NIH grant: Keratinocyte signaling mediates neuropathic pain (1R01CA308976-01A1)

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NIH grant 1R01CA308976-01A1: Keratinocyte signaling mediates neuropathic pain
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Cheryl Louise Stucky. Award: $647147.
Start: 2026-08-07T00:00:00.
Project Summary:
Painful peripheral neuropathy occurs in up to 80% of patients receiving chemotherapy and is among the most
devastating complications of chemotherapies, severely reducing patient quality of life and leading to the
reduction or cessation of life-saving treatment. While chemotherapy-induced peripheral neuropathy (CIPN) has
primarily been viewed to result from direct toxicity of chemotherapeutic agents to sensory neurons of the
peripheral nervous system, recent work from our group has identified keratinocytes—the primary cell type of the
epidermis and first point of contact with environmental stimuli—as major drivers of pain in CIPN. Indeed, reducing
the ability of keratinocytes to transduce sensory stimuli largely prevents and reverses pain-like behaviors in a
mouse model of CIPN. However, it remains unclear exactly how keratinocytes contribute to increased
transduction and transmission of stimuli by sensory afferents in CIPN. Addressing this scientific gap will greatly
enhance our understanding of somatosensation and unearth a wellspring of potential analgesic targets to
improve outcomes for patients with cancer. The most salient mechanisms by which keratinocytes could sensitize
sensory afferent involve alterations to intercellular signaling pathways. Our preliminary data and work from others
clearly demonstrate that keratinocytes express cellular machinery associated with synaptogenesis and contain
synapse-like vesicles proximal to cutaneous afferents. Despite these findings, it is unknown whether these
synapse-like structures in keratinocytes are required for communication to sensory afferents. Additionally,
keratinocytes secrete growth factors and cytokines to influence their microenvironment (including neighboring
sensory afferents) through paracrine signaling. Our preliminary single-cell sequencing data from the epidermis
and dorsal root ganglia revealed elevated epidermal growth factor receptor (EGFR) signaling in keratinocytes
and sensory neurons during CIPN, which is correlated to heparin-binding epidermal growth factor (HB-EGF)
expression in keratinocytes. Thus, the central hypothesis of this proposal is that increased synaptic and paracrine
signaling from keratinocytes to sensory afferents causes increased nociceptor activity and sensitization in CIPN,
leading to pain. Indeed, this hypothesis could explain the seemingly paradoxical observation of chronic and
spontaneous pain in patients with CIPN despite a 30-60% reduction in cutaneous intraepidermal nerve fibers.
We will test this hypothesis using murine and patient-derived samples as follows: We will determine whether
synapse-like vesicles in keratinocytes convey stimuli to sensory neurons in CIPN, identify keratinocyte
populations adjacent to nerve endings, and evaluate HB-EGF to EGFR paracrine signaling between
keratinocytes and sensory neurons in CIPN. The use of mice is necessary because we will determine the effects
of synaptic signaling between keratinocytes and sensory neurons in vivo by using evoked and spontaneous pain
behavior assays and by performing in situ skin nerve recordings from mice with CIPN. These critical experiments
are not possible to perform in isolated tissues from human patients or in cell lines. Completion of these aims will
unambiguously define the mechanisms by which keratinocytes contribute to somatosensation in healthy
conditions and during CIPN. Moreover, this work will lay the foundation for developing topical analgesics that
alleviate pain and allow the continuation of life-saving therapies in patients with cancer.

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