JAK-STAT Signaling in Inflammatory Breast Cancer Enables Chemotherapy-Resistant Cell States
Laura E Stevens1,2,3, Guillermo Peluffo1,2,3, Xintao Qiu4
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Cancer Research
|November 21, 2022
Summary
Inflammatory breast cancer (IBC) stem cells rely on JAK2/STAT3 signaling. Combining paclitaxel with JAK2/STAT3 inhibitors overcomes chemotherapy resistance and prevents disease progression in IBC models.
Area of Science:
- Oncology
- Cancer Biology
- Molecular Medicine
Background:
- Inflammatory breast cancer (IBC) is an aggressive subtype with poor outcomes.
- CD44+CD24- cells exhibit stem-like properties and drive cancer progression.
- A CD44+CD24-pSTAT3+ subpopulation dependent on JAK2/STAT3 signaling was previously identified.
Purpose of the Study:
- To investigate the role of CD44+CD24- cells and JAK2/STAT3 signaling in IBC.
- To identify mechanisms of chemotherapy resistance in IBC.
- To evaluate combination therapy for IBC.
Main Methods:
- Analysis of CD44+CD24- cells in IBC.
- JAK2/STAT3 inhibition combined with chemotherapy (paclitaxel).
- Development and multi-omic profiling of chemo-resistant IBC cell lines.
- Single-cell analysis (CyTOF, scRNA-seq) and metabolomics.
Main Results:
- CD44+CD24- cells are prevalent in IBC and often pSTAT3+.
- Combination therapy reduced IBC xenograft growth more effectively than single agents.
- Chemo-resistant cells showed enrichment in inflammation and EMT-related genes.
- pSTAT3 regulates inflammation, EMT, and PDE4A in resistant cells.
- Elevated cAMP signaling and CREB were identified as potential targets.
- Chemotherapy induced a shift to basal/mesenchymal cell states, conferring resistance.
- Combination therapy prevented the emergence of chemo-resistant subpopulations.
Conclusions:
- JAK2/STAT3 signaling is a key driver of chemotherapy resistance in IBC.
- Combination of paclitaxel with JAK2/STAT3 inhibition is a promising therapeutic strategy for IBC.
- Targeting cAMP signaling may offer additional therapeutic avenues for IBC.
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