Figure S2 from Zeb1 in Stromal Myofibroblasts Promotes Kras-Driven Development of Pancreatic Cancer

Sangrador, Irene; Molero, Xavier; Campbell, Fiona; Franch-Expósito, Sebastià; Rovira-Rigau, Maria; Samper, Esther; Domínguez-Fraile, Manuel; Fillat, Cristina; Castells, Antoni; Vaquero, Eva C.

doi:10.1158/0008-5472.22416857.v1

Figure S2 from Zeb1 in Stromal Myofibroblasts Promotes Kras-Driven Development of Pancreatic Cancer

journal contribution

posted on 2023-03-31, 01:09 authored by Irene Sangrador, Xavier Molero, Fiona Campbell, Sebastià Franch-Expósito, Maria Rovira-Rigau, Esther Samper, Manuel Domínguez-Fraile, Cristina Fillat, Antoni Castells, Eva C. Vaquero

Zeb1 expression in transformed pancreata of KPC;Z+/+ and KPC;Z+/-

Funding

Spanish Ministry of Health

Centro de Investigación Biomédica en Red en el Área Temática de Enfermedades Hepáticas y Digestivas (CiberEHD)

Asociación Española de Gastroenterología (AEG)

Societat Catalana de Digestologia (SCD)

History

ARTICLE 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.