Principal Investigator

Donald
Simone
Awardee Organization

University Of Minnesota
United States

Fiscal Year
2023
Activity Code
R01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Neural Mechanisms of Cancer Pain

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-LPALPA1R 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.

Publications

  • Khasabova IA, Seybold VS, Simone DA. The role of PPARγ in chemotherapy-evoked pain. Neuroscience letters. 2021 May 14;753:135845. Epub 2021 Mar 24. PMID: 33774149
  • Cataldo G, Lunzer MM, Akgün E, Wong HL, Portoghese PS, Simone DA. MMG22 Potently Blocks Hyperalgesia in Cisplatin-treated Mice. Neuroscience. 2023 Apr 15;516:54-61. Epub 2023 Feb 17. PMID: 36805004
  • Rogness VM, Juliette J, Khasabova IA, Gupta K, Khasabov SG, Simone DA. Descending Facilitation of Nociceptive Transmission From the Rostral Ventromedial Medulla Contributes to Hyperalgesia in Mice with Sickle Cell Disease. Neuroscience. 2023 Aug 21;526:1-12. Epub 2023 Jun 16. PMID: 37330194
  • Khasabova IA, Golovko MY, Golovko SA, Simone DA, Khasabov SG. Intrathecal administration of Resolvin D1 and E1 decreases hyperalgesia in mice with bone cancer pain: Involvement of endocannabinoid signaling. Prostaglandins & other lipid mediators. 2020 Dec;151:106479. Epub 2020 Jul 31. PMID: 32745525
  • Khasabova II, Juliette J, Rogness VM, Khasabov SG, Golovko MY, Golovko SA, Kiven S, Gupta K, Belcher JD, Vercellotti GM, Seybold VS, Simone DA. A model of painful vaso-occlusive crisis in mice with sickle cell disease. Blood. 2022 Oct 20;140(16):1826-1830. PMID: 35960856
  • Khasabov SG, Rogness VM, Beeson MB, Vulchanova L, Yuan LL, Simone DA, Tran PV. The nAChR Chaperone TMEM35a (NACHO) Contributes to the Development of Hyperalgesia in Mice. Neuroscience. 2021 Mar 1;457:74-87. Epub 2021 Jan 7. PMID: 33422618
  • Uhelski ML, Bruce D, Speltz R, Wilcox GL, Simone DA. Topical Application of Loperamide/Oxymorphindole, Mu and Delta Opioid Receptor Agonists, Reduces Sensitization of C-fiber Nociceptors that Possess NaV1.8. Neuroscience. 2020 Oct 15;446:102-112. Epub 2020 Aug 25. PMID: 32858141
  • Speltz R, Lunzer MM, Shueb SS, Akgün E, Reed R, Kalyuzhny A, Portoghese PS, Simone DA. The bivalent ligand, MMG22, reduces neuropathic pain after nerve injury without the side effects of traditional opioids. Pain. 2020 Sep 1;161(9):2041-2057. PMID: 32345918
  • Khasabova IA, Khasabov SG, Johns M, Juliette J, Zheng A, Morgan H, Flippen A, Allen K, Golovko MY, Golovko SA, Zhang W, Marti J, Cain D, Seybold VS, Simone DA. Exosome-associated lysophosphatidic acid signaling contributes to cancer pain. Pain. 2023 Dec 1;164(12):2684-2695. Epub 2023 Jun 6. PMID: 37278638
  • Ivy ZK, Belcher JD, Khasabova IA, Chen C, Juliette JP, Abdulla F, Ruan C, Allen K, Nguyen J, Rogness VM, Beckman JD, Khasabov SG, Gupta K, Taylor RP, Simone DA, Vercellotti GM. Cold exposure induces vaso-occlusion and pain in sickle mice that depend on complement activation. Blood. 2023 Nov 30;142(22):1918-1927. PMID: 37774369