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A Unique Morphological Phenotype in Chemoresistant Triple-Negative Breast Cancer Reveals Metabolic Reprogramming and
Isabelle Sirois1,2, Adriana Aguilar-Mahecha1, Josiane Lafleur1
1Segal Cancer Center, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montréal, Québec, Canada.
Abstract:
The major obstacle in successfully treating triple-negative breast cancer (TNBC) is resistance to cytotoxic chemotherapy, the mainstay of treatment in this disease. Previous preclinical models of chemoresistance in TNBC have suffered from a lack of clinical relevance. Using a single high dose chemotherapy treatment, we developed a novel MDA-MB-436 cell-based model of chemoresistance characterized by a unique and complex morphologic phenotype, which consists of polyploid giant cancer cells giving rise to neuron-like mononuclear daughter cells filled with smaller but functional mitochondria and numerous lipid droplets. This resistant phenotype is associated with metabolic reprogramming with a shift to a greater dependence on fatty acids and oxidative phosphorylation. We validated both the molecular and histologic features of this model in a clinical cohort of primary chemoresistant TNBCs and identified several metabolic vulnerabilities including a dependence on PLIN4, a perilipin coating the observed lipid droplets, expressed both in the TNBC-resistant cells and clinical chemoresistant tumors treated with neoadjuvant doxorubicin-based chemotherapy. These findings thus reveal a novel mechanism of chemotherapy resistance that has therapeutic implications in the treatment of drug-resistant cancer. IMPLICATIONS: These findings underlie the importance of a novel morphologic-metabolic phenotype associated with chemotherapy resistance in TNBC, and bring to light novel therapeutic targets resulting from vulnerabilities in this phenotype, including the expression of PLIN4 essential for stabilizing lipid droplets in resistant cells.
Insights
Triple-negative breast cancer (TNBC) chemoresistance involves a unique cell shape change and increased reliance on fatty acids. Targeting PLIN4 may offer new therapeutic strategies for drug-resistant TNBC.
Area of Science:
- Oncology
- Cancer Biology
- Metabolic Research
Background:
- Chemotherapy resistance is a major challenge in treating triple-negative breast cancer (TNBC).
- Existing preclinical models often lack clinical relevance.
- Novel models are needed to understand and overcome TNBC chemoresistance.
Purpose of the Study:
- To develop a clinically relevant preclinical model of chemotherapy resistance in TNBC.
- To elucidate the morphologic and metabolic characteristics of chemoresistant TNBC.
- To identify novel therapeutic targets for drug-resistant TNBC.
Main Methods:
- Developed a novel MDA-MB-436 cell-based model using high-dose chemotherapy.
- Characterized the morphologic phenotype: polyploid giant cells forming neuron-like daughter cells with functional mitochondria and lipid droplets.
- Analyzed metabolic reprogramming, focusing on fatty acid metabolism and oxidative phosphorylation.
- Validated findings in a clinical cohort of primary chemoresistant TNBCs.
Main Results:
- The novel TNBC model exhibited a unique morphologic phenotype and metabolic reprogramming towards fatty acid dependence.
- This phenotype was validated in clinical samples of chemoresistant TNBC.
- A dependence on PLIN4, a protein coating lipid droplets, was identified in both the model and clinical samples.
Conclusions:
- A novel morphologic-metabolic phenotype is associated with chemotherapy resistance in TNBC.
- PLIN4 is a potential therapeutic target for drug-resistant TNBC due to its role in stabilizing lipid droplets.
- These findings offer new therapeutic implications for treating chemoresistant breast cancer.
