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Temporal evolution reveals bifurcated lineages in aggressive neuroendocrine small cell prostate cancer trans-differentiation (scRNA-Seq)

ABSTRACT: Trans-differentiation from an adenocarcinoma to a small cell neuroendocrine state is associated with therapy escape in multiple cancer types. The temporal transcriptional changes of this process remain largely undefined. Here, we performed a multi-omics time course analysis of our pan-small cell neuroendocrine cancer model (termed PARCB), a forward genetic transformation using human prostate basal cells. With integrative analyses of RNA sequencing and ATAC sequencing, a shared developmental trajectory is identified among all transformed patient samples. Further mapping with single cell resolution reveals two distinct lineages defined by mutually exclusive expression of ASCL1 and ASCL2. Temporal regulation by groups of transcription factors across developmental stages reveals that cellular reprogramming precedes the induction of neuronal programs. Lastly, TFAP4 and ASCL1/2 feedback were identified as potential regulators of ASCL1 and ASCL2 expression. Our study provides temporal transcriptional patterns and uncovers pan-tissue parallels between prostate and lung cancers, and normal neuroendocrine cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE240056 | GEO | 2023/11/24

REPOSITORIES: GEO

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Temporal evolution reveals bifurcated lineages in aggressive neuroendocrine small cell prostate cancer trans-differentiation (Bulk RNA-Seq)

Project description:Trans-differentiation from an adenocarcinoma to a small cell neuroendocrine state is associated with therapy escape in multiple cancer types. The temporal transcriptional changes of this process remain largely undefined. Here, we performed a multi-omics time course analysis of our pan-small cell neuroendocrine cancer model (termed PARCB), a forward genetic transformation using human prostate basal cells. With integrative analyses of RNA sequencing and ATAC sequencing, a shared developmental trajectory is identified among all transformed patient samples. Further mapping with single cell resolution reveals two distinct lineages defined by mutually exclusive expression of ASCL1 and ASCL2. Temporal regulation by groups of transcription factors across developmental stages reveals that cellular reprogramming precedes the induction of neuronal programs. Lastly, TFAP4 and ASCL1/2 feedback were identified as potential regulators of ASCL1 and ASCL2 expression. Our study provides temporal transcriptional patterns and uncovers pan-tissue parallels between prostate and lung cancers, and normal neuroendocrine cells.

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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]

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Temporal evolution reveals bifurcated lineages in aggressive neuroendocrine small cell prostate cancer trans-differentiation

Project description:Temporal evolution reveals bifurcated lineages in aggressive neuroendocrine small cell prostate cancer trans-differentiation

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Temporal evolution reveals bifurcated lineages in aggressive neuroendocrine small cell prostate cancer trans-differentiation

Project description:Temporal evolution reveals bifurcated lineages in aggressive neuroendocrine small cell prostate cancer trans-differentiation

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Temporal evolution reveals bifurcated lineages in aggressive neuroendocrine small cell prostate cancer trans-differentiation

Project description:Temporal evolution reveals bifurcated lineages in aggressive neuroendocrine small cell prostate cancer trans-differentiation

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Single nuclear RNA sequencing and 10X spatial transcriptomic profiling of murine tumors initiated by transplantation of engineered prostate organoids [snRNA-seq]

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Single nuclear RNA sequencing and 10X spatial transcriptomic profiling of murine tumors initiated by transplantation of engineered prostate organoids [visium]

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Temporal evolution reveals bifurcated lineages in aggressive neuroendocrine small cell prostate cancer trans-differentiation (scRNA-Seq)

Project description:Temporal evolution reveals bifurcated lineages in aggressive neuroendocrine small cell prostate cancer trans-differentiation (scRNA-Seq)

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