Since Otto Warburg’s first report on the increased uptake of glucose and lactate release by cancer cells, dysregulated metabolism has been acknowledged as a hallmark of cancer that promotes proliferation and metastasis. Over the last century, studies have shown that cancer metabolism is complex, and by-products of glucose and glutamine catabolism induce a cascade of both pro- and antitumorigenic processes. Some vitamins, which have traditionally been praised for preventing and inhibiting the proliferation of cancer cells, have also been proven to cause cancer progression in a dose-dependent manner. Importantly, recent findings have shown that the nervous system is a key player in tumor growth and metastasis via perineural invasion and tumor innervation. However, the link between cancer–nerve crosstalk and tumor metabolism remains unclear. Here, we discuss the roles of relatively underappreciated metabolites in cancer–nerve crosstalk, including lactate, vitamins, and amino acids, and propose the investigation of nutrients in cancer–nerve crosstalk based on their tumorigenicity and neuroregulatory capabilities. Continued research into the metabolic regulation of cancer–nerve crosstalk will provide a more comprehensive understanding of tumor mechanisms and may lead to the identification of potential targets for future cancer therapies.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related deaths, and perineural invasion (PNI), in which cancer cells infiltrate nerves, enables metastasis in most patients. PNI is largely attributed to Schwann cells (SC) that, when activated, accelerate cancer cell migration towards nerves. However, this cancer-associated reprogramming is generally under-appreciated. Additionally, tumor extracellular vesicle (EV) facilitation of cancer aggravation is well documented, but more investigation is required to better understand their role in PNI. Here, we assessed whether PDAC EVs mediate PNI via SC activation using tissue-engineered in vitro platforms and PANC-1 and HPNE human cell lines as models. Methods: NanoSight, Luminex®, and proteomic-pathway analyses characterized tumor (PANC-1) and healthy cell (HPNE) EVs. Human Schwann-like cells (sNF96.2) were embedded in decellularized nerve matrix hydrogels and then treated with EVs and a cargo-function-blocking antibody. Immunofluorescence and Luminex® multiplex assays assessed Schwann cell activation. Subsequently, sNF96.2 cells were co-cultured with EVs and either PANC-1 or HPNE cells; Transwell® invasion assays with SC-conditioned media were also conducted to establish a mechanism of in vitro PNI. Results: PANC-1 EVs contained higher levels of interleukin-8 (IL-8) signaling-associated proteins than HPNE EVs. Within nerve-mimetic in vitro testbeds, PANC-1 EVs promoted sNF96.2 activation per cytoskeletal marker alterations and secretion of pro-tumorigenic cytokines, e.g., chemokine ligand-2 (CCL2), via IL-8 cargoes. Furthermore, the IL-8/CCL2 axis heightened PANC-1 invasiveness. Conclusion: These findings highlight the potential role of PDAC EVs in PNI, which necessitates continued preclinical assessments with increased biodiversity to determine the efficacy of targeting IL-8/CCL2 for PNI.

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.