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Updated: Jun 28, 2025
Discovery of Driver Genes in Colorectal HT29-derived Cancer Stem-Like Tumorspheres
Published on: July 22, 2020
New treatment alternatives for primary and metastatic colorectal cancer by an integrated transcriptome and network
Caner Karaca1, Ezgi Demir Karaman2, Asim Leblebici1
1Department of Translational Oncology, Institute of Health Sciences, Dokuz Eylul University, Izmir, Turkey.
Abstract:
Metastatic colorectal cancer (CRC) is still in need of effective treatments. This study applies a holistic approach to propose new targets for treatment of primary and liver metastatic CRC and investigates their therapeutic potential in-vitro. An integrative analysis of primary and metastatic CRC samples was implemented for alternative target and treatment proposals. Integrated microarray samples were grouped based on a co-expression network analysis. Significant gene modules correlated with primary CRC and metastatic phenotypes were identified. Network clustering and pathway enrichments were applied to gene modules to prioritize potential targets, which were shortlisted by independent validation. Finally, drug-target interaction search led to three agents for primary and liver metastatic CRC phenotypes. Hesperadin and BAY-1217389 suppress colony formation over a 14-day period, with Hesperadin showing additional efficacy in reducing cell viability within 48 h. As both candidates target the G2/M phase proteins NEK2 or TTK, we confirmed their anti-proliferative properties by Ki-67 staining. Hesperadinin particular arrested the cell cycle at the G2/M phase. IL-29A treatment reduced migration and invasion capacities of TGF-β induced metastatic cell lines. In addition, this anti-metastatic treatment attenuated TGF-β dependent mesenchymal transition. Network analysis suggests IL-29A induces the JAK/STAT pathway in a preventive manner.
Insights
This study identified novel therapeutic targets for colorectal cancer (CRC) and liver metastases. Hesperadin, BAY-1217389, and IL-29A show promise in preclinical models for treating metastatic CRC.
Area of Science:
- Oncology
- Molecular Biology
- Bioinformatics
Background:
- Metastatic colorectal cancer (CRC) lacks effective treatments.
- A holistic approach is needed to identify new therapeutic targets for primary and liver metastatic CRC.
Purpose of the Study:
- To propose novel therapeutic targets for primary and liver metastatic CRC.
- To investigate the in-vitro therapeutic potential of identified agents.
- To validate drug-target interactions for CRC treatment.
Main Methods:
- Integrative analysis of primary and metastatic CRC samples using microarray data.
- Co-expression network analysis to identify significant gene modules.
- Network clustering, pathway enrichment, and independent validation for target prioritization.
- Drug-target interaction search to identify potential therapeutic agents.
Main Results:
- Hesperadin and BAY-1217389 suppressed colony formation and reduced cell viability in CRC cells, targeting G2/M phase proteins NEK2 or TTK.
- Hesperadin induced G2/M phase cell cycle arrest.
- IL-29A reduced migration and invasion in TGF-β-induced metastatic cell lines, attenuating TGF-β-dependent epithelial-mesenchymal transition.
- Network analysis indicated IL-29A activates the JAK/STAT pathway.
Conclusions:
- Hesperadin, BAY-1217389, and IL-29A represent promising therapeutic candidates for metastatic colorectal cancer.
- These agents target key pathways involved in CRC proliferation and metastasis.
- Further investigation is warranted to explore their clinical efficacy.
