Axl as a potential therapeutic target for adamantinomatous craniopharyngiomas: Based on single nucleus RNA-seq and spatial transcriptome profiling

Yiguang Chen; Xiaohai Liu; Yilamujiang Ainiwan; Mingchu Li; Jun Pan; Yongjian Chen; Zebin Xiao; Ziyu Wang; Xinru Xiao; Jie Tang; Gao Zeng; Jiantao Liang; Xin Su; Roberta Kungulli; Yuxiang Fan; Qingtang Lin; A Liya; Yifeng Zheng; Zexin Chen; Canli Xu; Hongqi Zhang; Ge Chen

doi:10.1016/j.canlet.2024.216905

Axl as a potential therapeutic target for adamantinomatous craniopharyngiomas: Based on single nucleus RNA-seq and spatial transcriptome profiling

Cancer Lett. 2024 Apr 25:592:216905. doi: 10.1016/j.canlet.2024.216905. Online ahead of print.

Authors

Yiguang Chen¹, Xiaohai Liu², Yilamujiang Ainiwan³, Mingchu Li², Jun Pan³, Yongjian Chen⁴, Zebin Xiao⁵, Ziyu Wang⁶, Xinru Xiao², Jie Tang², Gao Zeng², Jiantao Liang², Xin Su², Roberta Kungulli², Yuxiang Fan², Qingtang Lin², A Liya⁷, Yifeng Zheng⁷, Zexin Chen⁷, Canli Xu⁷, Hongqi Zhang⁸, Ge Chen⁹

Affiliations

¹ Department of Neurosurgery, Xuanwu Hospital Capital Medical University, Beijing, 100053, China; China International Neuroscience Institute (China-INI), Xuanwu Hospital, Capital Medical University, Beijing, 100053, China; Department of Neurosurgery, Nanfang Hospital, Southern Medical University, No. 1838, Guangzhou North Road, Guangzhou, Guangdong, 510515, China.
² Department of Neurosurgery, Xuanwu Hospital Capital Medical University, Beijing, 100053, China; China International Neuroscience Institute (China-INI), Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
³ Department of Neurosurgery, Nanfang Hospital, Southern Medical University, No. 1838, Guangzhou North Road, Guangzhou, Guangdong, 510515, China.
⁴ Dermatology and Venereology Division, Department of Medicine Solna, Center for Molecular Medicine, Karolinska Institute, Stockholm, 10005, Sweden.
⁵ Department of Pathology, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, China.
⁶ Cell Therapy Center, Beijing Institute of Geriatrics, Xuanwu Hospital Capital Medical University, National Clinical Research Center for Geriatric Diseases and Key Laboratory of Neurodegenerative Diseases, Ministry of Education, Beijing, 100053, China.
⁷ Guangdong Research Center of Organoid Engineering and Technology, Guangzhou, 510535, China.
⁸ Department of Neurosurgery, Xuanwu Hospital Capital Medical University, Beijing, 100053, China; China International Neuroscience Institute (China-INI), Xuanwu Hospital, Capital Medical University, Beijing, 100053, China. Electronic address: zhanghongqi@xwhosp.org.
⁹ Department of Neurosurgery, Xuanwu Hospital Capital Medical University, Beijing, 100053, China; China International Neuroscience Institute (China-INI), Xuanwu Hospital, Capital Medical University, Beijing, 100053, China. Electronic address: chenyiguang@mail.ccmu.edu.cn.

PMID: 38677641
DOI: 10.1016/j.canlet.2024.216905

Abstract

Craniopharyngiomas (CPs), particularly Adamantinomatous Craniopharyngiomas (ACPs), often exhibit a heightened risk of postoperative recurrence and severe complications of the endocrine and hypothalamic function. The primary objective of this study is to investigate potential novel targeted therapies within the microenvironment of ACP tumors. Cancer-Associated Fibroblasts (CAFs) were identified in the craniopharyngioma microenvironment, notably in regions characterized by cholesterol clefts, wet keratin, ghost cells, and fibrous stroma in ACPs. CAFs, alongside ghost cells, basaloid-like epithelium cells and calcifications, were found to secrete PROS1 and GAS6, which can activate AXL receptors on the surface of tumor epithelium cells, promoting immune suppression and tumor progression in ACPs. Additionally, the AXL inhibitor Bemcentinib effectively inhibited the proliferation organoids and enhanced the immunotherapeutic efficacy of Atezolizumab. Furthermore, neural crest-like cells were observed in the glial reactive tissue surrounding finger-like protrusions. Overall, our results revealed that the AXL might be a potentially effective therapeutic target for ACPs.

Keywords: AXL; Cancer-associated fibroblasts; Craniopharyngioma; Organoid; PD-L1.