LSD1i-mediated YAPON state induced sensitivity to an inhibitor of YAP/TEAD function, IAG933, which extended antitumor efficacy against NEPC. Altogether, these findings indicate that patients diagnosed with NEPC may obtain greater relative benefit from LSD1-targeted therapies compared to those with other mCRPC subtypes and that dual inhibition of LSD1 and YAP/TEAD function demonstrates a promising treatment strategy potentially extending to other YAPOFF cancers. SignificanceAcross prostate cancer subtypes, NEPC is exceptionally responsive to LSD1 inhibition and this response is enhanced in combination with a YAP/TEAD disruptor which may improve patient selection and outcomes. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=171 HEIGHT=200 SRC="FIGDIR/small/576106v2_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@77332eorg.highwire.dtl.DTLVardef@1c127d0org.highwire.dtl.DTLVardef@1cec77org.highwire.dtl.DTLVardef@e87ed7_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2022

Nucleosome patterns in circulating tumor DNA reveal transcriptional regulation of advanced prostate cancer phenotypes

Advanced prostate cancers comprise distinct phenotypes, but tumor classification remains clinically challenging. Here, we harnessed circulating tumor DNA (ctDNA) to study tumor phenotypes by ascertaining nucleosome positioning patterns associated with transcription regulation. We sequenced plasma ctDNA whole genomes from patient-derived xenografts representing a spectrum of androgen receptor active (ARPC) and neuroendocrine (NEPC) prostate cancers. Nucleosome patterns associated with transcriptional activity were reflected in ctDNA at regions of genes, promoters, histone modifications, transcription factor binding, and accessible chromatin. We identified the activity of key phenotype-defining transcriptional regulators from ctDNA, including AR, ASCL1, HOXB13, HNF4G, and NR3C1. Using these features, we designed a prediction model which distinguished NEPC from ARPC in patient plasma samples across three clinical cohorts with 97-100% sensitivity and 85-100% specificity. While phenotype classification is typically assessed by immunohistochemistry or transcriptome profiling, we demonstrate that ctDNA provides comparable results with numerous diagnostic advantages for precision oncology. STATEMENT OF SIGNIFICANCEThis study provides key insights into the dynamics of nucleosome positioning and gene regulation associated with cancer phenotypes that can be ascertained from ctDNA. The new methods established for phenotype classification extend the utility of ctDNA beyond assessments of DNA alterations with important implications for molecular diagnostics and precision oncology.

cancer biology↗