RT Journal Article
SR Electronic
T1 Insertional mutagenesis defines drivers and evolutionary relationships in pancreatic cancer metastasis
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.09.28.317701
DO 10.1101/2020.09.28.317701
A1 Suman Govindaraju
A1 Michelle Maurin
A1 Justin Y. Newberg
A1 Devin J. Jones
A1 Hubert Lee
A1 Judit E. Markovitz
A1 Michael B. Mann
A1 Michael A. Black
A1 Karen M. Mann
YR 2020
UL http://biorxiv.org/content/early/2020/09/29/2020.09.28.317701.abstract
AB Metastasis is a defining feature of pancreatic cancer, impacting patient quality of life and therapeutic outcomes. While recurrent mutations in KRAS and TP53 play important roles in primary tumor development and persist in metastases, the contributions of other genes to the metastatic process is understudied. Here, we define a network of metastasis-promoting genes and uncover positively selected genes in metastatic lesions from our Sleeping Beauty mouse model of pancreatic cancer using our recently described SB Driver Analysis statistical pipeline. We show that loss of single genes DLG1, PARD3, PKP4 and PTPRK promote pancreas cancer progression in a context-specific manner. Finally, we define clonal and sub-clonal insertion events that distinguish primary and individual metastatic tumors and use single cell sequencing to gain insight into the evolutionary relationships between sub-regions of primary pancreatic tumors and related metastases, which has important implications for pancreatic disease progression and therapeutic opportunities for patients.Competing Interest StatementThe authors have declared no competing interest.