Abstract
The transcription factor Zeb1 has been identified as a crucial player in Kras-dependent oncogenesis. In pancreatic ductal adenocarcinoma (PDAC), Zeb1 is highly expressed in myofibroblasts and correlates with poor prognosis. As Kras mutations are key drivers in PDAC, we aimed here to assess the necessity of Zeb1 for Kras-driven PDAC and to define the role of Zeb1-expressing myofibroblasts in PDAC development. Genetically engineered mice with conditional pancreatic KrasG12D and Trp53 mutations (KPC) were crossed with Zeb1 haploinsufficient mice (Z+/-). Extensive PDAC was prominent in all 20-week-old KPC;Z+/+ mice, whereas only low-grade precursor lesions were detected in age-matched KPC;Z+/- littermates, with PDAC developing eventually in KPC;Z+/- aged animals. Zeb1 expression in myofibroblasts occurred early in tumorigenesis and Zeb1 haploinsufficiency retarded native expansion of stromal myofibroblasts during precursor-to-cancer progression. Zeb1 downregulation in mPSC repressed their activated gene profile, impaired their migratory and proliferative activity, and attenuated their tumor-supporting features. Conditioned media from Z+/+ mouse-activated (myofibroblast-like) pancreatic stellate cells (mPSC) boosted Ras activity in pancreatic cancer cells carrying mutant Kras; this effect was not observed when using conditioned media from Z+/- mPSC, revealing a paracrinal cooperative axis between Zeb1-expressing PSC and oncogenic Kras-bearing tumor cells. We conclude that Zeb1-expressing stromal myofibroblasts enable a heterotypic collaboration with the Kras-fated epithelial compartment, thus supporting pancreatic malignancy.Significance: Zeb1 expression in stromal myofibroblasts supports PDAC development via collaboration with the epithelial compartment bearing oncogenic Kras mutations. Cancer Res; 78(10); 2624-37. ©2018 AACR.
Highlights
Pancreatic cancer development is no longer viewed as a successful crusade of a clone of cells endowed with oncogenic supplies
Given that pancreatic stellate cells (PSC) are prolific producers of secreted factors with protumoral attributes [36], we hypothesized that Zeb1 in mouse PSCs (mPSC) supports Ras activity in pancreatic cancer cells bearing oncogenic Kras
As oncogenic Kras is a key driver of pancreatic ductal adenocarcinoma (PDAC) generation, we hypothesized that Zeb1 can play a critical role in successful pancreatic Kras-mediated tumorigenesis
Summary
Pancreatic cancer development is no longer viewed as a successful crusade of a clone of cells endowed with oncogenic supplies. Tissue microenvironment surrounding neoplastic cells has emerged as a critical collaborator with a proven influence on neighboring tumor cell [1]. The stromal tumor compartment, known as desmoplastic reaction, provides a permissive territory that enables an advantageous cross-talk between stromal and cancer cells. Myofibroblasts are the most abundant cell type in pancreatic desmoplasia. They emerge from resident quiescent pancreatic stellate cells (PSC) that differentiate into highly proliferating a-smooth muscle. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).
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