Pancreatic ductal adenocarcinoma (PDAC) remains recalcitrant to all forms of cancer treatment and carries a five-year survival rate of only 8%1. 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 agents2–4. However, KRAS*-independent disease recurrence following genetic extinction of Kras* in mouse models anticipates the need for co-extinction strategies5,6. 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. In an inducible mouse model of pancreatic ductal adenocarcinoma, the signalling defect that underlies 90% of these tumours causes increased cell-surface expression of syndecan 1, leading to misregulation of macropinocytosis, and linking the defective signalling with nutrient-salvage pathways.
Syndecan1 is a critical mediator of macropinocytosis in pancreatic cancer
W. Yao,Johnathon L. Rose,Wei Wang,S. Seth,Hong Jiang,A. Taguchi,Jintan Liu,Liang Yan,A. Kapoor,Pingping Hou,Ziheng Chen,Qiuyun Wang,L. Nezi,Zhaohui Xu,Jun Yao,Baoli Hu,P. Pettazzoni,I. Ho,Ningping Feng,V. Ramamoorthy,Shan Jiang,Pingna Deng,Grace Ma,P. Den,Zhi Tan,Shu Zhang,Huamin Wang,Y. A. Wang,Angela Deem,Jason B. Fleming,A. Carugo,T. Heffernan,A. Maitra,A. Viale,Haoqiang Ying,S. Hanash,Ronald A. DePinho,G. Draetta
Published 2019 in Nature
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- Publication year
2019
- Venue
Nature
- Publication date
2019-02-27
- Fields of study
Biology, Medicine
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Semantic Scholar, PubMed
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