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. In breast cancer, CD44+CD24− cells possess stem cell-like features and contribute to disease progression, and we previously described a CD44+CD24−pSTAT3+ breast cancer cell subpopulation that is dependent on JAK2/STAT3 signaling. Here we report that CD44+CD24− cells are the most frequent cell type in IBC and are commonly pSTAT3+. Combination of JAK2/STAT3 inhibition with paclitaxel decreased IBC xenograft growth more than either agent alone. IBC cell lines resistant to paclitaxel and doxorubicin were developed and characterized to mimic therapeutic resistance in patients. Multi-omic profiling of parental and resistant cells revealed enrichment of genes associated with lineage identity and inflammation in chemotherapy-resistant derivatives. Integrated pSTAT3 chromatin immunoprecipitation sequencing and RNA sequencing (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. Investigation of cellular dynamics and heterogeneity at the single cell level during chemotherapy and acquired resistance by CyTOF and single cell RNA-seq identified mechanisms of resistance including a shift from luminal to basal/mesenchymal cell states through selection for rare preexisting subpopulations or an acquired change. Finally, combination treatment with paclitaxel and JAK2/STAT3 inhibition prevented the emergence of the mesenchymal chemo-resistant subpopulation. These results provide mechanistic rational for combination of chemotherapy with inhibition of JAK2/STAT3 signaling as a more effective therapeutic strategy in IBC.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Nov 21, 2022
- Source ID
- 10.1158/0008-5472.can-22-0423
Entities
People
- Alanna L. Pyke
- Alex Toker
- Alexander Meissner
- Anne Fassl
- Anne Trinh
- Beth A Overmoyer
- Bojana Jovanovic
- Callahan M. Wilde
- Daniel Temko
- David A Frank
- Franziska Michor
- Guillermo Peluffo
- Henry W Long
- Jacob D Jaffe
- Jacqueline Salas
- Kendell Clement
- Kornélia Polyák
- Laura E. Stevens
- Malvina Papanastasiou
- Marco Seehawer
- Maša Alečković
- Natalie L. Kingston
- Nicholas W Harper
- Ningxuan Zhou
- Piotr Sicinski
- Renee C Geck
- Sarah R Walker
- Shaokun Shu
- Shawn B. Egri
- So Yeon Park
- Vanessa Almendro
- Xintao Qiu
- Zheqi Li
Organizations
- Beth Israel Deaconess Medical Center
- Brigham and Women's Hospital
- Dana–Farber Cancer Institute
- Harvard Medical School
- Harvard University
- National Cancer Institute
- Seoul National University
- Susan G. Komen for the Cure
- United States Department of Defense
- V Foundation for Cancer Research