TY - JOUR
T1 - Neural landscape is associated with functional outcomes in irradiated patients with oropharyngeal squamous cell carcinoma
AU - Islam, Shajedul
AU - Gleber-Netto, Frederico O.
AU - Mulcahy, Collin F.
AU - Glaun, Mica D.E.
AU - Srivastava, Snigdha
AU - Hunt, Patrick J.
AU - Williams, Michelle D.
AU - Barbon, Carly E.
AU - Spiotto, Michael
AU - Zhao, Weilu
AU - Adebayo, Adewale
AU - Akhter, Shamima
AU - Xie, Tongxin
AU - Debnath, Kala Chand
AU - Sathishkumar, Hinduja Naidu
AU - Myers, Blake
AU - Lothumalla, Sahana
AU - Yaman, Ismail
AU - Burks, Jared K.
AU - Gomez, Javier
AU - Rao, Xiayu
AU - Wang, Jing
AU - Woodman, Karin
AU - Mansour, Jobran
AU - Arenkiel, Benjamin
AU - Osman, Kate L.
AU - Haxton, Chandler
AU - Lever, Teresa E.
AU - Hutcheson, Katherine A.
AU - Amit, Moran
N1 - Publisher Copyright:
Copyright © 2024 The Authors, some rights reserved.
PY - 2024/7/31
Y1 - 2024/7/31
N2 - The incidence of human papilloma virus–mediated oropharyngeal squamous cell carcinoma (OPSCC) has increased over the past 40 years, particularly among young individuals with a favorable prognosis; however, current therapy often leads to unfortunate side effects, such as dysphagia. Despite the emphasis on dysphagia in previous studies, there is an important research gap in understanding the correlation between neuronal changes and patient-reported and functional outcomes in patients with OPSCC. To address this issue, we examined pathologic tissue samples from patients with OPSCC using multiplex immunofluorescence staining and machine learning to correlate tumor-associated neuronal changes with prospectively collected patient-reported and functional outcomes. We found that tumor enrichment of adrenergic (TH+) and CGRP+ sensory–afferent nerves correlated with poorer swallowing outcomes. Functional electromyography recordings showed correlations between growing (GAP43+) and immature cholinergic (ChAT+DCX+) nerves and denervation patterns in survivors of OPSCC. A murine model of radiation-induced dysphagia further confirmed that immature cholinergic and CGRP+ nerves were correlated with impaired swallowing. Preclinical interventional studies also supported the independent contributions of CGRP+ and cholinergic (ChAT+) nerves to dysphagia in treated mouse models of OPSCC. Our results suggest that CGRP+ and ChAT+ neuronal signaling play distinct roles in tumor- and radiation-induced dysphagia in OPSCC and offer a comprehensive dataset on the neural landscape of OPSCC. These insights may guide early interventions for swallow preservation and the repurposing of neurology-related drugs, such as CGRP blockers, in clinical oncology and survivorship.
AB - The incidence of human papilloma virus–mediated oropharyngeal squamous cell carcinoma (OPSCC) has increased over the past 40 years, particularly among young individuals with a favorable prognosis; however, current therapy often leads to unfortunate side effects, such as dysphagia. Despite the emphasis on dysphagia in previous studies, there is an important research gap in understanding the correlation between neuronal changes and patient-reported and functional outcomes in patients with OPSCC. To address this issue, we examined pathologic tissue samples from patients with OPSCC using multiplex immunofluorescence staining and machine learning to correlate tumor-associated neuronal changes with prospectively collected patient-reported and functional outcomes. We found that tumor enrichment of adrenergic (TH+) and CGRP+ sensory–afferent nerves correlated with poorer swallowing outcomes. Functional electromyography recordings showed correlations between growing (GAP43+) and immature cholinergic (ChAT+DCX+) nerves and denervation patterns in survivors of OPSCC. A murine model of radiation-induced dysphagia further confirmed that immature cholinergic and CGRP+ nerves were correlated with impaired swallowing. Preclinical interventional studies also supported the independent contributions of CGRP+ and cholinergic (ChAT+) nerves to dysphagia in treated mouse models of OPSCC. Our results suggest that CGRP+ and ChAT+ neuronal signaling play distinct roles in tumor- and radiation-induced dysphagia in OPSCC and offer a comprehensive dataset on the neural landscape of OPSCC. These insights may guide early interventions for swallow preservation and the repurposing of neurology-related drugs, such as CGRP blockers, in clinical oncology and survivorship.
UR - http://www.scopus.com/inward/record.url?scp=85200297778&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85200297778&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.abq5585
DO - 10.1126/scitranslmed.abq5585
M3 - Article
C2 - 39083586
AN - SCOPUS:85200297778
SN - 1946-6234
VL - 16
JO - Science translational medicine
JF - Science translational medicine
IS - 758
M1 - eabq5585
ER -