Nerve-to-cancer transfer of mitochondria during cancer metastasis – Nature

Report on Nerve-to-Cancer Transfer of Mitochondria During Cancer Metastasis

Introduction

The nervous system plays a crucial role in cancer biology, with intratumoural nerve density being linked to metastasis. However, the specific impact of cancer-associated neurons and the communication mechanisms at the nerve–cancer interface are not fully understood. Previous studies have shown cancer dependency on nerves, but the mechanisms driving nerve-mediated cancer aggressivity remain unclear. This report emphasizes the Sustainable Development Goals (SDGs), particularly SDG 3 (Good Health and Well-being) and SDG 9 (Industry, Innovation and Infrastructure), highlighting innovative research in cancer treatment and understanding.

Metabolic Plasticity and Cancer Progression

Cancer cells exhibit metabolic plasticity, adapting their energy production mechanisms, including glycolysis and oxidative phosphorylation (OXPHOS), to survive and metastasize. While much focus has been on cell-autonomous metabolic changes, non-autonomous mechanisms involving the tumor microenvironment, including stromal cells and neurons, are less understood.

Role of Cancer-Associated Neurons

• Cancer-infiltrating neurons influence cancer aggressivity and metabolism.
• Pathological analyses associate cancer innervation with poor clinical outcomes.
• Denervation studies show impaired tumor growth and altered cancer metabolism.

These findings underscore the metabolic dependency of cancer cells on nerves, suggesting metabolic support mechanisms at the nerve–cancer interface.

Experimental Models and Findings

Nerve Withdrawal and Tumor Bioenergetics

1. Breast cancer denervation using botulinum neurotoxin type A (BoNT/A) in mouse models led to decreased tumor growth and downregulation of metabolic pathways, especially the tricarboxylic acid cycle.
2. Histopathology showed reduced invasive lesions in denervated tumors, highlighting the importance of innervation in cancer progression.

Cancer-Induced Neuronal Metabolic Reprogramming

• In vitro coculture of breast cancer cells with neuronal stem cells (NSCs) demonstrated cancer-induced neuronal differentiation and increased mitochondrial mass in neurons.
• Cancer cells cocultured with neurons showed enhanced mitochondrial respiration and metabolic activity.
• Neuronal differentiation involved a metabolic shift from glycolysis to oxidative metabolism, increasing mitochondrial efficiency.

Neuron-to-Cancer Mitochondrial Transfer

1. Confocal microscopy and flow cytometry confirmed the transfer of mitochondria from neurons to cancer cells via tunnelling nanotubes.
2. Cell–cell contact was identified as the primary route for mitochondrial transfer.
3. Neuronal cells exhibited higher mitochondrial transfer rates compared to other cell types.
4. Transferred mitochondria were functional, restoring mitochondrial DNA and respiration in recipient cancer cells lacking mtDNA.

In Vivo Evidence of Mitochondrial Transfer

• Human prostate cancer samples showed increased mitochondrial load in cancer cells near nerves, which was reduced following chemical denervation.
• Mouse xenograft models demonstrated mitochondrial transfer from host neurons to breast cancer cells, confirmed by genetic reporters and mtDNA sequencing.
• Denervation reduced mitochondrial transfer, confirming the neuronal origin of transferred mitochondria.

Innovative Methodology: MitoTRACER

A novel genetic reporter system, MitoTRACER, was developed to permanently label cancer cells receiving mitochondria from neurons, enabling lineage tracing and functional analysis.

• Recipient cancer cells switch from red to green fluorescence upon mitochondrial acquisition.
• MitoTRACER allows real-time observation and permanent marking of mitochondrial transfer events.
• The system demonstrated dose-dependent and cumulative mitochondrial transfer in vitro.

Functional Impact of Mitochondrial Transfer on Cancer Cells

1. Recipient cancer cells with transferred mitochondria exhibited increased stemness, anchorage-independent growth, and mammosphere formation.
2. Metabolic profiling showed enhanced oxidative phosphorylation, ATP production, and a more energetic phenotype.
3. Improved redox balance and resistance to oxidative and shear stress were observed, key factors in metastatic resilience.
4. In vivo, mitochondria-recipient cancer cells showed higher metastatic potential, particularly in liver and brain metastases.

Fate of Recipient Cells During Metastasis

Lineage tracing in preclinical models revealed that cancer cells acquiring neuronal mitochondria in primary tumors are selectively enriched at metastatic sites, indicating enhanced metastatic capabilities.

• Mixed-cell spheroids transplanted into mammary fat pads showed increased green fluorescent cells in lung and brain metastases compared to primary tumors.
• Host-mediated neuronal mitochondrial transfer confirmed enrichment of recipient cells in metastatic sites.
• Similar findings were observed in melanoma models, with notable enrichment in brain metastases.

Discussion and Implications for Sustainable Development Goals (SDGs)

This study elucidates a novel mechanism by which cancer-associated neurons support tumor metabolism and metastasis through mitochondrial transfer. The findings have significant implications for SDG 3 (Good Health and Well-being) by advancing understanding of cancer biology and potential therapeutic targets to reduce cancer mortality.

• Understanding nerve–cancer metabolic interactions can lead to innovative cancer treatments, aligning with SDG 9 (Industry, Innovation and Infrastructure).
• Targeting mitochondrial transfer mechanisms may prevent metastatic dissemination, contributing to improved health outcomes.
• Research supports the development of precision medicine approaches, fostering sustainable healthcare innovation.

Conclusion

The nerve-to-cancer transfer of mitochondria enhances cancer metabolic plasticity, stemness, and metastatic potential. This metabolic support from neurons represents a critical aspect of cancer progression and offers promising avenues for therapeutic intervention. Integrating these insights into cancer research supports the achievement of Sustainable Development Goals related to health and innovation.

References and Data Availability

• Plasmids and bioinformatic datasets from the study are publicly available in the Addgene database and NCBI Sequence Read Archive.
• Custom code for data analysis is accessible via GitHub repositories.

1. Sustainable Development Goals (SDGs) Addressed or Connected to the Issues Highlighted in the Article

1. SDG 3: Good Health and Well-being
   • The article focuses on cancer biology, specifically breast cancer and prostate cancer, and the mechanisms of cancer metastasis, which directly relate to ensuring healthy lives and promoting well-being at all ages.
   • Understanding nerve-to-cancer mitochondrial transfer and its role in cancer progression can contribute to improved cancer treatments and outcomes.
2. SDG 9: Industry, Innovation and Infrastructure
   • The development of novel genetic reporter technologies such as MitoTRACER and advanced imaging and sequencing techniques reflects innovation in scientific research infrastructure.
3. SDG 17: Partnerships for the Goals
   • The article mentions collaborations among various institutions and the sharing of data and code, highlighting partnerships essential for advancing scientific knowledge and achieving health-related goals.

2. Specific Targets Under Those SDGs Identified Based on the Article’s Content

1. SDG 3: Good Health and Well-being
   • Target 3.4: By 2030, reduce by one third premature mortality from non-communicable diseases through prevention and treatment and promote mental health and well-being.
   • Target 3.b: Support the research and development of vaccines and medicines for the communicable and non-communicable diseases that primarily affect developing countries.
2. SDG 9: Industry, Innovation and Infrastructure
   • Target 9.5: Enhance scientific research, upgrade the technological capabilities of industrial sectors, including encouraging innovation and substantially increasing the number of research and development workers.
3. SDG 17: Partnerships for the Goals
   • Target 17.6: Enhance North-South, South-South and triangular regional and international cooperation on and access to science, technology and innovation.
   • Target 17.8: Fully operationalize the technology bank and science, technology and innovation capacity-building mechanism for least developed countries.

3. Indicators Mentioned or Implied in the Article to Measure Progress Towards the Identified Targets

1. Health-related Indicators (SDG 3)
   • Incidence and progression rates of breast and prostate cancer, including metastasis rates.
   • Survival rates and clinical outcomes associated with cancer innervation and mitochondrial transfer.
   • Reduction in tumor growth and metastasis following interventions such as chemical denervation (e.g., BoNT/A treatment).
2. Innovation and Research Indicators (SDG 9)
   • Development and application of novel genetic reporter systems (e.g., MitoTRACER) to trace mitochondrial transfer.
   • Number and impact of advanced imaging and sequencing techniques used in cancer research.
   • Publication and sharing of research data and custom code (e.g., GitHub repositories).
3. Partnership and Collaboration Indicators (SDG 17)
   • Number of collaborative studies and multi-institutional research projects.
   • Data and resource sharing platforms utilized (e.g., Addgene plasmid repository, NCBI Sequence Read Archive).
   • Participation in clinical trials and shared research initiatives.

4. Table of SDGs, Targets, and Indicators Relevant to the Article

SDGs	Targets	Indicators
SDG 3: Good Health and Well-being	3.4: Reduce premature mortality from non-communicable diseases through prevention and treatment. 3.b: Support research and development of medicines for non-communicable diseases.	Cancer incidence and metastasis rates. Survival and clinical outcomes related to cancer innervation. Effectiveness of interventions like chemical denervation (BoNT/A) in reducing tumor growth.
SDG 9: Industry, Innovation and Infrastructure	9.5: Enhance scientific research and technological capabilities.	Development and use of novel genetic tools (e.g., MitoTRACER). Application of advanced imaging and sequencing technologies. Publication and sharing of research data and code repositories.
SDG 17: Partnerships for the Goals	17.6: Enhance international cooperation on science, technology, and innovation. 17.8: Operationalize technology banks and capacity-building mechanisms.	Number of collaborative research projects and multi-institutional studies. Use of shared data repositories (Addgene, NCBI SRA). Participation in clinical trials and shared research initiatives.

Source: nature.com