Critical changes in hypothalamic gene networks in response to pancreatic cancer as found by single-cell RNA sequencing.

Autor:	Huisman C; Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, United States; Knight Cancer Institute, Oregon Health & Science University, Portland, United States. Electronic address: huisman@ohsu.edu., Norgard MA; Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, United States., Levasseur PR; Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, United States., Krasnow SM; Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, United States., van der Wijst MGP; Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands., Olson B; Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, United States; Medical Scientist Training Program, Oregon Health & Science University, Portland, United States., Marks DL; Papé Family Pediatric Research Institute, Oregon Health & Science University, Portland, United States; Knight Cancer Institute, Oregon Health & Science University, Portland, United States; Brenden-Colson Center for Pancreatic Care, Oregon Health & Science University, Portland, United States. Electronic address: marksd@ohsu.edu.
Jazyk:	angličtina
Zdroj:	Molecular metabolism [Mol Metab] 2022 Apr; Vol. 58, pp. 101441. Date of Electronic Publication: 2022 Jan 11.
DOI:	10.1016/j.molmet.2022.101441
Abstrakt:	Objective: Cancer cachexia is a devastating chronic condition characterized by involuntary weight loss, muscle wasting, abnormal fat metabolism, anorexia, and fatigue. However, the molecular mechanisms underlying this syndrome remain poorly understood. In particular, the hypothalamus may play a central role in cachexia, given that it has direct access to peripheral signals because of its anatomical location and attenuated blood-brain barrier. Furthermore, this region has a critical role in regulating appetite and metabolism. Methods: To provide a detailed analysis of the hypothalamic response to cachexia, we performed single-cell RNA-seq combined with RNA-seq of the medial basal hypothalamus (MBH) in a mouse model for pancreatic cancer. Results: We found many cell type-specific changes, such as inflamed endothelial cells, stressed oligodendrocyes and both inflammatory and moderating microglia. Lcn2, a newly discovered hunger suppressing hormone, was the highest induced gene. Interestingly, cerebral treatment with LCN2 not only induced many of the observed molecular changes in cachexia but also affected gene expression in food-intake decreasing POMC neurons. In addition, we found that many of the cachexia-induced molecular changes found in the hypothalamus mimic those at the primary tumor site. Conclusion: Our data reveal that multiple cell types in the MBH are affected by tumor-derived factors or host factors that are induced by tumor growth, leading to a marked change in the microenvironment of neurons critical for behavioral, metabolic, and neuroendocrine outputs dysregulated during cachexia. The mechanistic insights provided in this study explain many of the clinical features of cachexia and will be useful for future therapeutic development. (Copyright © 2022 The Authors. Published by Elsevier GmbH.. All rights reserved.)
Databáze:	MEDLINE
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