Metastatic Pancreatic Cancer Is Dependent on Oncogenic Kras in Mice

Abstract

Pancreatic cancer is one of the deadliest human malignancies, and its prognosis has not improved over the past 40 years. Mouse models that spontaneously develop pancreatic adenocarcinoma and mimic the progression of the human disease are emerging as a new tool to investigate the basic biology of this disease and identify potential therapeutic targets. Here, we describe a new model of metastatic pancreatic adenocarcinoma based on pancreas-specific, inducible and reversible expression of an oncogenic form of Kras, together with pancreas-specific expression of a mutant form of the tumor suppressor p53. Using high-resolution magnetic resonance imaging to follow individual animals in longitudinal studies, we show that both primary and metastatic lesions depend on continuous Kras activity for their maintenance. However, re-activation of Kras* following prolonged inactivation leads to rapid tumor relapse, raising the concern that Kras*-resistance might eventually be acquired. Thus, our data identifies Kras* as a key oncogene in pancreatic cancer maintenance, but raises the possibility of acquired resistance should Kras inhibitors become available for use in pancreatic cancer.

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.…”

The Transcription Factor GLI1 Modulates the Inflammatory Response during Pancreatic Tissue Remodeling

“…7F), followed by serum starvation and treatment with either cancer cell conditioned media (CCM) from primary iKras* tumor cells (28) or control media for 0, 6, and 24 h; we then collected cells for RNA extraction (scheme in Fig. 7F).…”

Ribonucleoprotein HNRNPA2B1 Interacts With and Regulates Oncogenic KRAS in Pancreatic Ductal Adenocarcinoma Cells

“…16,17 "KRAS addiction" has been deeply investigated in murine and human cancer models or in clinical studies. [18][19][20][21][22][23][24][25] Pancreatic Ductal Adenocarcinoma (PDAC) is a nearly uniformly fatal disease despite intensive treatment, with less than 1-5% of patients surviving 5 years. 26,27 PDAC is one of the bestdefined KRAS-driven human malignancies, with a wealth of molecular studies identifying mutant KRAS as the initiating event in the vast majority of cases.…”