Critical changes in hypothalamic gene networks in response to pancreatic cancer as found by single-cell RNA sequencing.
Critical changes in hypothalamic gene networks in response to pancreatic cancer as found by single-cell RNA sequencing.
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DOI：
10.1016/j.molmet.2022.101441
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发表时间：
2022-04
影响因子：
8.1
通讯作者：
Marks DL
中科院分区：
文献类型：
--
作者：
Huisman C;Norgard MA;Levasseur PR;Krasnow SM;van der Wijst MGP;Olson B;Marks DL
癌症恶病质是一种破坏性的慢性疾病，其特征是非自愿的体重减轻、肌肉萎缩、脂肪代谢异常、食欲减退和疲劳。然而，这种综合征背后的分子机制仍然知之甚少。特别是，下丘脑可能在恶病质中发挥中心作用，因为它的解剖位置和减弱的血脑屏障可以直接接触到外周信号。此外，这个区域在调节食欲和新陈代谢方面起着至关重要的作用。为了提供下丘脑对恶病质反应的详细分析，我们在小鼠胰腺癌模型上进行了单细胞RNA-SEQ联合内侧基底下丘脑(MBH)的RNA-SEQ。我们发现了许多细胞类型的变化，如炎症的内皮细胞，应激性少突胶质细胞，以及炎性和缓和的小胶质细胞。Lcn2是一种新发现的饥饿抑制激素，是诱导程度最高的基因。有趣的是，用Lcn2脑治疗不仅诱导了恶病质的许多观察到的分子变化，而且还影响了摄食减少的POMC神经元的基因表达。此外，我们还发现，在下丘脑中发现的许多恶病质诱导的分子变化与原发肿瘤部位的分子变化相似。我们的数据显示，MBH中的多种细胞类型受到肿瘤来源的因素或宿主因素的影响，这些因素是由肿瘤生长诱导的，导致在恶病质期间对行为、代谢和神经内分泌输出调节失调的神经元微环境发生显著变化。这项研究提供的机制见解解释了恶病质的许多临床特征，并将对未来的治疗开发有用。单细胞RNA测序揭示了下丘脑对癌症恶病质的反应。肿瘤衍生因子诱导下丘脑内皮细胞炎症。Plin4是一种新的癌症恶病质少突胶质细胞恶病质标志物。新型饥饿激素Lcn2激活摄食量减少的POMC神经元。癌症恶病质引起下丘脑的炎性反应和缓和的小胶质细胞。
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. 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. 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. 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. Single-cell RNA-sequencing reveals hypothalamic response to cancer cachexia. Tumor-derived factors induce endothelial inflammation in the hypothalamus. Plin4 is a novel cachexia marker in oligodendrocytes for cancer cachexia. Novel hunger hormone LCN2 activates food-intake decreasing POMC neurons. Inflammatory and a moderating microglia in the hypothalamus respond to cancer cachexia.
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影响因子：
8.8
作者：
Kohnke S;Buller S;Nuzzaci D;Ridley K;Lam B;Pivonkova H;Bentsen MA;Alonge KM;Zhao C;Tadross J;Holmqvist S;Shimizu T;Hathaway H;Li H;Macklin W;Schwartz MW;Richardson WD;Yeo GSH;Franklin RJM;Karadottir RT;Rowitch DH;Blouet C
通讯作者：
Blouet C
影响因子：
64.8
作者：
Mosialou I;Shikhel S;Liu JM;Maurizi A;Luo N;He Z;Huang Y;Zong H;Friedman RA;Barasch J;Lanzano P;Deng L;Leibel RL;Rubin M;Nickolas T;Chung W;Zeltser LM;Williams KW;Pessin JE;Kousteni S
通讯作者：
Kousteni S
影响因子：
32.4
作者：
Hammond, Timothy R.;Dufort, Connor;Stevens, Beth
通讯作者：
Stevens, Beth
影响因子：
7.3
作者：
Foley K;Rucki AA;Xiao Q;Zhou D;Leubner A;Mo G;Kleponis J;Wu AA;Sharma R;Jiang Q;Anders RA;Iacobuzio-Donahue CA;Hajjar KA;Maitra A;Jaffee EM;Zheng L
通讯作者：
Zheng L
影响因子：
14.8
作者：
Efremova, Mirjana;Vento-Tormo, Miquel;Vento-Tormo, Roser
通讯作者：
Vento-Tormo, Roser