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: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)41-52
Number of pages12
JournalCancer Research
Volume77
Issue number1
DOIs
StatePublished - Jan 1 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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