Metastatic Pancreatic Cancer Is Dependent on Oncogenic Kras in Mice

PLoS One

Meredith A. Collins¹  Stefanie Galbán²  Yaqing Zhang²  Craig J. Galbán³  Marina Pasca di Magliano³  Jean-Christophe Brisset³  Filip Bednar⁴  Kevin A. Heist⁴  Josette Pierre⁴ 

[1] Cellular and Molecular Biology Program, University of Michigan, Ann Arbor, Michigan, United States of America;Center for Molecular Imaging, University of Michigan, Ann Arbor, Michigan, United States of America;Department of Radiology, University of Michigan, Ann Arbor, Michigan, United States of America;Department of Surgery, University of Michigan, Ann Arbor, Michigan, United States of America

关键词: Mouse models;    Pancreatic cancer;    Metastatic tumors;    Magnetic resonance imaging;    Histology;    Pancreas;    Carcinogenesis;    Lung and intrathoracic tumors;   

DOI  :  10.1371/journal.pone.0049707

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY