RapidCaP, a Novel GEM Model for Metastatic Prostate Cancer Analysis and Therapy, Reveals Myc as a Driver of Pten-Mutant Metastasis

Abstract

Genetically engineered mouse (GEM) models are a pillar of functional cancer research. Here, we developed RapidCaP, a GEM modeling system that uses surgical injection for viral gene delivery to the prostate. We show that in Pten defi ciency, loss of p53 suffi ces to trigger metastasis to distant sites at greater than 50% penetrance by four months, consistent with results from human prostate cancer genome analysis. Live bioluminescence tracking showed that endogenous primary and metastatic disease responds to castration before developing lethal castration resistance. To our surprise, the resulting lesions showed no activation of Akt but activation of the Myc oncogene. Using RapidCaP, we fi nd that Myc drives local prostate metastasis and is critical for maintenance of metastasis, as shown by using the Brd4 inhibitor JQ1. Taken together, our data suggest that a "MYC-switch" away from AKT forms a critical and druggable event in PTEN -mutant prostate cancer metastasis and castration resistance. SIGNIFICANCE:The RapidCaP system introduces fast and fl exible genetics for functional analysis and therapy for endogenous metastatic prostate cancer. The approach introduces targeting of MYC as a critical strategy against PTEN -defi cient lethal prostate cancer. Cancer Discov; 4(3); 318-33. ©2014AACR.

Inhibition of the GTPase Rac1 Mediates the Antimigratory Effects of Metformin in Prostate Cancer Cells

“…Therefore, we are aware that we need to confirm the effect of metformin on the formation of metastasis in another mouse model. Thus, it would be interesting to test the effects of metformin in the "RapidCaP" model recently described by Cho and colleagues (60). In this new model, unlike our study, mice develop metastasis from mouse prostate tumors.…”

Pancreatic cancer modeling using retrograde viral vector delivery and in vivo CRISPR/Cas9-mediated somatic genome editing

“…Since viral-Cre infection of the lung, prostate, bladder, and muscle can initiate cancer in adult tissues (Jackson et al 2001;Kirsch et al 2007;Puzio-Kuter et al 2009;Cho et al 2014), we considered how best to deliver viral-Cre to the pancreas without infecting other cells within the peritoneal cavity. To specifically initiate recombination in cells within the adult pancreas while keeping the virus contained within the target organ, we used retrograde pancreatic ductal injection.…”

Dual Targeting of Bromodomain and Extraterminal Domain Proteins, and WNT or MAPK Signaling, Inhibits c-MYC Expression and Proliferation of Colorectal Cancer Cells

“…Given the ability of BET inhibitors to repress c-MYC expression in a range of tumor types (7,9,32,33) and the importance of c-MYC in promoting the initiation and progression of colon cancer, we sought to determine the effect of BET inhibitors on the growth of colorectal cancer cells and the role of c-MYC in mediating these effects. By analyzing a panel of 20 colon cancer cell lines, we found that sensitivity to JQ1 was significantly associated with the magnitude of repression of c-MYC.…”