Heterogeneous stromal signaling within the tumor microenvironment controls the metastasis of pancreatic cancer

Agnieszka A. Rucki, Kelly Foley, Pingbo Zhang, Qian Xiao, Jennifer Kleponis, Annie A. Wu, Rajni Sharma, Guanglan Mo, Angen Liu, Jennifer Van Eyk, Elizabeth M. Jaffee, Lei Zheng

Research output: Research - peer-reviewArticle

Abstract

Understanding how stromal signals regulate the development of pancreatic ductal adenocarcinoma (PDAC) may suggest novel therapeutic interventions in this disease. In this study, we assessed the metastatic role of stromal signals suggested to be important in the PDAC microenvironment. Src and IGF-1R phosphorylated the prometastatic molecule Annexin A2 (AnxA2) at Y23 and Y333 in response to stromal signals HGF and IGF-1, respectively, and IGF-1 expression was regulated by the Sonic Hedgehog (Shh) pathway. Both Shh and HGF were heterogeneously expressed in PDAC stroma, and only dual inhibition of these pathways could significantly suppress AnxA2 phosphorylation, PDAC growth, and metastasis. Taken together, our results illuminate tumor-stromal interactions, which drive metastasis, and provide a mechanism-based rationale for a stroma-directed therapy for PDAC.

LanguageEnglish (US)
Pages41-52
Number of pages12
JournalCancer Research
Volume77
Issue number1
DOIs
StatePublished - Jan 1 2017

Fingerprint

Tumor Microenvironment
Pancreatic Neoplasms
Adenocarcinoma
Neoplasm Metastasis
Insulin-Like Growth Factor I
Therapeutics
Annexin A2
Annexins
Phosphorylation
Growth
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Heterogeneous stromal signaling within the tumor microenvironment controls the metastasis of pancreatic cancer. / Rucki, Agnieszka A.; Foley, Kelly; Zhang, Pingbo; Xiao, Qian; Kleponis, Jennifer; Wu, Annie A.; Sharma, Rajni; Mo, Guanglan; Liu, Angen; Van Eyk, Jennifer; Jaffee, Elizabeth M.; Zheng, Lei.

In: Cancer Research, Vol. 77, No. 1, 01.01.2017, p. 41-52.

Research output: Research - peer-reviewArticle

Rucki, AA, Foley, K, Zhang, P, Xiao, Q, Kleponis, J, Wu, AA, Sharma, R, Mo, G, Liu, A, Van Eyk, J, Jaffee, EM & Zheng, L 2017, 'Heterogeneous stromal signaling within the tumor microenvironment controls the metastasis of pancreatic cancer' Cancer Research, vol 77, no. 1, pp. 41-52. DOI: 10.1158/0008-5472.CAN-16-1383
Rucki, Agnieszka A. ; Foley, Kelly ; Zhang, Pingbo ; Xiao, Qian ; Kleponis, Jennifer ; Wu, Annie A. ; Sharma, Rajni ; Mo, Guanglan ; Liu, Angen ; Van Eyk, Jennifer ; Jaffee, Elizabeth M. ; Zheng, Lei. / Heterogeneous stromal signaling within the tumor microenvironment controls the metastasis of pancreatic cancer. In: Cancer Research. 2017 ; Vol. 77, No. 1. pp. 41-52
@article{fdbbbd2e21fb475b9c3864dced9da0c4,
title = "Heterogeneous stromal signaling within the tumor microenvironment controls the metastasis of pancreatic cancer",
abstract = "Understanding how stromal signals regulate the development of pancreatic ductal adenocarcinoma (PDAC) may suggest novel therapeutic interventions in this disease. In this study, we assessed the metastatic role of stromal signals suggested to be important in the PDAC microenvironment. Src and IGF-1R phosphorylated the prometastatic molecule Annexin A2 (AnxA2) at Y23 and Y333 in response to stromal signals HGF and IGF-1, respectively, and IGF-1 expression was regulated by the Sonic Hedgehog (Shh) pathway. Both Shh and HGF were heterogeneously expressed in PDAC stroma, and only dual inhibition of these pathways could significantly suppress AnxA2 phosphorylation, PDAC growth, and metastasis. Taken together, our results illuminate tumor-stromal interactions, which drive metastasis, and provide a mechanism-based rationale for a stroma-directed therapy for PDAC.",
author = "Rucki, {Agnieszka A.} and Kelly Foley and Pingbo Zhang and Qian Xiao and Jennifer Kleponis and Wu, {Annie A.} and Rajni Sharma and Guanglan Mo and Angen Liu and {Van Eyk}, Jennifer and Jaffee, {Elizabeth M.} and Lei Zheng",
year = "2017",
month = "1",
doi = "10.1158/0008-5472.CAN-16-1383",
volume = "77",
pages = "41--52",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "1",

}

TY - JOUR

T1 - Heterogeneous stromal signaling within the tumor microenvironment controls the metastasis of pancreatic cancer

AU - Rucki,Agnieszka A.

AU - Foley,Kelly

AU - Zhang,Pingbo

AU - Xiao,Qian

AU - Kleponis,Jennifer

AU - Wu,Annie A.

AU - Sharma,Rajni

AU - Mo,Guanglan

AU - Liu,Angen

AU - Van Eyk,Jennifer

AU - Jaffee,Elizabeth M.

AU - Zheng,Lei

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Understanding how stromal signals regulate the development of pancreatic ductal adenocarcinoma (PDAC) may suggest novel therapeutic interventions in this disease. In this study, we assessed the metastatic role of stromal signals suggested to be important in the PDAC microenvironment. Src and IGF-1R phosphorylated the prometastatic molecule Annexin A2 (AnxA2) at Y23 and Y333 in response to stromal signals HGF and IGF-1, respectively, and IGF-1 expression was regulated by the Sonic Hedgehog (Shh) pathway. Both Shh and HGF were heterogeneously expressed in PDAC stroma, and only dual inhibition of these pathways could significantly suppress AnxA2 phosphorylation, PDAC growth, and metastasis. Taken together, our results illuminate tumor-stromal interactions, which drive metastasis, and provide a mechanism-based rationale for a stroma-directed therapy for PDAC.

AB - Understanding how stromal signals regulate the development of pancreatic ductal adenocarcinoma (PDAC) may suggest novel therapeutic interventions in this disease. In this study, we assessed the metastatic role of stromal signals suggested to be important in the PDAC microenvironment. Src and IGF-1R phosphorylated the prometastatic molecule Annexin A2 (AnxA2) at Y23 and Y333 in response to stromal signals HGF and IGF-1, respectively, and IGF-1 expression was regulated by the Sonic Hedgehog (Shh) pathway. Both Shh and HGF were heterogeneously expressed in PDAC stroma, and only dual inhibition of these pathways could significantly suppress AnxA2 phosphorylation, PDAC growth, and metastasis. Taken together, our results illuminate tumor-stromal interactions, which drive metastasis, and provide a mechanism-based rationale for a stroma-directed therapy for PDAC.

UR - http://www.scopus.com/inward/record.url?scp=85009230903&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85009230903&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-16-1383

DO - 10.1158/0008-5472.CAN-16-1383

M3 - Article

VL - 77

SP - 41

EP - 52

JO - Cancer Research

T2 - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 1

ER -