Hedgehog pathway blockade with the cancer drug LDE225 disrupts taste organs and taste sensation.
Taste sensation on the anterior tongue requires chorda tympani nerve function and connections with continuously renewing taste receptor cells. However, it is unclear which signaling pathways regulate the receptor cells to maintain chorda tympani sensation. Hedgehog (HH) signaling controls cell proliferation and differentiation in numerous tissues and is active in taste papillae and taste buds. In contrast, uncontrolled HH signaling drives tumorigenesis, including the common skin cancer, basal cell carcinoma. Systemic HH pathway inhibitors (HPIs) lead to basal cell carcinoma regression, but these drugs cause severe taste disturbances. We tested the hypothesis that taste disruption by HPIs reflects a direct requirement for HH signaling in maintaining taste organs and gustatory sensation. In mice treated with the HPI LDE225 up to 28 days, HH-responding cells were lost in fungiform papilla epithelium, and papillae acquired a conical apex. Taste buds were either absent or severely reduced in size in more than 90% of aberrant papillae. Taste bud remnants expressed the taste cell marker keratin 8, and papillae retained expression of nerve markers, neurofilament and P2X3. Chorda tympani nerve responses to taste stimuli were markedly reduced or absent in LDE225-treated mice. Responses to touch were retained, however, whereas cold responses were retained after 16 days of treatment but lost after 28 days. These data identify a critical, modality-specific requirement for HH signaling in maintaining taste papillae, taste buds and neurophysiological taste function, supporting the proposition that taste disturbances in HPI-treated patients are an on-target response to HH pathway blockade in taste organs.
Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, Michigan;
Archana
A
Kumari
Department of Dermatology, Medical School, University of Michigan, Ann Arbor, Michigan;
Alexandre N
AN
Ermilov
Department of Cell and Developmental Biology, Medical School, University of Michigan, Ann Arbor, Michigan.
Benjamin L
BL
Allen
Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, Michigan; Department of Molecular and Integrative Physiology, Medical School, University of Michigan, Ann Arbor, Michigan; and.
Robert M
RM
Bradley
Department of Dermatology, Medical School, University of Michigan, Ann Arbor, Michigan; Department of Cell and Developmental Biology, Medical School, University of Michigan, Ann Arbor, Michigan.
Andrzej A
AA
Dlugosz
Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, Michigan; chmist@umich.edu.
Charlotte M
CM
Mistretta
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D005260:Female; D053823:Hedgehog Proteins / Q000378:metabolism*; D051379:Mice; D011725:Pyridines / Q000494:pharmacology*; D015398:Signal Transduction; D013649:Taste; D013650:Taste Buds / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D014110:Touch
D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D053823:Hedgehog Proteins; D011725:Pyridines; C561435:sonidegib
cancer drugs and taste sensation; chorda tympani nerve responses; hedgehog pathway inhibitors; hedgehog signaling and taste; taste bud and fungiform papillae