Scheff Lab

We are currently pursuing three main projects:

CGRP Signaling and Cancer

Calcitonin gene-related peptide (CGRP) is the primary neurotransmitter released by sensory neurons in the oral cavity. Local transmitter release from intratumoral sensory nerves has been linked to tumorigenesis.

We hypothesize that oral cancer and sensory neurons interact, such that, oral cancer induces axon sprouting, sensitization and plasticity in neurons, and efferent neuronal activity promotes oral carcinogenesis.

Using a global Calca knockout mouse as well as CGRP receptor antagonism, we discovered enhanced tumor immunosurveillance in the absence of CGRP signaling. Understanding the relationship between sensory neurons and cancer will aid in repurposing clinically available nervous system drugs for the treatment of cancer. 

Anti-CGRP immunoreactivity in tissue from HNSCC patients and oral cancer mouse models. See the full article “Sensory neurotransmitter calcitonin gene-related peptide modulates tumor growth and inflammation in oral squamous cell carcinoma” in Advanced Biology Special Issue: Cancer Neuroscience

The primary goals of this project are to:

  1. Use multispectral imaging and spatial genomics to assess immune profiles in close proximity to CGRP-containing intratumoral nerves
  2. Determine the impact of CGRP-Ramp1 signaling on tumor infiltrating immune cells on tumor immunity and tumorigenesis
  3. Investigate the therapeutic efficacy of anti-CGRP antibodies to boost cancer immunosurveillance and response to immune checkpoint inhibitor therapy

Sympathetic Nervous System and Cancer

The second program is the investigation of the sympathetic nervous system (SNS) in driving tumor progression and exacerbating cancer pain via local adrenergic signaling in the cancer microenvironment. Several studies have described the correlation between elevated patient-reported pain and stress. Sympathetic neurotransmission is increased in preclinical models of oral cancer, and sympathectomy resulted in smaller, less invasive cancers.

We hypothesize that SNS exacerbates cancer pain and drives tumor progression via local adrenergic signaling in the cancer microenvironment.

The primary goals of this project are to:

  1. Explore adrenergic plasticity in nociceptive neurons and the impact of sympathetic neurotransmission in orofacial pain during oral cancer progression
  2. Understand the impact of acute, chronic, and social stress on sympathetic signaling during oral cancer progression and explore the use of beta-adrenergic antagonism to treat pain and slow tumor growth
  3. Investigate the prevalence of patient-reported pain and psychological symptom burden (e.g. stress) pre-treatment and through survivorship
Anti-tyrosine hydroxylase (TH) immunoreactivity in tissue from patients with HNSCC and oral cancer mouse models. See the full article “Sympathetic modulation of tumor necrosis factor alpha-induced nociception in the presence of oral squamous cell carcinoma” in PAIN.

Opioids and Cancer

The third program investigates the impact of exogenous opioids given for oral cancer pain on tumor immunity and response to treatment. The head and neck region has high sensory innervation, and the prevalence and intensity of HNSCC-associated pain at the primary site are greater than all other types of cancer. Immune cells express g-protein coupled opioid receptors with downstream inhibitory signaling that can regulate immune cell function.

We hypothesize that cancer immunosurveillance is impaired by the immunosuppressive actions of exogenous opioids, and peripherally restricted opioid antagonists could be leveraged as a novel therapeutic tactic for cancer treatment.

The primary goals of this project are to:

  1. Investigate the impact of mu opioid receptor signaling on T cell function and overall tumor-associated immunity
  2. Determine the functional implications of peripheral mu opioid receptor signaling in response to immune checkpoint inhibitor therapy
  3. Explore the relationship between exogenous opioids and tumor infiltrating lymphocytes and response to treatment in head and neck cancer patients

Funding

UPMC Head and Neck Developmental Research Project Award 2022-2023

Rita Allen Foundation Pain Award 2021

NIH NIDCR R01DE030892

Virginia Kaufman Research Foundation Pain Research Challenge Award 2021

Hillman Cancer Center Developmental Pilot Program Award 2022

NIH NIDCR R00DE028019

Publications

  • Amit M, Scheff NN (Eds). Cancer Neuroscience. Springer Cham. eBook 2023 Jul 25. doi.org/10.1007/978-3-031-32429-1

  • Scheff NN, Harris AL, Li J, Horan NL, Kubik MW, Kim SW, Nilsen ML. Pretreatment pain predicts perineural invasion in patients with head and neck squamous cell carcinoma. Support Care Cancer. 2023 Jun 21;31(7):405. doi: 10.1007/s00520-023-07872-7. [PMID: 37341777]

  • Scheff NN, Nilson ML, Li J, Harris AL, Acharya R, Swartz A, Hsieh RW, Anderson JL, Ferris RL, Menk AV, Delgoffe GM, Zandberg DP. The effect of opioids on the efficacy of immunotherapy in recurrent/metastatic squamous cell carcinoma of the head and neck. Oral Oncol. 2023 May. doi.org/10.1016/j.oraloncology.2023.106363.

  • Horan NL, McIlvried LA, Atherton MA, Yuan MM, Dolan JC, Scheff NN. The impact of tumor immunogenicity on cancer pain phenotype using syngeneic oral cancer mouse models. Front Pain Res (Lausanne). 2022 Sept 12;3:991725. doi.org/10.3389/fpain.2022.991725. [PMID: 36172037]

  • McIlvried LA, Atherton MA, Horan NL, Goch TN, Scheff NN. Sensory neurotransmitter calcitonin gene-related peptide modulates tumor growth and inflammation in oral squamous cell carcinoma. Adv Biol (Weinh). 2022 Apr 7;e2200019. doi:10.1002/adbi.202200019. [PMID: 35388989]

  • Atherton MA, Park S, Horan NL, Nicholson SL, Dolan JC, Schmidt BL, Scheff NN. Sympathetic modulation of tumor necrosis factor alpha-induced nociception in the presence of oral squamous cell carcinoma. PAIN. 2022 Apr 20. doi:10.1097/j.pain.0000000000002655 [PMID: 35714327]

  • Scheff NN, Wall IM, Nicholson S, Williams H, Chen E, Tu NH, Dolan JC, Janal MN, Bunnett NW, Schmidt BL. Oral cancer induced TRPV1 sensitization is mediated by PAR2 signaling in primary afferent neurons innervating the cancer microenvironment. Sci Rep. 2022 Mar 8;12(1):4121. doi.org/10.1038/s41598-022-08005-6. [PMID: 35260737]

  • Demir IE, Reyes CM, Alrawashdeh W, Ceyhan GO, Deborde S, Friess H, Görgülü K, Istvanffy R, Jungwirth D, Kuner R, Maryanovich M, Na’ara S, Renders S, Saloman JL, Scheff NN, Steenfadt H, Stupakov P, Thiel V, Verma D, Yilmaz BS, White RA, Wang TC, Wong RJ, Frenette PS, Gil Z, Davis BM. Future directions in preclinical and translational cancer neuroscience research. Nat Cancer. 2021 Nov;1:1027-1031. doi.org/10.1038/s43018-020-00146-9. [PMID: 34327335]

  • Demir IE, Reyes CM, Alrawashdeh W, Ceyhan GO, Deborde S, Friess H, Görgülü K, Istvanffy R, Jungwirth D, Kuner R, Maryanovich M, Na’ara S, Renders S, Saloman JL, Scheff NN, Steenfadt H, Stupakov P, Thiel V, Verma D, Yilmaz BS, White RA, Wang TC, Wong RJ, Frenette PS, Gil Z, Davis BM. Clinically actionable strategies for studying neural influences in cancer. Cancer Cell. 2020 Jul 13;38(1):11-14. doi.org/10.1016/j.ccell.2020.05.023. [PMID: 32531270]

  • Scheff NN, Saloman JL. Neuroimmunology of cancer and associated symptomology. Immunol Cell Biol. 2021 Oct;99(9):949-961. Epub 2021 Sep 12. doi.org/10.1111/imcb.12496. [PMID: 34355434]

  • Nilsen ML, Belsky MA, Scheff NN, Johnson JT, Zandberg DP, Skinner H, Ferris R. Late and long-term treatment-related effects and survivorship for head and neck cancer patients. Curr Treat Options Oncol. 2020 Oct 3;21(12):92. Review. doi.org/10.1007/s11864-020-00797-x. [PMID: 33009956]

  • Pineda Farias JB, Saloman JL, Scheff NN. Animal models of cancer-related pain: current perspectives in translation. Front. Pharm. 2020 Nov 26;11:610894. doi.org/10.3389/fphar.2020.610894. [PMID: 33381048]

  • Scheff NN, Ye Y, Conley ZR, Quan JW, Lam YR, Klares RIII, Singh K, Dolan JC, Schmidt BL, Aouizerat BE. ADAM17-EGFR signaling contributes to oral cancer pain. PAIN. 2020 Oct;161 (10):2330-2343. doi.org/10.1097/j.pain.0000000000001926. [PMID: 32453136]