Maneli, Giovanni (2025) Glucose impacts onto the reciprocal reprogramming between mammary adipocytes and cancer cells and reduce Tamoxifen responsiveness. [Tesi di dottorato]

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Abstract

Over the past two decades, the global prevalence of diabetes has increased dramatically, driven by substantial shifts in environmental conditions, human behavior, and lifestyle patterns. Diabetes-related hyperglycemia is associated with an increased risk of developing BC and also with a reduced response to endocrine and chemotherapy treatments. An established hallmark of cancer cells is metabolic reprogramming, largely consisting in the exacerbated glucose uptake. Adipocytes in the tumor microenvironment contribute toward breast cancer (BC) progression and are highly responsive to metabolic fluctuations. Metabolic conditions characterizing obesity and/or diabetes associate with increased BC incidence and mortality. In line with the availability of biomedical and information engineering methodologies for understanding the impact of metabolic alterations on chronic diseases, BC-adipocytes interaction and the impact of glucose in such dialogue have been explored. Thus, mammary Adipose-derived Mesenchymal Stem Cells (MAd-MSCs) were differentiated into adipocytes and co-cultured with ER+ BC cells while exposed to glucose concentration resembling hyperglycemia or normoglycemia in humans (25mM or 5.5mM). Obtained results highlighted that co-culture with adipocytes in a glucose-rich environment determined a re-program of BC cell transcriptome driving lipid accumulation, a hallmark of BC aggressiveness, promoting stem-like properties and reducing Tamoxifen responsiveness. Moreover, data point out to a transcriptional effect through which BC cells induce adipocytes de-lipidation, paralleled by pluripotency gain, as source of lipids when glucose lowering occurs. Thus, modulating plasticity of peri-tumoral adipocytes may represent a key point for halting BC progression in metabolically unbalanced patients. Such results provide additional cues to define the role of glucose in the dialogue between adipose and cancer cells in breast and, therefore, for BC managements in the concurrence of obesity/diabetes.

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