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Yao, Wantong; Rose, Johnathon L; Wang, Wei; Seth, Sahil; Jiang, Hong; Taguchi, Ayumu; Liu, Jintan; Yan, Liang; Kapoor, Avnish; Hou, Pingping; Chen, Ziheng; Wang, Qiuyun; Nezi, Luigi; Xu, Zhaohui; Yao, Jun; Hu, Baoli; Pettazzoni, Piergiorgio F; Ho, I Lin; Feng, Ningping; Ramamoorthy, Vandhana; Jiang, Shan; Deng, Pingna; Ma, Grace J; Den, Peter; Tan, Zhi; Zhang, Shu Xing; Wang, Huamin; Wang, Y Alan; Deem, Angela K; Fleming, Jason B; Carugo, Alessandro; Heffernan, Timothy P; Maitra, Anirban; Viale, Andrea; Ying, Haoqiang; Hanash, Samir; DePinho, Ronald A; Draetta, Giulio F
Nature (London), 04/2019, Letnik: 568, Številka: 7752Journal Article
Pancreatic ductal adenocarcinoma (PDAC) remains recalcitrant to all forms of cancer treatment and carries a five-year survival rate of only 8% . Inhibition of oncogenic KRAS (hereafter KRAS*), the earliest lesion in disease development that is present in more than 90% of PDACs, and its signalling surrogates has yielded encouraging preclinical results with experimental agents . However, KRAS*-independent disease recurrence following genetic extinction of Kras* in mouse models anticipates the need for co-extinction strategies . Multiple oncogenic processes are initiated at the cell surface, where KRAS* physically and functionally interacts to direct signalling that is essential for malignant transformation and tumour maintenance. Insights into the complexity of the functional cell-surface-protein repertoire (surfaceome) have been technologically limited until recently and-in the case of PDAC-the genetic control of the function and composition of the PDAC surfaceome in the context of KRAS* signalling remains largely unknown. Here we develop an unbiased, functional target-discovery platform to query KRAS*-dependent changes of the PDAC surfaceome, which reveals syndecan 1 (SDC1, also known as CD138) as a protein that is upregulated at the cell surface by KRAS*. Localization of SDC1 at the cell surface-where it regulates macropinocytosis, an essential metabolic pathway that fuels PDAC cell growth-is essential for disease maintenance and progression. Thus, our study forges a mechanistic link between KRAS* signalling and a targetable molecule driving nutrient salvage pathways in PDAC and validates oncogene-driven surfaceome annotation as a strategy to identify cancer-specific vulnerabilities.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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Vir: Osebne bibliografije
in: SICRIS
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