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应激颗粒决定肥胖相关胰腺癌的发展。

Stress Granules Determine the Development of Obesity-Associated Pancreatic Cancer.

机构信息

Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.

Department of Surgery, University Medical Center Mainz, JGU-Mainz, Mainz, Germany.

出版信息

Cancer Discov. 2022 Aug 5;12(8):1984-2005. doi: 10.1158/2159-8290.CD-21-1672.

DOI:10.1158/2159-8290.CD-21-1672
PMID:35674408
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9357213/
Abstract

UNLABELLED

Obesity is a global epidemic and a major predisposing factor for cancer. Increasing evidence shows that obesity-associated stress is a key driver of cancer risk and progression. Previous work has identified the phase-separation organelles, stress granules (SG), as mutant KRAS-dependent mediators of stress adaptation. However, the dependence of tumorigenesis on these organelles is unknown. Here, we establish a causal link between SGs and pancreatic ductal adenocarcinoma (PDAC). Importantly, we uncover that dependence on SGs is drastically heightened in obesity-associated PDAC. Furthermore, we identify a previously unknown regulator and component of SGs, namely, the serine/arginine protein kinase 2 (SRPK2), as a specific determinant of SG formation in obesity-associated PDAC. We show that SRPK2-mediated SG formation in obesity-associated PDAC is driven by hyperactivation of the IGF1/PI3K/mTOR/S6K1 pathway and that S6K1 inhibition selectively attenuates SGs and impairs obesity-associated PDAC development.

SIGNIFICANCE

: We show that stress adaptation via the phase-separation organelles SGs mediates PDAC development. Moreover, preexisting stress conditions such as obesity are a driving force behind tumor SG dependence, and enhanced SG levels are key determinants and a chemopreventive target for obesity-associated PDAC. This article is highlighted in the In This Issue feature, p. 1825.

摘要

未加标签

肥胖是一种全球性的流行病，也是癌症的一个主要诱发因素。越来越多的证据表明，肥胖相关的压力是癌症风险和进展的关键驱动因素。先前的工作已经确定了相分离细胞器，应激颗粒（SG），作为应激适应的突变 KRAS 依赖性介质。然而，肿瘤发生对这些细胞器的依赖性尚不清楚。在这里，我们建立了 SG 与胰腺导管腺癌（PDAC）之间的因果关系。重要的是，我们发现肥胖相关的 PDAC 对 SG 的依赖性大大增加。此外，我们发现了 SG 的一个以前未知的调节因子和组成部分，即丝氨酸/精氨酸蛋白激酶 2（SRPK2），它是肥胖相关 PDAC 中 SG 形成的一个特定决定因素。我们表明，肥胖相关 PDAC 中由 SRPK2 介导的 SG 形成是由 IGF1/PI3K/mTOR/S6K1 通路的过度激活驱动的，并且 S6K1 抑制选择性地减弱 SG 并损害肥胖相关 PDAC 的发展。

意义

我们表明，通过相分离细胞器 SG 进行的应激适应介导了 PDAC 的发展。此外，肥胖等现有应激条件是肿瘤 SG 依赖性的驱动力，增强的 SG 水平是肥胖相关 PDAC 的关键决定因素和化学预防靶点。本文在本期特色文章中重点介绍，第 1825 页。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6554/9357213/09a23fac9c80/nihms-1816193-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6554/9357213/472eff3bd576/nihms-1816193-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6554/9357213/083cf545e71b/nihms-1816193-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6554/9357213/c7ccc418babb/nihms-1816193-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6554/9357213/0c4a847a92ce/nihms-1816193-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6554/9357213/8c52bbff5131/nihms-1816193-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6554/9357213/9156c74e51ff/nihms-1816193-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6554/9357213/09a23fac9c80/nihms-1816193-f0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6554/9357213/472eff3bd576/nihms-1816193-f0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6554/9357213/083cf545e71b/nihms-1816193-f0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6554/9357213/c7ccc418babb/nihms-1816193-f0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6554/9357213/0c4a847a92ce/nihms-1816193-f0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6554/9357213/8c52bbff5131/nihms-1816193-f0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6554/9357213/9156c74e51ff/nihms-1816193-f0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6554/9357213/09a23fac9c80/nihms-1816193-f0007.jpg

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