Heterogeneous Stromal Signaling within the Tumor Microenvironment Controls the Metastasis of Pancreatic Cancer.
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. Cancer Res; 77(1); 41-52. ©2016 AACR.
The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|Graduate Program in Cellular and Molecular Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Agnieszka A
AA
Rucki
The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|Graduate Program in Cellular and Molecular Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Kelly
K
Foley
Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Pingbo
P
Zhang
The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Qian
Q
Xiao
The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Jennifer
J
Kleponis
The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Annie A
AA
Wu
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Rajni
R
Sharma
The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|The Skip Viragh Center for Pancreatic Cancer, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Guanglan
G
Mo
The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Angen
A
Liu
Department of Medicine, Biological Chemistry and Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Jennifer
J
Van Eyk
The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|Graduate Program in Cellular and Molecular Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|The Skip Viragh Center for Pancreatic Cancer, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Elizabeth M
EM
Jaffee
The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland. lzheng6@jhmi.edu.|Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|Graduate Program in Cellular and Molecular Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|The Skip Viragh Center for Pancreatic Cancer, The Johns Hopkins University School of Medicine, Baltimore, Maryland.|Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
Lei
L
Zheng
D000818:Animals; D015153:Blotting, Western; D021441:Carcinoma, Pancreatic Ductal / Q000473:pathology*; D002853:Chromatography, Liquid; D004797:Enzyme-Linked Immunosorbent Assay; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009361:Neoplasm Invasiveness / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D017154:Stromal Cells / Q000378:metabolism; D053719:Tandem Mass Spectrometry; D059016:Tumor Microenvironment / Q000502:physiology*