These findings represent the first pathway shown to play a direct causal role in driving metastatic prostate cancer and are published online February 14 and will appear in an upcoming print issue of Nature Medicine.
“In this study, we show that this oncogene-tumor suppressor cascade – or this pathway of four genes – induces prostate tumor development and metastasis in a mouse model,” said Karen Cichowski, PhD, a researcher and assistant professor of Medicine in the Division of Genetics at BWH and senior author of the paper. “We were also able to demonstrate that this pathway is deregulated in human prostate cancer and may predict outcome for patients with prostate cancer.”
Performing both protein and transcriptional pattern analysis in more than 250 human prostate tumors, researchers were able to determine that this genetic pathway was deregulated in patients with more advanced disease, and if it was deregulated the patient was more likely to develop metastatic prostate cancer.
“This finding has important clinical implications, because it suggests that this pathway may be a prognostic indicator of future progression of prostate cancer,” Cichowski said.
Cichowski, in collaboration with Massimo Loda, MD and William Hahn, MD, PhD, physicians in Medical Oncology at Dana-Farber Cancer Institute, Junxia Min, a fellow in the Division of Genetics at BWH and the first author of the paper, and colleagues identified this pathway by performing a cellular screen of genes within the RasGAP gene family. It is known that one gene in this family is associated with different cancers, but other genes in this family have not been extensively researched. They found that DAB2IP is a new cancer-causing gene and that its loss triggers a cascade of signals: some responsible for initiating tumor growth, and others responsible for causing metastasis. By utilizing a genetically-engineered cell system in which cells are injected into mouse prostates, researchers used genetic approaches to identify both the upstream genes responsible for controlling DAB2IP and essential downstream signals, thus allowing researchers to identify the entire genetic pathway.
“One of the genes in this pathway encodes an enzyme, and from a therapeutic standpoint may be ‘drugable’. Therefore further work may ultimately lead to the development of therapies that could impact both primary prostate cancers and metastases,” Cichowski said.
This research was supported by grants from the US Department of Defense and the Ludwig Center at Dana-Farber/Harvard Cancer Center.