Chromatin profiles classify castration-resistant prostate cancers suggesting therapeutic targets

Abstract

In castration-resistant prostate cancer (CRPC), the loss of androgen receptor (AR) dependence leads to clinically aggressive tumors with few therapeutic options. We used ATAC-seq (assay for transposase-accessible chromatin sequencing), RNA-seq, and DNA sequencing to investigate 22 organoids, six patient-derived xenografts, and 12 cell lines. We identified the well-characterized AR-dependent and neuroendocrine subtypes, as well as two AR-negative/low groups: a Wnt-dependent subtype, and a stem cell–like (SCL) subtype driven by activator protein–1 (AP-1) transcription factors. We used transcriptomic signatures to classify 366 patients, which showed that SCL is the second most common subtype of CRPC after AR-dependent. Our data suggest that AP-1 interacts with the YAP/TAZ and TEAD proteins to maintain subtype-specific chromatin accessibility and transcriptomic landscapes in this group. Together, this molecular classification reveals drug targets and can potentially guide therapeutic decisions.

Lineage plasticity in prostate cancer depends on JAK/STAT inflammatory signaling

“…Collectively, these findings suggest a therapeutic strategy by which CRPC patients with JAK/STAT-high, AR-low signaling [defined as stem-like by Tang et al . ( 36 )] would be candidates for combined JAK and FGFR inhibition in order to reprogram tumor cells to an AR-high luminal state and restore sensitivity to AR-targeted therapy. Those with increased FGFR signaling and no JAK/STAT activation [defined as Wnt subtype by Tang et al .…”

“…The four PDOs that display luminal reprogramming all fall within the stem-like subtype [also defined by increased JAK/STAT activation in Tang et al . ( 36 )], whereas the two CRPC-adeno PDOs with growth inhibition fall with the Wnt subtype (Fig. 5F), providing evidence of specific and exploitable therapeutic vulnerabilities for molecularly distinct subtypes of human CRPC.…”

“…Shown are (1) baseline attributes, including an oncoprint of the TP53 , RB1 , and PTEN genotypes, transcriptional subtypes based on Tang et al . ( 36 ), and low versus null AR protein expression; (2) a heatmap of baseline gene signatures in the human organoids using publicly available bulk RNA-seq based on mean Z -scored expression of JAK/STAT signaling, FGFR signaling, and EMT gene sets (see methods); and (3) functional changes in human organoids with null to low AR expression after treatment with Rux and Erda, including cell viability, and log2 fold change (FC) in AR and VIM protein expression. ( G ) Western blot of lineage markers and JAK/STAT signaling components in MSKPCA3 organoid after 14 days of treatment with Erda 100 nM, Rux 10 μM, or with Erda 100 nM and Rux 10 μM combination.…”

“…Finally, we mapped the Rux-with-Erda sensitivity profiles to four subtypes of human CRPC (AR + , Stem-like, Wnt, and NEPC) recently reported based on integrated chromatin accessibility and transcriptome analysis ( 36 ). The four PDOs that display luminal reprogramming all fall within the stem-like subtype [also defined by increased JAK/STAT activation in Tang et al .…”

Dysfunction of the Polycomb protein RYBP and of 5-methylcytosine oxidases leads to widespread CpG island hypermethylation and cell transformation

“…Another characteristic finding in our study was the increased expression of AP-1 genes, which may be a critical event in certain types of lung cancer (Kim and Minna, 2022). The TEAD transcription factors that are negatively controlled by the Hippo pathway often co-localize and collaborate with AP-1 proteins, and this combined activity drives cell proliferation (Tang et al, 2022; Zanconato et al, 2015). We found several induced CGI hypermethylation events that have the potential to be cancer drivers.…”