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Discoidin Domain Receptor Tyrosine Kinase 1 (DDR1) Is a Novel Therapeutic Target in Liposarcoma: A Tissue Microarray
Dylan C Dean1, Wenlong Feng1,2, Robert L Walker1
1Sarcoma Biology Laboratory, Department of Orthopaedics, Sylvester Comprehensive Cancer Center and the University of Miami Miller School of Medicine, Miami, FL, USA.
Background:
Liposarcoma is the most commonly diagnosed subtype of soft tissue sarcoma. As these tumors often arise near vital organs and neurovascular structures, complete resection can be challenging; consequently, recurrence rates are high. Additionally, available chemotherapeutic agents have shown limited benefit and substantial toxicities. There is, therefore, a clear and unmet need for novel therapeutics for liposarcoma. Discoidin domain receptor tyrosine kinase 1 (DDR1) is involved in adhesion, proliferation, differentiation, migration, and metastasis in several cancers. However, the expression and clinical importance of DDR1 in liposarcoma are unknown.
Questions/Purposes:
The purposes of this study were to assess (1) the expression, (2) the association between DDR1 and survival, and (3) the functional roles of DDR1 in liposarcoma.
Methods:
The correlation between DDR1 expression in tumor tissues and clinicopathological features and survival was assessed via immunohistochemical staining of a liposarcoma tissue microarray. It contained 53 samples from 42 patients with liposarcoma and 11 patients with lipoma. The association between DDR1 and survival in liposarcoma was analyzed by Kaplan-Meier plots and log-rank tests. The DDR1 knockout liposarcoma cell lines were generated by CRISPR-Cas9 technology. The DDR1-specific and highly selective DDR1 inhibitor 7RH was applied to determine the impact of DDR1 expression on liposarcoma cell growth and proliferation. In addition, the effect of DDR1 inhibition on liposarcoma growth was further accessed in a three-dimensional cell culture model to mimic DDR1 effects in vivo.
Results:
The results demonstrate elevated expression of DDR1 in all liposarcoma subtypes relative to benign lipomas. Specifically, high DDR1 expression was seen in 55% (23 of 42) of liposarcomas and no benign lipomas. However, DDR1 expression was not found to be associated with poor survival in patients with liposarcoma. DDR1 knockout or treatment of 7RH showed decreased liposarcoma cell growth and proliferation.
Conclusion:
DDR1 is aberrantly expressed in liposarcoma, and it contributes to several markers of oncogenesis in these tumors.
Clinical Relevance:
This work supports DDR1 as a promising therapeutic target in liposarcoma.
Insights
Discoidin domain receptor tyrosine kinase 1 (DDR1) is highly expressed in liposarcoma, driving cancer cell growth. Inhibiting DDR1 significantly reduces liposarcoma proliferation, highlighting its potential as a novel therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Liposarcoma, a common soft tissue sarcoma, presents challenges in surgical resection and has limited effective chemotherapy options.
- Discoidin domain receptor tyrosine kinase 1 (DDR1) plays a role in various cancers, but its significance in liposarcoma remains unexplored.
Purpose of the Study:
- To investigate DDR1 expression in liposarcoma.
- To determine the association between DDR1 and patient survival.
- To elucidate the functional role of DDR1 in liposarcoma oncogenesis.
Main Methods:
- Immunohistochemical staining of liposarcoma tissue microarrays to assess DDR1 expression.
- Kaplan-Meier analysis to correlate DDR1 expression with survival outcomes.
- CRISPR-Cas9 technology to generate DDR1 knockout cell lines and in vitro/3D cell culture models to evaluate DDR1 inhibition using a selective inhibitor (7RH).
Main Results:
- DDR1 expression was significantly elevated in liposarcoma tissues compared to benign lipomas.
- High DDR1 expression did not correlate with poorer patient survival.
- DDR1 knockout or inhibition with 7RH markedly reduced liposarcoma cell growth and proliferation.
Conclusions:
- Aberrant DDR1 expression is a feature of liposarcoma, contributing to oncogenic processes.
- DDR1 represents a promising therapeutic target for liposarcoma treatment.
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