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ASCL1 is activated downsrteam of ROR2/CREB signaling pathway to support lineage plasticity [ChIP-seq]

ABSTRACT: Lineage plasticity has been shown to be a form of therapy-induced drug resistance. In prostate cancer, androgen receptor (AR) pathway inhibitors have led to accretion of tumor relapse with loss of AR signaling and a shift from a luminal state to an alternate program. Although different genomic and epigenomic aberrations have been correlated with lineage reprogramming, the molecular and signaling mechanisms orchestrating the development of lineage plasticity under the pressure of AR-targeted therapies are not fully understood. Here, a survey of receptor tyrosine kinases (RTKs) identified ROR2 as the top-upregulated RTK following AR pathway inhibition, which feeds into lineage plasticity by promoting stem cell-like and neuronal networks. Mechanistically, we demonstrated that ROR2 activates the ERK/CREB signaling pathway to modulate the expression of the lineage commitment transcription factor, ASCL1. Collectively, our findings nominate ROR2 as a potential therapeutic target to reverse the ENZ-induced plastic phenotype and potentially re-sensitize tumors to AR pathway inhibitors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE224421 | GEO | 2023/08/01

REPOSITORIES: GEO

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ASCL1 is activated downsrteam of ROR2/CREB signaling pathway to support lineage plasticity [RNA-seq]

Project description:Lineage plasticity has been shown to be a form of therapy-induced drug resistance. In prostate cancer, androgen receptor (AR) pathway inhibitors have led to accretion of tumor relapse with loss of AR signaling and a shift from a luminal state to an alternate program. Although different genomic and epigenomic aberrations have been correlated with lineage reprogramming, the molecular and signaling mechanisms orchestrating the development of lineage plasticity under the pressure of AR-targeted therapies are not fully understood. Here, a survey of receptor tyrosine kinases (RTKs) identified ROR2 as the top-upregulated RTK following AR pathway inhibition, which feeds into lineage plasticity by promoting stem cell-like and neuronal networks. Mechanistically, we demonstrated that ROR2 activates the ERK/CREB signaling pathway to modulate the expression of the lineage commitment transcription factor, ASCL1. Collectively, our findings nominate ROR2 as a potential therapeutic target to reverse the ENZ-induced plastic phenotype and potentially re-sensitize tumors to AR pathway inhibitors.

2023-08-01 | GSE224420 | GEO

ASCL1 is activated downsrteam of ROR2/CREB signaling pathway to support lineage plasticity.

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Project description:Emerging evidence indicates that various cancers, including prostate, breast, melanoma and lung cancers, could gain resistance to targeted therapies by acquiring lineage plasticity. Although various genomic and transcriptomic aberrations correlate with lineage plasticity-driven resistance, the molecular mechanisms and kinetics of acquiring lineage plasticity are not fully elucidated. Through integrated transcriptomic and single cell RNA-seq (scRNA-seq) analysis of more than 80,000 cells, we show that the ectopic activation of Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway drives lineage plasticity and Androgen Receptor (AR) targeted therapy resistance in PCa with TP53/RB1-deficiency. Ectopic activation of JAK-STAT signaling enables Heterogeneous and AR-independent subclones to emerge upon the selective pressure of AR targeted therapy, including subclones expressing multi-lineage, progenitor-like and epithelial to mesenchymal transition (EMT)-like lineage survival transcriptional programs. Both genetic and pharmaceutical inactivation of key components of the JAK-STAT signaling pathway significantly re-sensitizes resistant PCa tumors to AR targeted therapy. In summary, these results show for the first time that JAK-STAT signaling pathway is a key effector in driving lineage plasticity and represents a potential therapeutic target for overcoming AR targeted therapy resistance.

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