Dataset Information

Single cell RNA trajectory analysis reveals a CD9 positive cell state to contribute to exit from stem cell-like and embryonic diapause states and transit to drug resistant states

ABSTRACT: Bromo- and extra-terminal domain (BET) inhibitors (BETi) have been shown to decrease tumor growth in preclinical models and clinical trials. However, toxicity and rapid emergence of resistance have limited their clinical implementation. To identify state changes underlying acquisition of resistance to the JQ1 BETi, we reanalyzed single-cell RNAseq data from JQ1 sensitive and resistant SUM149 and SUM159 triple negative breast cancer cell lines. Parental and JQ1-resistant SUM149 and SUM159 exhibited a stem cell-like and embryonic diapause (SCLED) cell state as well as a transitional cell state between the SCLED state existing both treatment naïve and treated cells, and a number of JQ1 resistant cell states. A transitional cell state transcriptional signature but not a SCLED state transcriptional signature predicted worsened outcomes in basal-like breast cancer patients suggesting that transit from the SCLED state to drug resistant states contributes to patient outcomes. Entry of SUM149 and SUM159 into the transitional cell state was characterized by elevated expression of the CD9 tetraspanin. Knockdown or inhibition of CD9 sensitized cells to multiple targeted and cytotoxic drugs in vitro. Importantly, CD9 knockdown or blockade sensitized SUM149 to JQ1 in vivo by trapping cells in the SCLED state and limiting transit to resistant cell states. Thus, CD9 appears to be critical for transition from a SCLED state into treatment resistant cell states and warrants exploration as a therapeutic target in basal-like breast cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE221183 | GEO | 2023/06/01

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Targeting the epigenome to modulate gene expression programs driving cancer development has emerged as an exciting avenue for therapeutic intervention. Pharmacological inhibition of the bromodomain and extraterminal (BET) family of chromatin adapter proteins has proven effective in this regard, suppressing growth of diverse cancer types mainly through downregulation of the c-MYC oncogene and its downstream transcriptional program. While initially effective, resistance to BET inhibitors (BETi) typically occurs through mechanisms that reactivate MYC expression. We have previously shown that lung adenocarcinoma (LAC) is inhibited by JQ1 through suppression of FOSL1, suggesting that the epigenetic landscape of tumor cells from different origins and differentiation states influences BETi response. Here, we assessed how these differences affect mechanisms of BETi resistance through the establishment of isogenic pairs of JQ1 sensitive and resistant LAC cell lines. We found that resistance to JQ1 in LAC occurs independent of FOSL1 while MYC levels remain unchanged between resistant cells and their JQ1 treated parental counterparts. Furthermore, while epithelial-mesenchymal transition (EMT) is observed upon resistance, TGF- induced EMT did not confer resistance in JQ1 sensitive LAC lines, suggesting this is a consequence, rather than a driver of BETi resistance in our model systems. Importantly, siRNA knockdown demonstrated that JQ1 resistant cell lines are still dependent on BRD4 expression and we found that phosphorylation of BRD4 is elevated in resistant LACs, identifying casein kinase 2 (CK2) as a candidate protein mediating this effect. Inhibition of CK2, as well as downstream transcriptional targets of phosphorylated BRD4 - including AXL and activators of the PI3K pathway - synergize with JQ1 to inhibit BETi resistant LAC. Overall, this demonstrates that the mechanism of resistance to BETi varies depending on cancer type, with LAC cells developing JQ1 resistance independent of MYC re-activation, and identifying CK2 phosphorylation of BRD4 as a potential target to overcome resistance in this cancer.

Dataset Information

Single cell RNA trajectory analysis reveals a CD9 positive cell state to contribute to exit from stem cell-like and embryonic diapause states and transit to drug resistant states

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets