GSE175975
JAK-STAT Signaling Confers Lineage Plasticity and AR Targeted Therapy Resistance in Prostate Cancer
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. Overall design: 1) Examination of transcriptomic changes in LNCaP/AR prostate cancer cell lines with modifications of TP53/RB1/SOX2 genes. There is total 8 different conditions with 3 biological replicates each. 2) Single cell RNA-seq examine the transcrptomic changes in LNCaP/AR prostate cancer cell lines with various CRISPR guides targeting TP53/RB1/JAK1 and treated with enzalutamide or vehicle. There is total 6 different conditions, with more than 10,000 cells being sequenced each.