Neurons duped into delivering mitochondria to cancer cells found fueling tumor spread
University of South Alabama researchers report that neurons can transfer mitochondria directly to cancer cells, enhancing their metastatic potential.
Oncologists have long suspected that tumors thrive partly by enlisting help from surrounding nerves. Pathologists studying cancer tissues have observed that tumors nestled among dense networks of nerves often grow faster and spread farther.
Previous rodent and human studies demonstrated that cutting off this neural input slowed cancer growth. How neurons influence the growth of cancer cells has remained unclear.
Intercellular mitochondrial transfer is a recognized cellular rescue attempt where healthy donor cells revive compromised recipients by donating functional mitochondria. For example, astrocytes, a type of non-neuronal nervous system cell, can transfer healthy mitochondria to injured neurons to help them recover from injury by replacing a damaged or defective mitochondrion.
In the study, "Nerve-to-cancer transfer of mitochondria during cancer metastasis," published in Nature, researchers employed murine breast cancer models and advanced lineage-tracing reporters to test whether neurons confer metabolic assets to tumor cells via mitochondrial transfer.
Researchers performed chemical denervation by injecting botulinum neurotoxin A (BoNT/A) around breast tumors in mice. Denervation refers to the deliberate interruption of nerve supply to a tumor to chemically disable local nerve function.
The team then compared these denervated tumors to saline-injected controls using transcriptomic profiling, histopathology, and measurements of mitochondrial content.
Denervated tumors showed a marked reduction in mitochondrial load, downregulation of metabolic gene pathways (notably the tricarboxylic acid cycle), and significantly lower incidence of invasive lesions (from 55% in controls to 12% in denervated mice). These findings demonstrate that nerve inputs actively sustain tumor bioenergetics and promote progression.
Next, to test mitochondrial transfer from neurons to cancer cells, the team engineered neurons to express mitochondria tagged with fluorescent markers with a novel tracking system called MitoTRACER. The system allowed researchers to monitor cancer cells after mitochondrial transfer, enabling detailed tracing of their fate during disease progression.
Direct mitochondrial transfer was observed via tunneling nanotubes, initiated by neurons towards the cancer cells. Rho-zero cancer cells regained oxidative phosphorylation and uridine-independent growth after acquiring neuronal mitochondria, confirming functional rescue.
MitoTRACER revealed that recipient cancer cells displayed enhanced respiration, higher ATP, improved redox balance, and greater resistance to oxidative and mechanical stress.
In animal models, these labeled recipient cells were significantly enriched in metastases, especially in the brain and liver, indicating that neuronal mitochondria confer a selective advantage during dissemination.
Together, these two experimental arms show that nerves both sustain tumor energetics broadly and act as direct donors of functional mitochondria, a dual mechanism that promotes cancer survival and spread.
Denervation experiments established that disrupting nerve input deprives cancer cells of essential bioenergetic capacity, reducing their invasiveness. Cancer cells that had received neuronal mitochondria more readily survived metastatic stressors such as oxidative damage and mechanical shear forces, common hurdles faced during cancer dissemination.
While the exact signaling is still unclear, the study suggests that cancer cells are the initiating party, recruiting and instructing neurons to produce and deliver mitochondria, rather than neurons independently sensing distress and attempting rescue.
Based on the findings, targeting nerve availability to tumor sites may offer a promising strategy for researchers seeking ways to curb tumor progression. As with any good study, more research is needed to see where the new knowledge leads.
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