Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice

Abstract

Pancreatic cancer is almost invariably associated with mutations in the KRAS gene, most commonly KRAS G12D , that result in a dominant-active form of the KRAS GTPase. However, how KRAS mutations promote pancreatic carcinogenesis is not fully understood, and whether oncogenic KRAS is required for the maintenance of pancreatic cancer has not been established. To address these questions, we generated two mouse models of pancreatic tumorigenesis: mice transgenic for inducible Kras G12D , which allows for inducible, pancreas-specific, and reversible expression of the oncogenic Kras G12D , with or without inactivation of one allele of the tumor suppressor gene p53. Here, we report that, early in tumorigenesis, induction of oncogenic Kras G12D reversibly altered normal epithelial differentiation following tissue damage, leading to precancerous lesions. Inactivation of Kras G12D in established precursor lesions and during progression to cancer led to regression of the lesions, indicating that Kras G12D was required for tumor cell survival. Strikingly, during all stages of carcinogenesis, Kras G12D upregulated Hedgehog signaling, inflammatory pathways, and several pathways known to mediate paracrine interactions between epithelial cells and their surrounding microenvironment, thus promoting formation and maintenance of the fibroinflammatory stroma that plays a pivotal role in pancreatic cancer. Our data establish that epithelial Kras G12D influences multiple cell types to drive pancreatic tumorigenesis and is essential for tumor maintenance. They also strongly support the notion that inhibiting Kras G12D , or its downstream effectors, could provide a new approach for the treatment of pancreatic cancer.

GRP78 haploinsufficiency suppresses acinar-to-ductal metaplasia, signaling, and mutant Kras -driven pancreatic tumorigenesis in mice

“…The recent observation that activating KRAS mutations were present in >90% of pancreatic PanIN-1 lesions suggests that the acquisition of KRAS mutations likely precedes the formation of these precursor lesions (36). In addition to its role in tumor initiation, oncogenic KRAS is also required for PDAC maintenance (37). Despite its well-known role in cancer, development of drugs targeting KRAS directly has been unfruitful, underscoring the need for alternative approaches (3).…”

Functional implication of Dclk1 and Dclk1-expressing cells in cancer

“…21,22 The functional importance of mutant Kras, a member of the GTPase enzyme family, in pancreatic cancer, even in the setting of metastatic disease, has been shown in a series of seminal papers. [23][24][25] Consequently, the finding by Sureban and coworkers that siRNA-mediated knockdown of Dclk1 in human pancreatic cancer cells resulted in downregulation of Kras expression was of great interest. 19 The authors followed up this study with a more in depth analysis of pancreatic cancer cells with reduced Dclk1 gene expression, and demonstrated that Dclk1 regulated pluripotency and angiogenic programs via distinct miRNAs.…”

Effect of arenobufagin on human pancreatic carcinoma cells

“…Certain genetic studies have shown that K-Ras activation and mutation is necessary for the initiation of PC (26)(27)(28), and an inducible pancreas-specific expression system was used to show that K-Ras expression is also required for tumor maintenance (29). These mutations lock K-Ras and its downstream proteins, such as Akt and Erk, in a constitutively activated form.…”