The Role of Oncogenic Kras in Pancreatic Cancer Progression and Maintence.

[摘要] Pancreatic ductal adenocarcinoma (PDA), the fourth leading cause of cancer death in the U.S., is a devastating disease. Current therapies are largely ineffective, and development of better approaches depends on a greater knowledge of its biology. The Kras oncogene, often mutated in human pancreatic cancer, is important for the onset of pancreatic cancer.To study the role of Kras in the progression and maintenance of pancreatic cancer I have characterized a new mouse model, inducible-KrasG12D (iKras*), that allows for tissue-specific, temporally regulated and reversible expression of mutant Kras* in the pancreatic epithelium. Upon activation of Kras* expression, iKras* mice undergo tumorigenesis characteristic of human pancreatic cancer. Strikingly, withdrawal of Kras* expression resulted in rapid reversion of the carcinogenesis process and repair of the pancreatic tissue. Furthermore, I have crossed iKras* mice with animals containing a mutant form of the tumor suppressor p53 (p53R172H). Here, activation of Kras* gave rise to the formation of invasive tumors and metastases. Inactivation of Kras* resulted in regression of primary tumors and metastases. These results show that Kras* is continuously required during pancreatic carcinogenesis, even in the context of other genetic alterations, thus validating Kras* as a therapeutic target. The lack of inhibitors targeting Kras* prevents clinical applications of these findings. The MAPK pathway is activated by Kras*, and its activation accompaniesprecancerous lesion formation and is retained in invasive tumors. To investigate the requirement of the MAPK pathway during pancreatic carcinogenesis, I inhibited MEK1/2, a key pathway component, in iKras* mice using the small molecule antagonist PD325901. Abrogation of MAPK signaling prevented the initiation of pancreatic tumorigenesis. Strikingly, MEK1/2 blockade in mice bearing precursor lesions resulted in the redifferentiation of the lesions into normal acinar cells. These results define the biological role of the MAPK pathway during the initiation and maintenance of pancreatic precancerous lesions. Importantly, my data suggest that MAPK signaling promotes carcinogenesis by enabling dedifferentiation of acinar cells making them susceptible to malignant transformation. Taken together, my data indicate that activation of Kras*, and subsequently the MAPK pathway, is required for both the formation and maintenance of PanIN lesions and pancreatic cancer.

[发布机构] University of Michigan

[效力级别] Mouse Models

[关键词] Pancreatic Cancer;Mouse Models;Oncogenic Kras;MAPK Signaling;Molecular;Cellular and Developmental Biology;Health Sciences;Cellular & Molecular Biology