Nemzeti Gyógyszerkutatási és Fejlesztési Laboratórium (PharmaLab)(RRF-2.3.1-21-2022-00015)
Támogató: NKFIH
(BO/00174/22)
(184018) Támogató: Tempus
The epithelial-to-mesenchymal transition (EMT) represents a hallmark event in the
evolution of lung cancer. This work aims to study a recently described EMT-regulating
protein, Tks4, and to explore its potential as a prognostic biomarker in non–small
cell lung cancer. In this study, we used CRISPR/Cas9 method to knockout (KO) Tks4
to study its functional roles in invadopodia formation, migration, and regulation
of EMT marker expressions and we identified Tks4-interacting proteins. Tks4-KO A549
cells exhibited an EMT-like phenotype characterized by elongated morphology and increased
expression of EMT markers. Furthermore, analyses of a large-scale lung cancer database
and a patient-derived tissue array data revealed that the Tks4 mRNA level was decreased
in more aggressive lung cancer stages. To understand the regulatory role of Tks4 in
lung cancer, we performed a Tks4-interactome analysis via Tks4 immunoprecipitation-mass
spectrometry on five different cell lines and identified CAPZA1 as a novel Tks4 partner
protein. Thus, we propose that the absence of Tks4 leads to disruption of a connectome
of multiple proteins and that the resulting undocking and likely mislocalization of
signaling molecules impairs actin cytoskeleton rearrangement and activates EMT-like
cell fate switches, both of which likely influence disease severity.
