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Area of Science:

  • Oncology
  • Neuroscience
  • Immunology

Background:

  • Tumour innervation correlates with poor patient outcomes in various cancers.
  • Enhanced nerve presence in highly metastatic mammary tumours suggests a role in metastasis regulation.

Purpose of the Study:

  • To investigate the role of tumour innervation in breast cancer metastasis.
  • To elucidate the mechanisms by which sensory neurons influence tumour progression.
  • To identify potential therapeutic targets within the neuro-cancer axis.

Main Methods:

  • Analysis of tumour innervation in mouse mammary tumours with varying metastatic potential.
  • Investigating the role of SLIT2 in tumour vasculature and its effect on innervation.
  • Utilizing 3D co-cultures and in vivo models to study the effects of substance P (SP) on breast cancer cells.
  • Examining the interaction between dying cancer cells, released ssRNAs, and Toll-like receptor 7 (TLR7).
  • Assessing the efficacy of the TACR1 antagonist aprepitant in preclinical models.

Main Results:

  • Highly metastatic tumours exhibited increased innervation, driven by SLIT2 in tumour vasculature.
  • Breast cancer cells induced calcium activity in sensory neurons, leading to substance P (SP) release.
  • Neuronal SP promoted tumour growth, invasion, and metastasis, correlating with lymph node spread in patients.
  • SP-induced death of TACR1high cancer cells released ssRNAs that activated TLR7, promoting a prometastatic gene expression program.
  • This SP- and ssRNA-induced TLR7 signature was linked to reduced breast cancer survival.
  • Aprepitant treatment suppressed breast cancer growth and metastasis in multiple models.

Conclusions:

  • Tumour innervation, driven by sensory neuron-derived SP, promotes breast cancer growth and metastasis.
  • A novel axis involving neuropeptide signaling, ssRNA release, and TLR7 activation contributes to metastatic progression.
  • Targeting the tachykinin receptor 1 (TACR1) with aprepitant offers a potential therapeutic strategy for breast cancer.