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

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 and mutations (KPC) were crossed with 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 haploinsufficiency retarded native expansion of stromal myofibroblasts during precursor-to-cancer progression. 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 ; 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. Zeb1 expression in stromal myofibroblasts supports PDAC development via collaboration with the epithelial compartment bearing oncogenic Kras mutations. .

Integrated multi-omics characterization of KRAS mutant colorectal cancer

“…found that lung macrophages and epithelium-secreted SPP1 drove tumor-associated inflammation, while SPP1 promoted early tumorigenesis by promoting the survival of KRAS-mutated cells, especially in KRAS-G12D-driven tumors 43 . Stromal myofibroblasts were reported to promote the development of pancreatic cancer via collaboration with the epithelial compartment harboring oncogenic Kras mutations 44 . The characterization of cellular profiles in the TME of CRC implies the immunomodulatory effect of KRAS mutation, particularly via promotion of inflammation and evasion of the immune response, ultimately leading to tumor progression, invasion, and progression.…”

Activated Pancreatic Stellate Cells Enhance the Warburg Effect to Cause the Malignant Development in Chronic Pancreatitis

“…It is worth noting that the KRAS mutation is also associated with the upregulation of HIF-1a and the Warburg effect in cancer cells (41)(42)(43). Several studies on tumor-stromal interactions in pancreatic cancer have suggested that PSCs and KRAS mutations have mutual regulation (44)(45)(46). In view of the presence of KRAS mutations in most pancreatic cancers, whether PSCs enhance the Warburg effect through mutual regulation with KRAS mutations and ultimately lead to the carcinogenesis of CP is worthy of further study.…”

Activated Pancreatic Stellate Cells Enhance the Warburg Effect to Cause the Malignant Development in Chronic Pancreatitis

“…It is worth noting that the KRAS mutation is also associated with the upregulation of HIF-1α and the Warburg effect in cancer cells (41)(42)(43). Several studies on tumor-stromal interactions in pancreatic cancer have suggested that PSCs and KRAS mutations have mutual regulation (44)(45)(46). In view of the presence of KRAS mutations in most pancreatic cancers, whether PSCs enhance the Warburg effect through mutual regulation with KRAS mutations and ultimately lead to the carcinogenesis of CP is worthy of further study.…”