PhD Defense in Neural Engineering
PhD Candidate: Jay Shiralkar
Location: Wickenden 105 (in person)
Advisor: Dominique Durand
Abstract:
Objective
Breast and skin cancers are one of the most lethal cancers with triple negative breast cancer (TNBC) and melanoma as most deadlier subtypes, respectively. It is well known that cancers are innervated with sensory, sympathetic and parasympathetic nerves and these nerves interact with stromal and tumoral cells in order to control and modify every significant aspect of tumor microenvironment. Despite the crucial roles of nerves, the neuroelectric phenomena in malignancy initiation, the branch specific origin of tumoral nerve activity and its implications on secondary metastasis are vastly unexplored.
Principle Global Hypothesis: Solid primary tumors with malignant nature are characterized by presence of neural impulses while the primary tumors with lower metastatic potential, are devoid of any significant neural activity. The neural activity originates in the autonomic nervous system with both its branches i.e. sympathetic and parasympathetic, exerting antagonistic effects on secondary distant metastasis.
Methods
Triple negative- 4T1, D2A1; HER2+ - MMTV/NeuT and B16-F10, B16-F1 cell lines were used for in-vivo modeling of solid breast and melanoma tumors. Neural recordings were obtained using a differential pair of electrodes, comprising drawn filled tubing (DFT) wires directly implanted in breast tumors while human grade microneurography needles implanted in melanoma tumors. Bioluminescence imaging was used to monitor the growth of the primary tumors as well as the secondary metastases to prevalent sites. Immunohistochemical (IHC) staining was used to confirm the presence of neurofilaments as well as sympathetic and parasympathetic fibers.
Results
Experiments show that the presence of neural activity is a unique and distinct feature of primary highly metastasizing tumors of breast and skin cancers while their counterparts with low metastatic potential have significantly reduced neural action potentials. Noradrenergic sympathetic nerves are the origin of this tumoral neuroelectric activity as 6-OHDA treatment completely abolished the entire peak activity. In breast tumor bearing mice, the two branches of autonomic nervous system play antagonistic roles in secondary metastasis to thoracic region, whereby metastasis is accelerated post vagotomy while delayed after chemical ablation of sympathetic nerves in 4T1 tumors. In melanomas, sympathectomy caused contrasting effect in two sexes, where sympathectomized male mice showed earlier metastasis while female mice undergone sympathectomy showed delayed metastasis compared to animals with no treatment.
Significance
Early detection of malignancy is a decisive aspect in reducing mortality and improving overall survival due to the cancer. Chronic neural activity can be recorded and quantified from primary metastasizing tumors as the cancer progresses in vivo and can be used as a neural marker for tumor microenvironment status. Further, electrical activity of nerves in tumors could be established as a reliable clinical marker for differentiating malignancy from benign