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 RamamoorthyShan 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, Giulio F. Draetta

Research output: Contribution to journalLetter

7 Citations (Scopus)

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 agents 2–4 . However, KRAS*-independent disease recurrence following genetic extinction of Kras* in mouse models anticipates the need for co-extinction strategies 5,6 . 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.

Original languageEnglish (US)
Pages (from-to)410-414
Number of pages5
JournalNature
Volume568
Issue number7752
DOIs
StatePublished - Apr 18 2019

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Syndecan-1
Pancreatic Neoplasms
Adenocarcinoma
Maintenance
Neoplasms
Metabolic Networks and Pathways
Oncogenes
Disease Progression
Membrane Proteins
Recurrence
Food
Proteins

ASJC Scopus subject areas

  • General

Cite this

Syndecan 1 is a critical mediator of macropinocytosis in pancreatic cancer. / 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.

In: Nature, Vol. 568, No. 7752, 18.04.2019, p. 410-414.

Research output: Contribution to journalLetter

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, Wang, YA, Deem, AK, Fleming, JB, Carugo, A, Heffernan, TP, Maitra, A, Viale, A, Ying, H, Hanash, S, DePinho, RA & Draetta, GF 2019, 'Syndecan 1 is a critical mediator of macropinocytosis in pancreatic cancer', Nature, vol. 568, no. 7752, pp. 410-414. https://doi.org/10.1038/s41586-019-1062-1
Yao W, Rose JL, Wang W, Seth S, Jiang H, Taguchi A et al. Syndecan 1 is a critical mediator of macropinocytosis in pancreatic cancer. Nature. 2019 Apr 18;568(7752):410-414. https://doi.org/10.1038/s41586-019-1062-1
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. / Syndecan 1 is a critical mediator of macropinocytosis in pancreatic cancer. In: Nature. 2019 ; Vol. 568, No. 7752. pp. 410-414.
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title = "Syndecan 1 is a critical mediator of macropinocytosis in pancreatic cancer",
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 agents 2–4 . However, KRAS*-independent disease recurrence following genetic extinction of Kras* in mouse models anticipates the need for co-extinction strategies 5,6 . 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.",
author = "Wantong Yao and Rose, {Johnathon L.} and Wei Wang and Sahil Seth and Hong Jiang and Ayumu Taguchi and Jintan Liu and Liang Yan and Avnish Kapoor and Pingping Hou and Ziheng Chen and Qiuyun Wang and Luigi Nezi and Zhaohui Xu and Jun Yao and Baoli Hu and Pettazzoni, {Piergiorgio F.} and Ho, {I. Lin} and Ningping Feng and Vandhana Ramamoorthy and Shan Jiang and Pingna Deng and Ma, {Grace J.} and Peter Den and Zhi Tan and Zhang, {Shu Xing} and Huamin Wang and Wang, {Y. Alan} and Deem, {Angela K.} and Fleming, {Jason B.} and Alessandro Carugo and Heffernan, {Timothy P.} and Anirban Maitra and Andrea Viale and Haoqiang Ying and Samir Hanash and DePinho, {Ronald A.} and Draetta, {Giulio F.}",
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T1 - Syndecan 1 is a critical mediator of macropinocytosis in pancreatic cancer

AU - Yao, Wantong

AU - Rose, Johnathon L.

AU - Wang, Wei

AU - Seth, Sahil

AU - Jiang, Hong

AU - Taguchi, Ayumu

AU - Liu, Jintan

AU - Yan, Liang

AU - Kapoor, Avnish

AU - Hou, Pingping

AU - Chen, Ziheng

AU - Wang, Qiuyun

AU - Nezi, Luigi

AU - Xu, Zhaohui

AU - Yao, Jun

AU - Hu, Baoli

AU - Pettazzoni, Piergiorgio F.

AU - Ho, I. Lin

AU - Feng, Ningping

AU - Ramamoorthy, Vandhana

AU - Jiang, Shan

AU - Deng, Pingna

AU - Ma, Grace J.

AU - Den, Peter

AU - Tan, Zhi

AU - Zhang, Shu Xing

AU - Wang, Huamin

AU - Wang, Y. Alan

AU - Deem, Angela K.

AU - Fleming, Jason B.

AU - Carugo, Alessandro

AU - Heffernan, Timothy P.

AU - Maitra, Anirban

AU - Viale, Andrea

AU - Ying, Haoqiang

AU - Hanash, Samir

AU - DePinho, Ronald A.

AU - Draetta, Giulio F.

PY - 2019/4/18

Y1 - 2019/4/18

N2 - 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 agents 2–4 . However, KRAS*-independent disease recurrence following genetic extinction of Kras* in mouse models anticipates the need for co-extinction strategies 5,6 . 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.

AB - 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 agents 2–4 . However, KRAS*-independent disease recurrence following genetic extinction of Kras* in mouse models anticipates the need for co-extinction strategies 5,6 . 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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JF - Nature

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