Investigating a Potential Link Between Metabolic-Neurotrophic Coupling in Breast Tumor Innervation in Bioengineered Models

Metabolic reprogramming is a well-established hallmark of cancer, contributing to adverse behaviors like invasion, metastasis and recruitment of tissue-resident cells to the tumor microenvironment. Among recruitment capabilities, innervation has emerged as an active contributor of disease progression. Despite association with poor patient prognosis, mechanisms governing nerve recruitment at various stages of progression remain poorly understood. This study investigates how different stages of breast cancer cells are associated with the metabolic link of cancer and their pro-axonogenic capability. Here, we used human isogenic MCF10 mammary epithelial cell line series, three-dimensional collagen hydrogels, human adipose stromal cells (ASCs) and freshly isolated rat sensory neurons. Multiphoton optical redox imaging coupled with ATP production rate assays validated direct metabolic inhibition and highlighted the utilization of glutamine in progressed cells. We identified the expressions of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) from pre-malignant and malignant cultures, respectively. Interestingly, when treated with metabolic inhibitors, monocultures of MCF10 cells reduced neurotrophin release while cocultures with ASCs showed no or even elevated neurotrophin secretion. Together, these findings raise the possibility that breast tumor innervation is shaped in part by stage-specific metabolic-neurotrophic coupling, presenting a concrete mechanistic question for future investigation.