Assistant Professor of Biomedical Engineering University of Arkansas Fayetteville, Arkansas, United States
Introduction: While primary, early-stage breast cancer is curable, metastatic breast cancer remains a clinically significant problem. Analyses of clinical samples have shown that the increased infiltration of nerve fibers into the mammary tumors, a phenomenon known as tumor innervation, is highly correlated with metastatic potential of breast cancer. Literature suggests that metabolic dysregulation could in fact be linked to tumor innervation and heightened metastatic potential. For instance, metabolic rewiring such as lactate accumulation from aerobic glycolysis and glutamine addiction of cancer cells leads to changes in the tumor microenvironment that increases secretion of neurotrophins. Yet, much remains unknown about the upstream molecular and cellular mechanisms leading to breast tumor innervation. This talk will highlight our recent efforts in understanding breast tumor innervation using tissue engineered models.
Materials and
Methods: A panel of human mammary epithelial cells with varied levels of malignancy was co-embedded with human adipose stromal cells (ASCs) in tumor-mimetic collagen I hydrogels. Pharmacological inhibitors were added to the co-cultures to perturb specific metabolic pathways. Changes in metabolic activities were confirmed using multiphoton microscopy optical redox imaging where real-time autofluorescence of metabolic cofactors NADH and FAD was captured. Further, neurotrophin secretion and subsequent dorsal root ganglia neurite infiltration into the 3D co-cultures were measured in vitro.
Results, Conclusions, and Discussions: Our results so far indicate that glutaminase inhibition seems to be a potent regulator of neurotrophic behavior of breast cancer cells and ASCs. For instance, the presence of glutaminase inhibitor heavily shifted the metabolic preferences of our co-cultures as indicated by optical redox imaging, and significantly reduced neurotrophic factor secretion in vitro, more so than when treated with lactate dehydrogenase inhibitor. DRG neurite infiltration study also aligned with our observations of co-cultures. Interestingly, early-stage breast cancer cells seem to exhibit strong neurotrophic behavior in our models. Future work will focus on further unraveling potential mechanisms of metabolic rewiring effects and results and validating our in vitro results using animal models and patient samples to help determine the therapeutic potential of targeting breast tumor innervation.
Acknowledgements (Optional): This work was supported by the National Institutes of Health through the award numbers P20GM139768 and R37CA279722, Arkansas Biosciences Institute, and University of Arkansas Women’s Giving Circle.
