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Targeting TYRO3 inhibits epithelial-mesenchymal transition and increases drug sensitivity in colon cancer
1Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Abstract:
Colon cancer is the third leading cause of death from cancer worldwide with less than 10% survival rate at the late stage. Although mutations of certain genes have been implicated in familial colon cancer development, the etiology of the majority of colon cancer remains unknown. Herein, we identified TYRO3 as a potential oncogene. Immunohistochemical staining results demonstrated that levels of TYRO3 were markedly elevated in polyps and colon cancer cells and were negatively correlated with prognosis. Overexpression of TYRO3 enhanced cell motility, invasion, anchorage-independent growth and metastatic ability, while knockdown of TYRO3 impaired all these processes. Results from meta-analysis showed that TYRO3 was associated with epithelial-mesenchymal transition (EMT) signatures. Gain-of-function and loss-of-function experiments demonstrated that expression of SNAI1, the master regulator of EMT, was regulated by TYRO3 and played a major role in mediating TYRO3-induced EMT processes. The murine model also demonstrated that Tyro3 and Snai1 were upregulated in the early stage of colon cancer development. To provide a proof-of-concept that TYRO3 is a druggable target in colon cancer therapy, we raised anti-TYRO3 human antibodies and showed that treatment with the human antibody abolished TYRO3-induced EMT process. More importantly, administration of this anti-TYRO3 antibody increased drug sensitivity in primary cultured colon cancer cells and xenografted mouse tumors. These findings demonstrate that TYRO3 is a novel oncogene and a druggable target in colon cancer.
Insights
TYRO3 is identified as a novel oncogene driving colon cancer progression and metastasis. Targeting TYRO3 with antibodies shows promise in blocking epithelial-mesenchymal transition and enhancing drug sensitivity in colon cancer therapy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Colon cancer is a leading cause of cancer death globally, with poor survival rates in late stages.
- The genetic basis for most colon cancer cases remains largely unknown.
- Identifying novel oncogenes is crucial for developing effective colon cancer treatments.
Purpose of the Study:
- To investigate the role of TYRO3 in colon cancer development and progression.
- To explore TYRO3 as a potential therapeutic target for colon cancer.
- To elucidate the mechanism by which TYRO3 influences colon cancer cell behavior.
Main Methods:
- Immunohistochemical staining of TYRO3 in colon polyps and cancer tissues.
- In vitro experiments assessing cell motility, invasion, and anchorage-independent growth upon TYRO3 modulation (overexpression and knockdown).
- Meta-analysis to correlate TYRO3 with epithelial-mesenchymal transition (EMT) signatures.
- Murine models to study TYRO3 and SNAI1 expression in early colon cancer development.
- Development and testing of anti-TYRO3 human antibodies in vitro and in vivo.
Main Results:
- TYRO3 levels were significantly elevated in colon polyps and cancer, correlating negatively with prognosis.
- TYRO3 overexpression enhanced colon cancer cell motility, invasion, and metastasis, while knockdown impaired these processes.
- TYRO3 was found to regulate SNAI1, a key mediator of EMT, and was associated with EMT signatures.
- Anti-TYRO3 antibodies effectively blocked TYRO3-induced EMT and increased sensitivity to chemotherapy in colon cancer models.
Conclusions:
- TYRO3 functions as a novel oncogene in colon cancer, promoting cell motility, invasion, and metastasis.
- TYRO3-induced EMT is mediated through the regulation of SNAI1.
- TYRO3 represents a druggable target for colon cancer therapy, with anti-TYRO3 antibodies showing therapeutic potential.
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