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Matrix compliance permits NF-κB activation to drive therapy resistance in breast cancer
- Source :
- The Journal of experimental medicine, vol 218, iss 5, The Journal of Experimental Medicine
- Publication Year :
- 2021
- Publisher :
- eScholarship, University of California, 2021.
-
Abstract
- Soft extracellular matrix protects breast cancer cells from apoptosis and reduces the efficacy of chemo- and radiation therapies through enhanced NF-κB signaling and diminished proapoptotic JNK activity. Therapeutic targeting of the NF-κB–JNK axis may thwart treatment resistance in breast cancer.<br />Triple-negative breast cancers (TNBCs) are associated with poor survival mediated by treatment resistance. TNBCs are fibrotic, yet little is known regarding how the extracellular matrix (ECM) evolves following therapy and whether it impacts treatment response. Analysis revealed that while primary untreated TNBCs are surrounded by a rigid stromal microenvironment, chemotherapy-resistant residual tumors inhabit a softer niche. TNBC organoid cultures and xenograft studies showed that organoids interacting with soft ECM exhibit striking resistance to chemotherapy, ionizing radiation, and death receptor ligand TRAIL. A stiff ECM enhanced proapoptotic JNK activity to sensitize cells to treatment, whereas a soft ECM promoted treatment resistance by elevating NF-κB activity and compromising JNK activity. Treatment-resistant residual TNBCs residing within soft stroma had elevated activated NF-κB levels, and disengaging NF-κB activity sensitized tumors in a soft matrix to therapy. Thus, the biophysical properties of the ECM modify treatment response, and agents that modulate stiffness-dependent NF-κB or JNK activity could enhance therapeutic efficacy in patients with TNBC.
- Subjects :
- 0301 basic medicine
Nude
Apoptosis
Triple Negative Breast Neoplasms
Mice, SCID
Matrix (biology)
Medical and Health Sciences
Extracellular matrix
chemistry.chemical_compound
Mice
0302 clinical medicine
Mice, Inbred NOD
Tumor Microenvironment
Immunology and Allergy
skin and connective tissue diseases
Triple-negative breast cancer
Cancer
Tumor
NF-kappa B
Chemoradiotherapy
Neoadjuvant Therapy
Extracellular Matrix
Paclitaxel
5.1 Pharmaceuticals
030220 oncology & carcinogenesis
6.1 Pharmaceuticals
Stromal cell
Cell Survival
Immunology
Mice, Nude
SCID
Article
Cell Line
03 medical and health sciences
Breast cancer
Stroma
Cell Line, Tumor
Breast Cancer
Organoid
medicine
Animals
Humans
Solid Tumors
business.industry
JNK Mitogen-Activated Protein Kinases
medicine.disease
Xenograft Model Antitumor Assays
Enzyme Activation
030104 developmental biology
chemistry
Cancer research
Inbred NOD
business
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- The Journal of experimental medicine, vol 218, iss 5, The Journal of Experimental Medicine
- Accession number :
- edsair.doi.dedup.....b6a0d84f31459646821dcdba2f815b36