Investigating a Potential Link Between Metabolic-Neurotrophic Coupling in Breast Tumor Innervation in Bioengineered Models
- 1Department of Biomedical Engineering, University of Arkansas, Fayetteville, AR 72701, USA
- 2Arkansas Integrative Metabolic Research Center, University of Arkansas, Fayetteville, AR 72701, USA
- 3Winthrop P Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
Abstract
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.
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BibTeX
@article{alakokko2026investigating,
title = {{Investigating a Potential Link Between Metabolic-Neurotrophic Coupling in Breast Tumor Innervation in Bioengineered Models}},
author = {Nikolas Ala-Kokko and Emory Gregory and Alan Woessner and Bing Guan and Winifred Middleton and Donald J. Johann and Narasimhan Rajaram and Timothy J. Muldoon and Younghye Song},
journal = {Cells},
year = {2026},
month = oct,
doi = {10.3390/cells15211959},
url = {https://www.mdpi.com/2073-4409/15/21/1959},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Investigating a Potential Link Between Metabolic-Neurotrophic Coupling in Breast Tumor Innervation in Bioengineered Models
AU - Nikolas Ala-Kokko
AU - Emory Gregory
AU - Alan Woessner
AU - Bing Guan
AU - Winifred Middleton
AU - Donald J. Johann
AU - Narasimhan Rajaram
AU - Timothy J. Muldoon
AU - Younghye Song
PY - 2026
DA - 2026/10/28
JO - Cells
DO - 10.3390/cells15211959
UR - https://www.mdpi.com/2073-4409/15/21/1959
AB - 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.
SN - 2073-4409
ER -