Matrix compliance permits NF-κB activation to drive therapy resistance in breast cancer

Area of Science:

• Oncology
• Biophysics
• Cancer Biology

Background:

• Triple-negative breast cancer (TNBC) presents poor survival outcomes due to treatment resistance.
• The role of the extracellular matrix (ECM) in therapy resistance within TNBC is not well understood.
• TNBCs are characterized by fibrosis, indicating a significant stromal component.

Purpose of the Study:

• To investigate how the ECM's biophysical properties influence treatment response in TNBC.
• To elucidate the molecular mechanisms by which ECM stiffness affects chemotherapy and radiation resistance.
• To identify potential therapeutic strategies targeting ECM-mediated resistance.

Main Methods:

• Analysis of ECM stiffness in primary versus residual TNBC tumors.
• Utilizing TNBC organoid cultures and xenograft models to study ECM-tumor interactions.
• Assessing the impact of ECM stiffness on sensitivity to chemotherapy, ionizing radiation, and TRAIL.
• Measuring JNK and NF-κB signaling pathway activation in response to ECM stiffness.

Main Results:

• Primary TNBCs are associated with a rigid ECM, while residual tumors reside in a softer niche.
• Organoids cultured in soft ECM exhibit increased resistance to chemotherapy, radiation, and TRAIL.
• Stiff ECM enhances JNK activity, sensitizing cells to treatment, whereas soft ECM elevates NF-κB activity, promoting resistance.
• Treatment-resistant TNBCs in soft stroma show elevated activated NF-κB; inhibiting NF-κB sensitizes these tumors to therapy.

Conclusions:

• The biophysical properties of the ECM significantly modulate treatment response in TNBC.
• ECM stiffness influences TNBC resistance through differential activation of NF-κB and JNK pathways.
• Targeting stiffness-dependent signaling pathways, such as NF-κB or JNK, may enhance therapeutic efficacy in TNBC patients.