JAK-STAT signaling in inflammatory breast cancer enables chemotherapy-resistant cell states

ABSTRACT: Inflammatory breast cancer (IBC) is a difficult-to-treat disease with poor clinical outcomes due to high risk of metastasis and resistance to treatment. We previously described a CD44+CD24-pSTAT3+ cancer cell subpopulation with stem cell-like features in breast cancer that is dependent on JAK/STAT3 signaling. Here we report that CD44+CD24- cells are the most frequent cell-type in IBC and are commonly pSTAT3+. Combination of JAK/STAT3 inhibition with paclitaxel decreased IBC xenograft growth more than either agent alone. We developed and characterized IBC cell lines resistant to paclitaxel and doxorubicin to mimic therapeutic resistance in patients. Multi-omic profiling of parental and resistant cells revealed genes associated with lineage identity and inflammation were enriched in chemotherapy resistant derivatives. Integrated pSTAT3 ChIP-seq and RNA-seq analyses showed pSTAT3 regulates genes related to inflammation and epithelial to mesenchymal transition (EMT) in resistant cells, as well as PDE4A, a cAMP-specific phosphodiesterase. Metabolomic characterization identified elevated cAMP signaling and CREB as a candidate therapeutic target in IBC. We also investigated cellular dynamics and heterogeneity at the single cell level during chemotherapy and acquired resistance by CyTOF and single cell RNA-seq. We identified mechanisms of resistance including a shift from luminal to basal/mesenchymal cell states through selection for rare pre-existing subpopulations or an acquired change. Lastly, we showed that combination treatment with paclitaxel and JAK/STAT3 inhibition prevented the emergence of this more mesenchymal chemo-resistant subpopulation. Our results provide mechanistic rational for combination of chemotherapy with inhibition of JAK/STAT3 signaling as a new more effective therapeutic strategy in IBC.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Kornelia Polyak  

PROVIDER: MSV000090647 | MassIVE | Fri Nov 04 13:48:00 GMT 2022

REPOSITORIES: MassIVE