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Notch signaling suppresses neuroendocrine differentiation and alters the tumor immune microenvironment in advanced prostate cancer

ABSTRACT: Neuroendocrine prostate cancer (NEPC) is an aggressive, androgen-independent variant of prostate cancer (PCa) that most commonly develops in patients as a mechanism of therapeutic resistance. The underlying mechanisms driving PCa lineage plasticity and trans-differentiation to a neuroendocrine lineage are not fully understood. Here, we identify Notch signaling as a key suppressor of neuroendocrine differentiation in PCa. Restoration of Notch signaling in NEPC models results in phenotypic conversion towards a non-neuroendocrine state with expression of prostate luminal cell markers and immunologic changes including up-regulation of MHC Class I and II and type I interferon signaling that correlate with changes in the tumor immune microenvironment. Overall, these data provide new insights into how Notch signaling influences PCa lineage plasticity and points to new therapeutic avenues to modulate it.

ORGANISM(S): Homo sapiens

PROVIDER: GSE234819 | GEO | 2024/08/28

REPOSITORIES: GEO

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Notch signaling suppresses neuroendocrine differentiation and alters the tumor immune microenvironment in advanced prostate cancer

Project description:Neuroendocrine prostate cancer (NEPC) is an aggressive, androgen-independent variant of prostate cancer (PCa) that most commonly develops in patients as a mechanism of therapeutic resistance. The underlying mechanisms driving PCa lineage plasticity and trans-differentiation to a neuroendocrine lineage are not fully understood. Here, we identify Notch signaling as a key suppressor of neuroendocrine differentiation in PCa. Restoration of Notch signaling in NEPC models results in phenotypic conversion towards a non-neuroendocrine state with expression of prostate luminal cell markers and immunologic changes including up-regulation of MHC Class I and II and type I interferon signaling that correlate with changes in the tumor immune microenvironment. Overall, these data provide new insights into how Notch signaling influences PCa lineage plasticity and points to new therapeutic avenues to modulate it.

2024-08-01 | GSE235036 | GEO

Role of Specialized Composition of SWI/SNF Complexes in Prostate Cancer Lineage Plasticity

Project description:Advanced prostate cancer initially responds to hormonal treatment, but ultimately becomes resistant and requires more potent therapies. One mechanism of resistance seen in 10% of these patients is through lineage plasticity, which manifests in a partial or complete small cell or neuroendocrine prostate cancer (NEPC) phenotype. Here, we investigate the role of the mammalian SWI/SNF chromatin remodeling complex in NEPC. Using large patient datasets, patient-derived organoids and cancer cell lines, we identify SWI/SNF subunits that are deregulated in NEPC, demonstrate that SMARCA4 (BRG1) overexpression is associated with aggressive disease and that SMARCA4 depletion impairs prostate cancer cell growth. We also show that SWI/SNF complexes interact with different lineage-specific factors in prostate adenocarcinoma and in NEPC cells, and that induction of lineage plasticity through depletion of REST is accompanied by changes in SWI/SNF genome occupancy. These data suggest a specific role for mSWI/SNF complexes in therapy-related lineage plasticity, which may be relevant for other solid tumors.

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Post-transcriptional gene regulation by microRNA-194 promotes neuroendocrine transdifferentiation in prostate cancer

Project description:Potent therapeutic inhibition of the androgen receptor (AR) in prostate adenocarcinoma can lead to the emergence of neuroendocrine prostate cancer (NEPC), a phenomenon associated with enhanced cell plasticity. Here, we show that microRNA-194 (miR-194) is a regulator of epithelial-neuroendocrine transdifferentiation. In clinical prostate cancer samples, miR-194 expression and activity were elevated in NEPC and inversely correlated with AR signalling. Over-expression of miR-194 facilitated the emergence of neuroendocrine features in prostate cancer cells, a process mediated by its ability to directly target a suite of genes involved in cell plasticity. One such target gene was FOXA1, which encodes a transcription factor with a vital role in maintaining the prostate epithelial lineage. Importantly, a miR-194 inhibitor blocked epithelial-neuroendocrine transdifferentiation and inhibited the growth of cell lines and patient-derived organoids possessing neuroendocrine features. Overall, our study reveals a post-transcriptional mechanism regulating the plasticity of prostate cancer cells and provides a rationale for targeting miR-194 in NEPC.

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Post-transcriptional gene regulation by microRNA-194 promotes neuroendocrine transdifferentiation in prostate cancer

2019-09-09 | GSE137071 | GEO

Post-transcriptional gene regulation by microRNA-194 promotes neuroendocrine transdifferentiation in prostate cancer [ChIP-Seq]

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Targeting SOX4/PCK2 signaling suppresses neuroendocrine differentiation of castration-resistant prostate cancer

Project description:Background: Neuroendocrine prostate cancer (NEPC), a lethal subset of prostate cancer, is characterized by loss of AR signaling and resulting resistance to AR-targeted therapy during neuroendocrine transdifferentiation, for which the molecular mechanisms remain unclear. Here, we report that SRY-Box transcription factor 4 (SOX4) is upregulated in NEPC, which induces neuroendocrine markers, neuroendocrine cell morphology, and NEPC cell aggressive behavior. Methods: To understand the function of SOX4 in the development and progression of NEPC, we detected malignancy characterization after over-expression or knock-down of SOX4 in prostate cancer cells. Xenograft tumors representing NEPC subtypes were analyzed by pathologists. Protein expression profiles were validated in patient tumor tissue. Diagnoses were complemented by transcriptome sequencing and ATAC sequencing of specific cell lines and public clinical datasets. Results: SOX4 expression was significantly elevated in NEPC. Activating SOX4 in non-NEPC cells induced NE transdifferentiation, while silencing it in NEPC cells impeded NEPC progression. SOX4 promote neuroendocrine characteristics by inducing PCK2-mediated metabolism changing. Conclusions: Elevated SOX4 drives NE transdifferentiation in PCa via PCK2-mediated . Altogether, these findings highlight SOX4 as a novel molecule to drive NEPC progression and suggest that it might be a potential therapeutic target for NEPC.

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FOXA2 and ASCL1 Cooperate in Driving Neuronal Lineage Commitment in Prostate Cancer [RNA-seq]

Project description:In castration-resistant prostate cancer, lineage plasticity mediates resistance to androgen receptor pathway inhibitors (ARPIs) and progression from adenocarcinoma to neuroendocrine prostate cancer (NEPC), a highly aggressive and poorly understood subtype. ASCL1 has emerged as a central regulator of the NEPC phenotype, driving neuroendocrine differentiation. However, ASCL1’s influence on neuronal lineage switching and maturation, as well as its partners in NEPC, remain largely unknown. Here, we provided insights into ASCL1’s cistrome reprogramming in ARPI-induced NEPC versus terminal NEPC and showed that ASCL1 binding pattern tailors the subsequent expression of transcription factor combinations that underlie discrete terminal NEPC identity. We identified FOXA2 as a major co-factor of ASCL1 in terminal NEPC that it is highly expressed in ASCL1-driven NEPC. FOXA2 and ASCL1 interact and work in concert to orchestrate terminal neuronal differentiation in prostate cancer, and regulate key neuroendocrine-associated genes including PROX1. Our findings provide insights into the molecular conduit underlying the interplay between different lineage determinant transcription factors to support the neuroendocrine identity in prostate cancer.

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FOXA2 and ASCL1 Cooperate in Driving Neuronal Lineage Commitment in Prostate Cancer [ChIP-seq]

2024-10-23 | GSE273956 | GEO

The placental gene PEG10 promotes progression of neuroendocrine prostate cancer [aCGH]

Project description:Neuroendocrine prostate cancer (NEPC) is proliferative, invasive, and untreatable. Its molecular pathogenesis remains poorly understood but appears to require TP53 and RB1 aberration. In this study we modeled the development of NEPC from conventional prostatic adenocarcinoma using a unique patient-derived xenograft and identified up-regulation of the placental gene PEG10. We found that the androgen receptor and the E2F/RB pathway dynamically regulate distinct post-transcriptional and post-translational isoforms of PEG10 at different stages of NEPC development. In vitro, PEG10 promoted cell cycle progression from G0/G1 in the context of TP53 loss, and regulated Snail expression via TGF-β signaling to promote invasion. Finally we show in vivo proof of principal using antisense oligonucleotide that PEG10 is a novel therapeutic target for NEPC. Six patient-derived xenograft tumors from the LTL331 xenograft lineage (PMID: 24356420; http://www.livingtumorcentre.com/) after differing lengths of time post-host castration. No replicates.

2015-01-05 | E-GEOD-59985 | biostudies-arrayexpress

RET Kinase Inhibition in Neuroendocrine Prostate Cancer, part 2

Project description:Increased treatment of metastatic castration resistant prostate cancer (mCRPC) with second-generation anti-androgen therapies (ADT) has coincided with a greater incidence of lethal, aggressive variant prostate cancer (AVPC) tumors that have lost androgen receptor (AR) signaling. AVPC tumors may also express neuroendocrine markers, termed neuroendocrine prostate cancer (NEPC). Recent evidence suggests kinase signaling may be an important driver of NEPC. To identify targetable kinases in NEPC, we performed global phosphoproteomics comparing AR-negative to AR-positive prostate cancer cell lines and identified multiple altered signaling pathways, including enrichment of RET kinase activity in the AR-negative cell lines. Clinical NEPC and NEPC patient derived xenografts displayed upregulated RET transcript and RET pathway activity. Pharmacologically inhibiting RET kinase in NEPC models dramatically reduced tumor growth and cell viability in mouse and human NEPC models. Our results suggest that targeting RET in NEPC tumors with high RET expression may be a novel treatment option.

2020-05-29 | PXD012971 | Pride

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