气候变化领域集成服务门户(CCPortal): PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response

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DOI	10.1073/pnas.2009290118
	PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response
	Li J.; Kaneda M.M.; Ma J.; Li M.; Shepard R.M.; Patel K.; Koga T.; Sarver A.; Furnari F.; Xu B.; Dhawan S.; Ning J.; Zhu H.; Wu A.; You G.; Jiang T.; Venteicher A.S.; Rich J.N.; Glass C.K.; Varner J.A.; Chen C.C.
发表日期	2021
ISSN	00278424
卷号	118 期号:16
英文摘要	Precision medicine in oncology leverages clinical observations of exceptional response. Toward an understanding of the molecular features that define this response, we applied an integrated, multiplatform analysis of RNA profiles derived from clinically annotated glioblastoma samples. This analysis suggested that specimens from exceptional responders are characterized by decreased accumulation of microglia/macrophages in the glioblastoma microenvironment. Glioblastoma-associated microglia/macrophages secreted interleukin 11 (IL11) to activate STAT3-MYC signaling in glioblastoma cells. This signaling induced stem cell states that confer enhanced tumorigenicity and resistance to the standard-of-care chemotherapy, temozolomide (TMZ). Targeting a myeloid cell restricted an isoform of phosphoinositide-3-kinase, phosphoinositide-3-kinase gamma isoform (PI3Kγ), by pharmacologic inhibition or genetic inactivation disrupted this signaling axis by reducing microglia/macrophage-associated IL11 secretion in the tumor microenvironment. Mirroring the clinical outcomes of exceptional responders, PI3Kγ inhibition synergistically enhanced the anti-neoplastic effects of TMZ in orthotopic murine glioblastoma models. Moreover, inhibition or genetic inactivation of PI3Kγ in murine glioblastoma models recapitulated expression profiles observed in clinical specimens isolated from exceptional responders. Our results suggest key contributions from tumor-associated microglia/macrophages in exceptional responses and highlight the translational potential for PI3Kγ inhibition as a glioblastoma therapy. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Exceptional responders; Glioblastoma; IL11; Microglia/macrophages; PI3Kγ
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/179837
作者单位	Department of Neurosurgery, University of Minnesota, Minneapolis, MN 55455, United States; Moores Cancer Center, University of California San Diego, San Diego, CA 92037, United States; Department of Neurosurgery, University of California, Los Angeles, CA 90095, United States; Institute for Health Informatics, University of Minnesota, Minneapolis, MN 55455, United States; Ludwig Institute for Cancer Research, University of California San Diego, San Diego, CA, United States; Department of Pediatrics, The First Hospital of China Medical University, Shenyang, 110122, China; Department of Neurosurgery, The First Hospital of China Medical University, Shenyang, 110122, China; Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 100070, China; Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, 100050, China; Department of Medicine, Division of Regenerative Medicine, University of California San Diego, San Diego, C...
推荐引用方式 GB/T 7714	Li J.,Kaneda M.M.,Ma J.,et al. PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response[J],2021,118(16).
APA	Li J..,Kaneda M.M..,Ma J..,Li M..,Shepard R.M..,...&Chen C.C..(2021).PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response.Proceedings of the National Academy of Sciences of the United States of America,118(16).
MLA	Li J.,et al."PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response".Proceedings of the National Academy of Sciences of the United States of America 118.16(2021).