Researchers discover new molecular mechanism in promoting melanoma angiogenesis and metastasis
A research team at LKS Faculty of Medicine, The University of Hong Kong (HKUMed) has discovered a new molecular pathway to govern melanoma angiogenesis and metastasis. The findings provide new insights into how melanoma undergoes metastasis and progression through secretion of pro-angiogenic factor to induce angiogenesis that paves the way for new therapeutic opportunities. The research is published in Advanced Science [1].
Malignant melanoma is a highly aggressive cancer that causes more than 80% of all skin cancer deaths. The high mortality rate of melanoma is primarily attributed to late presentation, drug resistance and metastasis. Cutaneous melanoma is surgically curable in the early stages, with survival rates of up to 98%, but may drop to 27% once it undergoes metastasis based on the statistics provided by the American Cancer Society. This transition involves activation of oncogenes expression to promote secretion of pro-angiogenic factors for blood vessel recruitment in a process called angiogenesis that increases metastatic propensity. Although current treatments in targeting a well-known pro-angiogenic factor VEGF and its receptor have shown notable antitumour potential, acquired drug resistance compromises their efficacy. In addition, melanoma tumours are highly heterogeneous with subpopulations of cells expressing other pro-angiogenic factors which contribute to melanoma angiogenesis and metastasis, highlighting the importance in identifying new regulators of angiogenesis to provide alternative therapeutic targets for metastatic melanoma.
Using melanoma cell lines and the mouse model for in vivo tumour and metastasis assays, the research team found that increased expression of an oncogene DEPDC1B in cutaneous melanoma was significantly associated with poor patient survival and positively correlated with a well-known oncogenic driver SOX10 in melanoma growth and metastasis. Consistently, DEPDC1B functions as a direct downstream target of SOX10 to partly mediate its oncogenic activity. The DEPDC1B-mediated enhancement of melanoma metastatic potential is acquired through secretion of pro-angiogenic factor SCUBE3, which is crucial for promoting angiogenesis. Mechanisitically, DEPDC1B regulates SCUBE3 protein stability through the competitive association with ubiquitin ligase CDC16 to prevent SCUBE3 from undergoing degradation. Importantly, expression of SOX10, DEPDC1B, and SCUBE3 are positively correlated with microvessel density in the advanced stage of melanomas. Altogether, the research findings revealed a new SOX10-DEPDC1B-SCUBE3 regulatory axis that promotes melanoma angiogenesis and facilitates its metastatic progression, suggesting the possibility of targeting secreted SCUBE3 as a therapeutic strategy against metastatic melanoma.
The research team has unravelled a new oncogenic mechanism by which DEPDC1B functions downstream of SOX10 to promote melanoma angiogenesis and metastasis. DEPDC1B competitively interacts with CDC16 in the cytosol to block the ubiquitination and degradation of SCUBE3, enabling stabilised SCUBE3 to be secreted from melanoma cells for blood vessel recruitment to facilitate melanoma growth, survival and metastasis.
Significance of the study
“Our findings underlie the possibility of using both DEPDC1B and SCUBE3 to serve as diagnostic and prognostic markers to improve the clinical assessment of patients with suspected malignant melanomas. Since secreted SCUBE3 is druggable, it is possible to generate SCUBE3 neutralising antibody for the early intervention of melanoma growth, angiogenesis and metastasis. Considering DEPDC1B is oncogenic in other cancer types, our studies have broader implications of DEPDC1B involved in stabilisation of other secreted factors to promote angiogenesis and metastasis in other tumour types,” said Dr Martin Cheung Chi-hang, Associate Professor, School of Biomedical Sciences, HKUMed, also the lead researcher of the study.
Reference
[1] Feng Hu, Ki On Fong, May Pui Lai Cheung, et. al. DEPDC1B Promotes Melanoma Angiogenesis and Metastasis through Sequestration of Ubiquitin Ligase CDC16 to Stabilize Secreted SCUBE3. Advanced Science Vol 9, Iss 10. doi: https://doi.org/10.1002/advs.202105226
