Dataset Information

Transcriptional Hallmarks of Drug Tolerance in Hormone-Dependent Cancers

ABSTRACT: Drug tolerance is a key step allowing the development of drug resistance in hormone-dependent breast cancer. While transcriptional heterogeneity has been correlated with tolerance, the transcriptional programs specifically driving it remain poorly understood. To address this, we profile and computationally mine 300’000 single-cell transcriptomes following drug adaptation in models of breast and prostate cancer, spanning seven different treatments (endocrine therapies and CDK-inhibitors), and validate these via integration with novel and published profiles of lesions treated with neo-adjuvant endocrine therapies. We identify a comprehensive spectrum of transcriptional programs and upstream regulators, correlated to different stages of drug tolerance, and conserved across first- and second-line therapies, and therapeutic approaches. Pre-existing programs cooperate with adaptive ones, with the former being more conserved across therapies. These newly identified programs suggest fine-tuning of existing cell states, rather than cell-type or lineage switches, as a main driver of tolerance and resistance. Notably, JAK-STAT signalling emerges as one of the critical regulators of these programs in both the early and late stages of drug tolerance and serves as a predictor of progression in primary hormone-dependent tumours treated with endocrine therapies.

ORGANISM(S): Homo sapiens

PROVIDER: GSE282702 | GEO | 2025/12/01

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Continued androgen receptor (AR) signaling is an established mechanism underlying castration-resistant prostate cancer (CRPC), and suppression of AR signaling remains a therapeutic goal of CRPC therapy. Constitutively active androgen receptor splicing variants (AR-Vs) lack the AR ligand-binding domain (AR-LBD), the intended target of androgen deprivation therapies (ADT) including new CRPC therapies such as abiraterone and MDV3100. While the canonical full-length AR (AR-FL) and AR-Vs are both increased in CRPC, their expression regulation, associated transcriptional programs, functional relationships, and respective roles in mediating responses to endocrine therapies have not been dissected. In this study, we show that suppression of canonical AR-FL signaling by targeting AR-LBD leads to increased AR-V expression in two cell line models of CRPC. Importantly, treatment-induced AR-Vs activate a distinct expression signature enriched for cell cycle genes without requiring the presence of AR-FL. Conversely, activation of AR-FL signaling suppresses the AR-V signature but activates expression programs mainly associated with macromolecular synthesis, metabolism, and differentiation. In prostate cancer cells and CRPC xenografts treated with MDV3100 and abiraterone, increased expression of two constitutively active AR-Vs, AR-V7 and ARV567ES, but not AR-FL, parallels increased expression of the AR-driven cell cycle gene UBE2C. In addition, protein expression of AR-V7, but not AR-FL, is positively correlated with UBE2C in clinical CRPC specimens. The cumulative in vitro and in vivo evidence support an adaptive shift toward AR-V-mediated signaling in at least a subset of CRPC tumors as the AR-LBD is rendered inactive, suggesting an important mechanism contributing to drug resistance to CRPC therapies. LNCaP cells lacking AR-V were transfected with AR-V7 with or without androgen stimulation of AR-FL (4 conditions); LNCaP95 cells expressing AR-Vs were treated with control siRNA or siRNA trageting AR-LBD or AR-DBD, with or without androgen stimulation of AR-FL (6 conditions); VCaP cells expressing AR-Vs in the presence of androgen were treated with control siRNA, siRNA trageting AR-LBD, DMSO or MDV3100 to inhibit AR-FL (4 conditions). Total 14 arrays with no replicates.

Dataset Information

Transcriptional Hallmarks of Drug Tolerance in Hormone-Dependent Cancers

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets