CD9 contributes to exit from a stem cell-like and embryonic diapause states and transit to drug resistant states 

ABSTRACT: In order to identify state changes that mediate the transition from sensitive to a resistant cell states, we applied RNA velocity analysis to an existing single-cell RNAseq (scRNAseq) dataset of BRD4 inhibitor sensitive and resistant SUM149 and SUM159 triple negative breast cancer cell lines. Both SUM149 and SUM159 cell lines treated with or without JQ1 had similar cell communities and trajectories including a stem cell-like and embryonic diapause (SCLED) cell state, a transiting cell state and a number of drug resistant states. Interestingly a transcriptional signature derived from the transiting state but not the SCLED state was associated with worsened outcomes in basal-like breast cancer patients as well as with a micrometastasis signature suggesting that the ability to transit from the SCLED state to drug resistant states could contribute to patient outcomes. The shift from the SCLED state to a transiting cell state was characterized by elevated expression of the CD9 tetraspanin. CD9 knockdown sensitized SUM149 tumor cells to JQ1 in vitro and in vivo trapping cells in the SCLED state and limiting transit to resistant cell states. CD9 knockdown sensitized SUM149 to multiple additional cytotoxic drugs suggesting a generalized role in drug resistance. Thus, CD9 appears to be critical for the ability of triple negative breast cancer cells to escape from a stem cell-like/embryonic diapause state and transition into a treatment resistant state.

ORGANISM(S): Homo sapiens

PROVIDER: GSE196952 | GEO | 2022/08/25

REPOSITORIES: GEO