Syndecan 1 is a critical mediator of macropinocytosis in pancreatic cancer

Wantong Yao, Johnathon L. Rose, Wei Wang, Sahil Seth, Hong Jiang, Ayumu Taguchi, Jintan Liu, Liang Yan, Avnish Kapoor, Pingping Hou, Ziheng Chen, Qiuyun Wang, Luigi Nezi, Zhaohui Xu, Jun Yao, Baoli Hu, Piergiorgio F. Pettazzoni, I Lin Ho, Ningping Feng, Vandhana Ramamoorthy, Shan Jiang, Pingna Deng, Grace J. Ma, Peter Den, Zhi Tan, Shu Xing Zhang, Huamin Wang, Y. Alan Wang, Angela K. Deem, Jason B. Fleming, Alessandro Carugo, Timothy P. Heffernan, Anirban Maitra, Andrea Viale, Haoqiang Ying, Samir Hanash, Ronald A. DePinho and Giulio F. Draetta ()
Additional contact information
Wantong Yao: University of Texas MD Anderson Cancer Center
Johnathon L. Rose: University of Texas MD Anderson Cancer Center
Wei Wang: University of Texas MD Anderson Cancer Center
Sahil Seth: University of Texas MD Anderson Cancer Center
Hong Jiang: University of Texas MD Anderson Cancer Center
Ayumu Taguchi: University of Texas MD Anderson Cancer Center
Jintan Liu: University of Texas MD Anderson Cancer Center
Liang Yan: University of Texas MD Anderson Cancer Center
Avnish Kapoor: University of Texas MD Anderson Cancer Center
Pingping Hou: University of Texas MD Anderson Cancer Center
Ziheng Chen: University of Texas MD Anderson Cancer Center
Qiuyun Wang: University of Texas MD Anderson Cancer Center
Luigi Nezi: University of Texas MD Anderson Cancer Center
Zhaohui Xu: University of Texas MD Anderson Cancer Center
Jun Yao: University of Texas MD Anderson Cancer Center
Baoli Hu: University of Texas MD Anderson Cancer Center
Piergiorgio F. Pettazzoni: University of Texas MD Anderson Cancer Center
I Lin Ho: University of Texas MD Anderson Cancer Center
Ningping Feng: University of Texas MD Anderson Cancer Center
Vandhana Ramamoorthy: University of Texas MD Anderson Cancer Center
Shan Jiang: University of Texas MD Anderson Cancer Center
Pingna Deng: University of Texas MD Anderson Cancer Center
Grace J. Ma: University of Texas MD Anderson Cancer Center
Peter Den: University of Texas MD Anderson Cancer Center
Zhi Tan: University of Texas MD Anderson Cancer Center
Shu Xing Zhang: University of Texas MD Anderson Cancer Center
Huamin Wang: University of Texas MD Anderson Cancer Center
Y. Alan Wang: University of Texas MD Anderson Cancer Center
Angela K. Deem: University of Texas MD Anderson Cancer Center
Jason B. Fleming: University of Texas MD Anderson Cancer Center
Alessandro Carugo: University of Texas MD Anderson Cancer Center
Timothy P. Heffernan: University of Texas MD Anderson Cancer Center
Anirban Maitra: University of Texas MD Anderson Cancer Center
Andrea Viale: University of Texas MD Anderson Cancer Center
Haoqiang Ying: University of Texas MD Anderson Cancer Center
Samir Hanash: University of Texas MD Anderson Cancer Center
Ronald A. DePinho: University of Texas MD Anderson Cancer Center
Giulio F. Draetta: University of Texas MD Anderson Cancer Center

Nature, 2019, vol. 568, issue 7752, 410-414

Abstract: 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.

Date: 2019
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-019-1062-1 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:568:y:2019:i:7752:d:10.1038_s41586-019-1062-1

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-019-1062-1

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().