Abstract：
: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.
journal_name
Naturejournal_title
Natureauthors
Yao W,Rose JL,Wang W,Seth S,Jiang H,Taguchi A,Liu J,Yan L,Kapoor A,Hou P,Chen Z,Wang Q,Nezi L,Xu Z,Yao J,Hu B,Pettazzoni PF,Ho IL,Feng N,Ramamoorthy V,Jiang S,Deng P,Ma GJ,Den P,Tan Z,Zhang SX,Wang H,doi
10.1038/s41586-019-1062-1subject
Has Abstractpub_date
2019-04-01 00:00:00pages
410-414issue
7752eissn
0028-0836issn
1476-4687pii
10.1038/s41586-019-1062-1journal_volume
568pub_type
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