Modulation of host immunity by sensory neurons

Saraiva-Santos, Telma; Zaninelli, Tiago H.; Pinho-Ribeiro, Felipe A.

doi:10.1016/j.it.2024.03.005

Cited by 4 publications

(2 citation statements)

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“…Tissue-agnostic approaches such as selective or non-selective inhibition of Trk (larotrectinib and entrectinib) have been approved by the FDA for fusion cancers and could be considered as future therapies to target nerves in sarcoma 54 . More recently, the FDA approval for antibodies against the CGRP (erenumab and fremanezumab) to treat chronic migraines [55][56][57][58] , brings up an exciting possibility of drug repurposing to ameliorate sarcoma progression and bone Sensory neurons modulate the tumor microenvironment via secondary mechanisms such as promoting vascularization 60 . In our xenograft orthotopic model of OS, we observed that blocking of sensory (TrkA + /CGRP + ) nerve fibers resulted in marked reduction in tumor-associated blood vessels (EMCN + /CD31 + ) and reduced pro-vasculogenic ligand VEGFA, as described in other contexts 18,25,61,62 .…”

Section: Discussionmentioning

confidence: 99%

“…Sensory neurons modulate the tumor microenvironment via secondary mechanisms such as promoting vascularization 60 . In our xenograft orthotopic model of OS, we observed that blocking of sensory (TrkA + /CGRP + ) nerve fibers resulted in marked reduction in tumor-associated blood vessels (EMCN + /CD31 + ) and reduced pro-vasculogenic ligand VEGFA, as described in other contexts 18,25,61,62 .…”

Section: Discussionmentioning

confidence: 99%

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TrkA⁺sensory neurons regulate osteosarcoma proliferation and vascularization to promote disease progression

Qin,

Ramesh,

et al. 2024

Preprint

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Bone pain is a presenting feature of bone cancers such as osteosarcoma (OS), relayed by skeletal-innervating peripheral afferent neurons. Potential functions of tumor-associated sensory neurons in bone cancers beyond pain sensation are unknown. To uncover neural regulatory functions, a chemical-genetic approach in mice with a knock-in allele for TrkA was used to functionally perturb sensory nerve innervation during OS growth and disease progression. TrkA inhibition in transgenic mice led to significant reductions in sarcoma-associated sensory innervation and vascularization, tumor growth and metastasis, and prolonged overall survival. Single-cell transcriptomics revealed that sarcoma denervation was associated with phenotypic alterations in both OS tumor cells and cells within the tumor microenvironment, and with reduced calcitonin gene-related peptide (CGRP) and vascular endothelial growth factor (VEGF) signaling. Multimodal and multi-omics analyses of human OS bone samples and human dorsal root ganglia neurons further implicated peripheral innervation and neurotrophin signaling in OS tumor biology. In order to curb tumor-associated axonal ingrowth, we next leveraged FDA-approved bupivacaine liposomes leading to significant reductions in sarcoma growth, vascularity, as well as alleviation of pain. In sum, TrkA-expressing peripheral neurons positively regulate key aspects of OS progression and sensory neural inhibition appears to disrupt calcitonin receptor signaling (CALCR) and VEGF signaling within the sarcoma microenvironment leading to significantly reduced tumor growth and improved survival. These data suggest that interventions to prevent pathological innervation of osteosarcoma represent a novel adjunctive therapy to improve clinical outcomes and survival.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

TrkA⁺sensory neurons regulate osteosarcoma proliferation and vascularization to promote disease progression

Qin,

Ramesh,

et al. 2024

Preprint

View full text Add to dashboard Cite

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The healing power of sensory neurons: New horizons for diabetic and neuropathic tissue repair

Lu,

Ramakrishnan,

Martino

2024

Clinical & Translational Med

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Hide-and-sick: How bacteria manipulate a neural circuit that makes you sick

Pinho-Ribeiro

2024

Neuron

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Modulation of host immunity by sensory neurons

Cited by 4 publications

References 83 publications

TrkA⁺sensory neurons regulate osteosarcoma proliferation and vascularization to promote disease progression

TrkA⁺sensory neurons regulate osteosarcoma proliferation and vascularization to promote disease progression

The healing power of sensory neurons: New horizons for diabetic and neuropathic tissue repair

Hide-and-sick: How bacteria manipulate a neural circuit that makes you sick

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Modulation of host immunity by sensory neurons

Cited by 4 publications

References 83 publications

TrkA+sensory neurons regulate osteosarcoma proliferation and vascularization to promote disease progression

TrkA+sensory neurons regulate osteosarcoma proliferation and vascularization to promote disease progression

The healing power of sensory neurons: New horizons for diabetic and neuropathic tissue repair

Hide-and-sick: How bacteria manipulate a neural circuit that makes you sick

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Product

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TrkA⁺sensory neurons regulate osteosarcoma proliferation and vascularization to promote disease progression

TrkA⁺sensory neurons regulate osteosarcoma proliferation and vascularization to promote disease progression