A requirement for Nedd9 in luminal progenitor cells prior to mammary tumorigenesis in MMTV-HER2/ErbB2 mice

Abstract

Overexpression of the NEDD9/HEF1/Cas-L scaffolding protein is frequent, and drives invasion and metastasis in breast, head and neck, colorectal, melanoma, lung, and other types of cancer. We have examined the consequences of genetic ablation of Nedd9 in the MMTV-HER2/ERBB2/neu mouse mammary tumor model. Unexpectedly, we found that only a limited effect on metastasis in MMTV-neu;Nedd9−/− mice compared to MMTV-neu;Nedd9+/+ mice, but instead a dramatic reduction in tumor incidence (18% versus 80%), and a significantly increased latency until tumor appearance. Orthotopic reinjection and tail vein injection of cells arising from tumors, coupled with in vivo analysis, indicated tumors arising in MMTV-neu;Nedd9−/− mice had undergone mutational selection that overcame the initial requirement for Nedd9. To better understand the defects in early tumor growth, we compared mammary progenitor cell pools from MMTV-neu;Nedd9−/− versus MMTV-neu;Nedd9+/+ mice. The MMTV-neu;Nedd9−/− genotype selectively reduced both the number and colony-forming potential of mammary luminal epithelial progenitor cells, while not affecting basal epithelial progenitors. MMTV-neu;Nedd9−/−mammospheres had striking defects in morphology and cell polarity. All of these defects were seen predominantly in the context of the HER2/neu oncogene, and were not associated with randomization of the plane of mitotic division, but rather with depressed expression the cell attachment protein FAK, accompanied by increased sensitivity to small molecule inhibitors of FAK and SRC. Surprisingly, in spite of these significant differences, only minimal changes were observed in the gene expression profile of Nedd9−/− mice, indicating critical Nedd9-dependent differences in cell growth properties were mediated via post-transcriptional regulation of cell signaling. Coupled with emerging data indicating a role for NEDD9 in progenitor cell populations during the morphogenesis of other tissues, these results indicate a functional requirement for NEDD9 in the growth of mammary cancer progenitor cells.

New signaling pathways govern the host response to C. albicans infection in various niches

“…Third, invasion-defective C. albicans mutants simulated the expression of NEDD9-target genes only weakly. NEDD9 has been shown to be essential for transduction of signals that result from stimulation by PDGF (Natarajan et al 2006) as well as overexpression of ERBB2 (Little et al 2014). Our data suggest that NEDD9 may govern the host cell response to C. albicans by transducing signals from both the PDGF BB and ERBB2 pathways.…”

Preclinical and clinical studies of the NEDD9 scaffold protein in cancer and other diseases

“…In a subsequent study, using a different mouse model, Little et al found that Nedd9 −/− mice were remarkably resistant to MMTV- neu (HER2) induction of mammary tumors [73]. MMTV-HER2 /neu;Nedd9 −/− mice had a dramatic reduction in tumor incidence (18 versus 80%), and a significantly increased latency until tumor appearance.…”

Nedd9 restrains renal cystogenesis in Pkd1 −/− mice

“…To date, NEDD9 has been most studied in the context of cancer, because deregulated expression of NEDD9 accompanies and promotes metastasis in a large and growing number of cancer types, whereas genetic ablation of NEDD9 has a significant modifier function for tumor initiation and progression (8,13,14). A particularly interesting feature of NEDD9 action in cancer is that both overexpression and loss of function have been found to be tumor promoting different cellular contexts, likely because either form of disruption of its scaffolding action impairs downstream processes.…”