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
N1 - Funding Information:
We thank Dr. Goggins for providing us with the hCAF cells. This work was supported in part by NIHR01 CA169702 to L. Zheng, NIHK23 CA148964-01 to L. Zheng, Viragh Foundation and the Skip Viragh Pancreatic Cancer Center at Johns Hopkins to E.M. Jaffee and L. Zheng, the NCI SPORE in Gastrointestinal CancersP50 CA062924 to E.M. Jaffee and L. Zheng, and a Lustgarten Foundation grant to L. Zheng. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2016 AACR.
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.
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U2 - 10.1158/0008-5472.CAN-16-1383
DO - 10.1158/0008-5472.CAN-16-1383
M3 - Article
C2 - 27821486
AN - SCOPUS:85009230903
SN - 0008-5472
VL - 77
SP - 41
EP - 52
JO - Cancer Research
JF - Cancer Research
IS - 1
ER -