Enhanced genetic instability and dasatinib sensitivity in mammary tumor cells lacking NEDD9
Mahendra K Singh1, Eugene Izumchenko, Andres J Klein-Szanto
1Departments of Developmental Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.
Abstract:
Elevated expression of the NEDD9/HEF1/Cas-L scaffolding protein promotes tumor cell invasion and metastasis in multiple cancer cell types. Conversely, generation of mammary tumors in the mouse mammary tumor virus (MMTV)-polyoma virus middle T (PyVT) genetic model is delayed by a Nedd9(-/-) genotype. These activities arise from the role of NEDD9 in assembling complexes and supporting activity of cancer signaling proteins, including FAK, Src, Shc, and AKT, and would support evaluation of NEDD9 expression as an unambiguous biomarker for tumor aggressiveness. However, we here show that despite the initial delay in tumor growth, cells derived from MMTV-PyVT;Nedd9(-/-) tumors are characteristically hyperaggressive versus MMTV-PyVT;Nedd9(+/+) cells in anchorage-independent growth, in growth on three-dimensional matrix produced by tumor-associated fibroblasts, and in formation of tumors after mammary orthotopic reinjection and of lung metastases after tail vein injection. This reversal suggests the specific selection of MMTV-PyVT;Nedd9(-/-) cells for growth in an in vivo microenvironment. Indeed, MMTV-PyVT;Nedd9(-/-) cells have increased cell cycle, centrosomal, and mitotic defects, phenotypes compatible with the increased selection of these cells for aggressive growth. Intriguingly, in spite of their aggressive phenotype, MMTV-PyVT;Nedd9(-/-) cells persistently have low levels of Src activation and are hypersensitive to the Src kinase inhibitor dasatinib. These studies identify NEDD9 as a complex modulator of different aspects of mammary tumor growth.
Insights
The scaffolding protein NEDD9 (non-EGF-like repeat containing adaptor protein) initially delays mammary tumor growth but its absence leads to hyperaggressive tumors. Nedd9 deficiency causes cell cycle defects and Src pathway alterations in aggressive mammary tumors.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- NEDD9 (HEF1/Cas-L) is a scaffolding protein implicated in promoting cancer cell invasion and metastasis.
- Loss of Nedd9 delays mammary tumor formation in the MMTV-PyVT mouse model.
- NEDD9 influences signaling pathways involving FAK, Src, Shc, and AKT, suggesting its role in tumor aggressiveness.
Purpose of the Study:
- To investigate the role of NEDD9 in mammary tumor growth and aggressiveness.
- To understand the paradoxical effect of Nedd9 deficiency on tumor progression.
- To explore the underlying mechanisms of altered tumor cell behavior in the absence of NEDD9.
Main Methods:
- Utilized the MMTV-PyVT mouse model with Nedd9 knockout (Nedd9-/-) and wild-type (Nedd9+/+) genotypes.
- Assessed tumor cell phenotypes including anchorage-independent growth and growth on 3D matrices.
- Evaluated tumor formation, metastasis, cell cycle, centrosomal/mitotic defects, and Src activation.
- Tested sensitivity to the Src kinase inhibitor dasatinib.
Main Results:
- Despite initial growth delay, MMTV-PyVT;Nedd9-/- tumors exhibited hyperaggressive phenotypes compared to MMTV-PyVT;Nedd9+/+ cells.
- Nedd9 deficiency led to increased cell cycle, centrosomal, and mitotic defects in tumor cells.
- MMTV-PyVT;Nedd9-/- cells showed low Src activation and hypersensitivity to dasatinib, contrasting with their aggressive phenotype.
Conclusions:
- NEDD9 acts as a complex modulator of mammary tumor growth, with context-dependent effects.
- Loss of NEDD9 can lead to selection of hyperaggressive tumor cell variants with specific defects.
- Targeting Src kinase may be a viable strategy for treating NEDD9-deficient aggressive mammary tumors.
Related Concept Videos
02:23Abnormal Proliferation
02:56Treatment Resistant Cancers
02:15Replicative Cell Senescence