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New target: Researchers identify pancreatic cancer resistance mechanism
Date:6/19/2014

se model experiments, including work by DePinho, Ying and colleagues, have demonstrated critical roles for those mutations in tumor initiation and progression.

Turning Kras on and off

To conduct the research, the team used a genetically engineered mouse model of inducible Kras-dependent pancreatic cancer developed in DePinho's lab when he was at the Dana-Farber Cancer Institute in Boston. The mice have a version of Kras that can be turned on by treating them with doxycycline, an antibiotic, and only develop pancreatic cancer when this occurs. Tumors develop swiftly and then begin to regress after 24 hours of cessation of doxycycline treatment.

Within three weeks of doxycycline cessation, tumors regressed completely in all 28 mice. Then, 20 of the mice had a recurrence between nine and 47 weeks later. The recurrent tumors had characteristics of aggressive disease, including spread to the lung or liver in 15 of the mice.

Half of the recurrent tumors had re-expression of the inducible Kras transgene, while the other half had no sign of the oncogene or of activation of its related molecular pathways.

If not Kras, then Yap1

To identify the driving molecular mechanism for the non-Kras recurrent tumors, the team conducted an analysis to identify copy number variations of genes in the tumors.

"The only gene amplified was Yap1, which made sense, because it's a known oncogene," said co-lead author Avnish Kapoor, Ph.D., a postdoctoral fellow in Genomic Medicine who conducted the analysis.

Functional studies conducted by Wantong Yao, Ph.D., also a postdoctoral fellow in Genomic Medicine, confirmed the finding.

Yap1-amplified recurrent tumors shrank when Yap1 expression was knocked down using RNA interference. Yap1 expression in the Kras-dependent mice stifled tumor regression and supported tumor growth after doxycycline withdrawal

Mapping the Yap1 pathway'/>"/>

Contact: Scott Merville
smerville@mdanderson.org
713-792-0661
University of Texas M. D. Anderson Cancer Center
Source:Eurekalert  

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