# Neural Mechanisms of Cancer Pain

> **NIH NIH R01** · UNIVERSITY OF MINNESOTA · 2022 · $367,614

## Abstract

ABSTRACT
The management of cancer pain remains a major challenge. Cancer pain is a complex pain
state that includes inflammatory, neuropathic components and a unique set of cancer-specific
components. Exosomes secreted by cancer cells is one of those cancer-specific factors. In
preliminary studies, exosomes confirmed by size and expression of protein markers, induced
acute mechanical and heat hyperalgesia following injection into the hind paw of both sexes of
naïve C3H/HeN mice. This project will test the hypothesis that exosomes secreted by
fibrosarcoma cells produce pain by sensitizing nociceptive primary afferent neurons via the
autotaxin (ATX)-lysophosphatidic acid (LPA)-LPA1 receptor (R) pathway. Exosomes isolated
from fibrosarcoma cell-conditioned media will be verified by size (Nanoparticle tracking
analysis), expression of the exosome-specific markers, and activity of ATX. Electrophysiological
studies in vivo will determine the contribution of ATX-LPA-LPA1R signaling to exosome-specific
sensitization of nociceptors. At the cellular level, acute sensitization of small dorsal root
ganglion (DRG) neurons from adult mice will be defined in a bioassay that measures the
occurrence of a calcium transient in response to depolarization with 25 mM KCl in vitro with
Indo-1. Whether the exosome-bound ATX-LPA complex released from fibrosarcoma cells
sensitizes DRG neurons through activation of LPA1 receptors will be determined using
pharmacological and molecular (siRNA) approaches. Resolvin D1 is proposed to attenuate
exosome-evoked sensitization of nociceptors and hyperalgesia by interfering with ATX-LPA-
LPA1R signaling. If exosome-mediated ATX-LPA-LPA1R signaling underlies hyperalgesia, it will
provide insight into a new strategy for managing bone cancer pain. Future studies will further
investigate the molecular, biochemical and electrophysiological mechanisms by which
exosomes released from cancer cells contribute to cancer pain.

## Key facts

- **NIH application ID:** 10412037
- **Project number:** 5R01CA241627-04
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** Donald Simone
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $367,614
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10412037

## Citation

> US National Institutes of Health, RePORTER application 10412037, Neural Mechanisms of Cancer Pain (5R01CA241627-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10412037. Licensed CC0.

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