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| Content Provider | Springer Nature Link |
|---|---|
| Author | O’Sullivan, Dermot Henry, Michael Joyce, Helena Walsh, Naomi Auley, Edel Mc Dowling, Paul Swan, Niall Moriarty, Michael Barnham, Paul Clynes, Martin Larkin, Annemarie |
| Copyright Year | 2014 |
| Abstract | Development of more effective therapeutic strategies for cancers of high unmet need requires the continued discovery of disease-specific protein targets for therapeutic antibody targeting. In order to identify novel proteins associated with cancer cell invasion/metastasis, we present here an alternative to antibody targeting of cell surface proteins with an established role in invasion; our functional antibody screening approach involves the isolation and selection of MAbs that are primarily screened for their ability to inhibit tumour invasion. A clonal population of the Mia PaCa-2, a pancreatic ductal adenocarcinoma (PDAC) cell line, which displays a highly invasive phenotype, was used to generate MAbs with the objective of identifying membrane targets directly involved in cancer invasion. Selected MAb 7B7 can significantly reduce invasion in a dose-responsive manner in Mia PaCa-2 clone 3 and DLKP-M squamous lung carcinoma cells. Using immunoprecipitation and liquid chromatography-tandem mass spectrometry (LC-MS-MS) analysis, the target antigen of anti-invasive antibody, 7B7, was determined to be the heterodimeric Ku antigen, Ku70/80, a core protein composed of the Ku70 and Ku80 subunits which is involved in non-homologous end-joining (NHEJ) DNA repair. RNA interference-mediated knockdown of Ku70 and Ku80 resulted in a marked decrease in the invasive capacity of Mia PaCa-2 clone 3 and DLKP-M cells, indicating that Ku70/Ku80 is functionally involved in pancreatic and lung cancer invasion. Immunohistochemical analysis demonstrated Ku70/Ku80 immunoreactivity in 37 PDAC tumours, indicating that this heterodimer is highly expressed in this aggressive cancer type. This study demonstrates that a functional MAb screening approach coupled with immunoprecipitation/proteomic analyses can be successfully applied to identify functional anti-invasive MAbs and potential novel targets for therapeutic antibody targeting. |
| Starting Page | 6983 |
| Ending Page | 6997 |
| Page Count | 15 |
| File Format | |
| ISSN | 10104283 |
| Journal | Tumor Biology |
| Volume Number | 35 |
| Issue Number | 7 |
| e-ISSN | 14230380 |
| Language | English |
| Publisher | Springer Netherlands |
| Publisher Date | 2014-04-18 |
| Publisher Place | Dordrecht |
| Access Restriction | Subscribed |
| Subject Keyword | Monoclonal antibody Cancer metastasis Cancer invasion Ku70/Ku80 Target discovery Cancer Research |
| Content Type | Text |
| Resource Type | Article |
| Subject | Medicine Cancer Research |
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