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 agents2,3,4. 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.
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All data are available from the corresponding author upon reasonable request.
Code for screen hit analysis are available upon request from the authors.
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We thank D. Bar-Sagi and C. Ramirez (New York University) for their suggestions and constructive feedback; R. Sanderson at University of Alabama for sharing SDC1 constructs; T. Tieu, M. Peoples, J. Ren and Q. Chang for technical assistance; D. Aten for help with the graphical abstract; and our colleagues at the Institute for Applied Cancer Science (IACS), the Flow Cytometry and Cellular Imaging Core, the Sequencing and Microarray Facility, the Department of Veterinary Medicine, Medical Graphics and Photography at The MD Anderson Cancer Center (MDACC) (Cancer Center Support Grant, CA016672). We thank all members of the laboratories of G.F.D., R.A.D., H.Y. and S.H. for discussions and reagents. The research was supported by the Odyssey Postdoctoral Fellowship at MDACC, the PanCAN-AACR Pathway to Leadership Grant (16-70-25-YAO) and 2017 Hirshberg foundation for pancreatic cancer research to W.Y.; Pancreatic Cancer Moon Shot Program at MDACC, CPRIT (RP160471), DOD (W81XWH-11-1-0418), and Harrington Discovery Institute Grant to G.F.D.; P01 Grant (P01CA117969 12, NIH) to H.W., A.M., R.A.D., G.F.D. and H.Y.
Nature thanks Channing Der, Harald Alfred Stenmark and the other anonymous reviewer(s) for their contribution to the peer review of this work.