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.
Marine nonindigenous species (NIS) are spreading at an alarming rate internationally through anthropogenic activities such as shipping and aquaculture, affecting local biodiversity and negatively impacting the ecosystem and human well‐being. Countries and international organizations have recognized this global threat and have begun implementing biosecurity management programs to ensure early detection, effective surveillance, and mitigation of marine NIS spread. Molecular techniques based on environmental DNA and RNA (eDNA/eRNA), collectively referred to as environmental nucleic acids (eNAs), have become a popular noninvasive tool for detecting NIS and monitoring biodiversity locally and globally. However, uncertainties about eNAs detection probabilities and the location of the source population impede the broad uptake of this tool in marine biosecurity programs. It's been hypothesized that most of these uncertainties can be explained by studying the molecules' dynamics within a marine environment and implementing eNAs distribution models. To contribute to further knowledge development in this area, our study reviews data from 20 recent reports on the degradation mechanisms and fate of eNAs in the marine environment. We classified the critical factors influencing eNAs' persistence that should be considered by biosecurity practitioners, outlining the complex interaction between the molecules' degradation processes and particular environmental conditions. To help guide the parameterization of eNAs distribution models, this review also summarizes and standardizes the marine decay rates of eDNA/eRNA from the literature. Finally, this manuscript outlines guidelines to help calculate accurate decay rates to build appropriate “fit‐for‐purpose” marine biosecurity tools for improved target detectability and greater resolution in assessing biodiversity.
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