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Differential Tks5 isoform expression contributes to metastatic invasion of lung adenocarcinoma
Carman Man-Chung Li1, Guoan Chen, Talya L Dayton
1David H. Koch Institute for Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
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.
Insights
The Tks5 protein shifts from a short to a long isoform during lung cancer metastasis. This isoform switch promotes invadopodia formation, driving cancer spread and poorer patient survival.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Metastasis is the primary cause of cancer mortality, with underlying molecular mechanisms often unclear.
- Tks5 protein is implicated in invadopodia formation, crucial cellular structures for invasion.
- Understanding Tks5's role in metastasis is vital for developing targeted therapies.
Purpose of the Study:
- To investigate the role of Tks5 isoforms in lung adenocarcinoma metastasis.
- To determine how the balance between Tks5long and Tks5short isoforms affects invadopodia activity and metastatic potential.
- To assess the clinical relevance of Tks5 isoform expression in human lung cancer patients.
Main Methods:
- Utilized a genetically engineered mouse model of lung adenocarcinoma.
- Analyzed Tks5 isoform expression in nonmetastatic and metastatic cells.
- Performed knockdown and overexpression experiments to study isoform function.
- Correlated Tks5 isoform levels with patient survival data.
Main Results:
- A switch from Tks5short to Tks5long expression was observed during metastatic progression.
- Increased Tks5long/Tks5short ratio correlated with enhanced invadopodia activity and metastasis.
- Tks5long promoted invadopodia formation and increased metastasis in vivo.
- Tks5short acted as a dominant-negative inhibitor of Tks5long.
- High Tks5long and low Tks5short expression in human lung adenocarcinomas predicted worse survival.
Conclusions:
- The balance of Tks5 isoforms is a critical regulator of invadopodia-mediated invasion and metastasis.
- Tks5long promotes metastasis, while Tks5short inhibits it.
- Tks5 isoform switching represents a potential therapeutic target for lung adenocarcinoma.
