title: Differential Tks5 isoform expression contributes to metastatic invasion of lung adenocarcinoma.
abstract: Metastasis accounts for the vast majority of cancer-related deaths, yet the molecular mechanisms that drive metastatic spread remain poorly understood. Here we report that Tks5, which has been linked to the formation of proteolytic cellular protrusions known as invadopodia, undergoes an isoform switch during metastatic progression in a genetically engineered mouse model of lung adenocarcinoma. Nonmetastatic primary tumor-derived cells predominantly expressed a short isoform, Tks5short, while metastatic primary tumor- and metastasis-derived cells acquired increased expression of the full-length isoform Tks5long. This elevation of Tks5long to Tks5short ratio correlated with a commensurate increase in invadopodia activity in metastatic cells compared with nonmetastatic cells. Further characterization of these isoforms by knockdown and overexpression experiments demonstrated that Tks5long promoted invadopodia in vitro and increased metastasis in transplant models and an autochthonous model of lung adenocarcinoma. Conversely, Tks5short decreased invadopodia stability and proteolysis, acting as a natural dominant-negative inhibitor to Tks5long. Importantly, high Tks5long and low Tks5short expressions in human lung adenocarcinomas correlated with metastatic disease and predicted worse survival of early stage patients. These data indicate that tipping the Tks5 isoform balance to a high Tks5long to Tks5short ratio promotes invadopodia-mediated invasion and metastasis.
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Carman Man-Chung
authors.initials: CM
authors.lastname: Li
authors.forename: Guoan
authors.initials: G
authors.lastname: Chen
authors.forename: Talya L
authors.initials: TL
authors.lastname: Dayton
authors.forename: Caroline
authors.initials: C
authors.lastname: Kim-Kiselak
authors.forename: Sebastian
authors.initials: S
authors.lastname: Hoersch
authors.forename: Charles A
authors.initials: CA
authors.lastname: Whittaker
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: David G
authors.initials: DG
authors.lastname: Beer
authors.forename: Monte M
authors.initials: MM
authors.lastname: Winslow
authors.forename: Tyler
authors.initials: T
authors.lastname: Jacks
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics*; D000230:Adenocarcinoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000818:Animals; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics; D028044:Phosphate-Binding Proteins; D010750:Phosphoproteins / Q000235:genetics*; D020033:Protein Isoforms; D016019:Survival Analysis
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C114235:Fish protein, mouse; D028044:Phosphate-Binding Proteins; D010750:Phosphoproteins; D020033:Protein Isoforms; C478582:SH3PXD2A protein, human
keywords: Tks5; invadopodia; lung adenocarcinoma; metastasis; mouse model; non-small-cell lung cancer