A Unique Morphological Phenotype in Chemoresistant Triple-Negative Breast Cancer Reveals Metabolic Reprogramming and PLIN4 Expression as a Molecular Vulnerability

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 chemore-sistant TNBCs and identified several metabolic vulnerabilities including a dependence on PLIN4, a perilipin coating the observed lipid droplets, expressed both in the TNBCresistant 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.

Intratumor Heterogeneity and Therapy Resistance: Contributions of Dormancy, Apoptosis Reversal (Anastasis) and Cell Fusion to Disease Recurrence

“…Consistent with these properties, a significant number of recent reports with different biological systems (e.g., tumor-derived cell lines, animal models, and specimens from cancer patients) have underscored the key roles played by PGCCs in tumorigenesis, metastasis, and disease relapse after conventional cancer treatments. The contributions that PGCCs make to therapy resistance is demonstrated for various types of solid tumors, including ovarian cancer [43,44], prostate cancer [23,47], brain cancer [26,28], renal cancer [54], colon cancer [46], and breast cancer [45,55], including the most aggressive form (triple negative) [55] for which chemotherapy remains the cornerstone therapeutic. There have been several reviews on the formation, stemness, and tumorigenicity of PGCCs before and after exposure to cancer therapeutic agents (e.g., [56][57][58][59]).…”

A New Prognostic Risk Model Based on PPAR Pathway-Related Genes in Kidney Renal Clear Cell Carcinoma

“…PLIN1 may affect tumor progression through PPARG/PPAR γ pathway in breast cancer [ 69 ]. At the same time, another member of the same family, PLIN4, has also been identified as a therapeutic target for triple-negative breast cancer [ 70 ].…”

Metabolic Constrains Rule Metastasis Progression

“…Analogously, docetaxel-resistant prostate cancer was shown to shunt several metabolic intermediates, namely lactate, glutamine, and glucose towards OXPHOS, with a concomitant decrease in intracellular ROS content [247]. Furthermore, doxorubicin resistance in a primary triple-negative breast cancer cell line was shown to be achieved through the OXPHOS upregulation, with a parallel reduction in lactate production [248]. Ultimately, Herlyn and collegues reported that upon cisplatin or vemurafenib treatment, the appereance of multidrug resistant melanoma cells rely on JARID1B up-regulation.…”

“…Along with carbohydrate metabolism, chemotherapy was reported to critically impact lipid-related pathways. In particular, two separate works on breast cancer revealed a significant increase in lipid droplets accumulation and cholesterol biosynthesis upon either doxorubicin [248] or tamoxifen [253]. It is worth noting that the silencing of perilipin, the proteic structural component of lipid droplets, resulted in reduced viability of doxorubicin-resistant breast cancer cells [248].…”