Inhibition of Shh Signaling through MAPK Activation Controls Chemotherapy-Induced Alopecia

Iain S. Haslam, Gui Xuan Zhou, Guo Jiang Xie, Xu Teng, Xiu Lan Ao, Zhi Peng Yan, Eleanor Smart, David Rutkowski, Justyna Wierzbicka, Yong Jian Zhou, Zhen Huang, Yan Ding Zhang, Nilofer Farjo, Bessam Farjo, Ralf Paus, Zhi Cao Yue

Research output: Contribution to journalArticle

Abstract

Chemotherapy-induced hair loss (alopecia) (CIA) remains a major unsolved problem in clinical oncology. CIA is often considered to be a consequence of the antimitotic and apoptosis-promoting properties of chemotherapy drugs acting on rapidly proliferating hair matrix keratinocytes. Here, we show that in a mouse model of CIA, the downregulation of Shh signaling in the hair matrix is a critical early event. Inhibition of Shh signaling recapitulated key morphological and functional features of CIA, whereas recombinant Shh protein partially rescued hair loss. Phosphoproteomics analysis revealed that activation of the MAPK pathway is a key upstream event, which can be further manipulated to rescue CIA. Finally, in organ-cultured human scalp hair follicles as well as in patients undergoing chemotherapy, reduced expression of SHH gene correlates with chemotherapy-induced hair follicle damage or the degree of CIA, respectively. Our work revealed that Shh signaling is an evolutionarily conserved key target in CIA pathobiology. Specifically targeting the intrafollicular MAPK-Shh axis may provide a promising strategy to manage CIA.

Original languageEnglish (US)
JournalJournal of Investigative Dermatology
DOIs
StateAccepted/In press - 2020

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

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  • Cite this

    Haslam, I. S., Zhou, G. X., Xie, G. J., Teng, X., Ao, X. L., Yan, Z. P., Smart, E., Rutkowski, D., Wierzbicka, J., Zhou, Y. J., Huang, Z., Zhang, Y. D., Farjo, N., Farjo, B., Paus, R., & Yue, Z. C. (Accepted/In press). Inhibition of Shh Signaling through MAPK Activation Controls Chemotherapy-Induced Alopecia. Journal of Investigative Dermatology. https://doi.org/10.1016/j.jid.2020.05.118