Biochimica et biophysica acta. Molecular basis of disease · 2024
Kinase library screening identifies IGF-1R as an oncogenic vulnerability in intrahepatic cholangiocarcinoma stem-like cells.
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Rattanasinchai Chotirat, Navasumrit Panida, Chornkrathok Chidchanok, Ruchirawat Mathuros
Аннотация
BACKGROUND: Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer of the peripheral bile ducts and is recognized by the abundance of cancer stem-like cells (CSCs) within the tumor mass. While CSC markers in iCCA are well-defined, the molecular vulnerabilities of this subpopulation remain elusive.
METHODS: The 96-well, three dimensional (3D) tumorsphere culture was adapted from a well-established CSC model, validated for CSC markers through gene expression analysis. Kinase library screening was then conducted to reveal potential oncogenic vulnerable pathways. RNA interference was utilized to stably silence the candidate gene in three iCCA cell lines and its impact on iCCA cell proliferation and tumorsphere formation efficiency (TFE) was evaluated.
RESULTS: Kinase inhibitor library screening identified the top 50 kinase inhibitors crucial for tumorsphere viability, with 11 inhibitors targeting the IGF-1R/PI3K/AKT axis. Further dose-dependent analysis of the top 'hit' inhibitors confirmed IGF-1R as the candidate molecule. Upon stably silencing of IGF-1R, all three iCCA cell lines exhibited decreased AKT activation, impeded proliferation and reduced TFE, indicating a decline in CSC subpopulations.
CONCLUSIONS: IGF-1R plays a critical role in maintaining iCCA-stem like cell populations.
GENERAL SIGNIFICANCE: Our data highlight the potential utility of IGF-1R as a prognostic marker of iCCA and a therapeutic target for eliminating its CSC subpopulation.
METHODS: The 96-well, three dimensional (3D) tumorsphere culture was adapted from a well-established CSC model, validated for CSC markers through gene expression analysis. Kinase library screening was then conducted to reveal potential oncogenic vulnerable pathways. RNA interference was utilized to stably silence the candidate gene in three iCCA cell lines and its impact on iCCA cell proliferation and tumorsphere formation efficiency (TFE) was evaluated.
RESULTS: Kinase inhibitor library screening identified the top 50 kinase inhibitors crucial for tumorsphere viability, with 11 inhibitors targeting the IGF-1R/PI3K/AKT axis. Further dose-dependent analysis of the top 'hit' inhibitors confirmed IGF-1R as the candidate molecule. Upon stably silencing of IGF-1R, all three iCCA cell lines exhibited decreased AKT activation, impeded proliferation and reduced TFE, indicating a decline in CSC subpopulations.
CONCLUSIONS: IGF-1R plays a critical role in maintaining iCCA-stem like cell populations.
GENERAL SIGNIFICANCE: Our data highlight the potential utility of IGF-1R as a prognostic marker of iCCA and a therapeutic target for eliminating its CSC subpopulation.