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Title: Intracellular trafficking of cancer-implicated proteins in women's cancers
Author: Jung, Youngrock
ISNI:       0000 0004 9350 2957
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2018
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Cancers from breast and ovary account for around 20% of women’s death from malignant neoplasms in the UK. Although survival from cancer has been improved, about half of cancer patients are not able to survive for more than ten years. To the date, over 600 genes have been identified to be implicated in malignant transformation and these genes can be grouped into two broad classes: oncogenes and tumour suppressor genes. In addition to the genetic or epigenetic status of these genes, aberrant intracellular trafficking of these proteins is another contributing factor that also drives deregulation in cell homeostasis. In this Ph.D. study, the intracellular trafficking of two cancer-implicated proteins was investigated: the oncogenic protein membrane type-1 matrix metalloproteinase (MT1-MMP) in breast cancer and the tumour suppressor protein opioid-binding protein cell-adhesion molecule like (OPCML) in ovarian cancer. MT1-MMP is an essential regulator of cancer cell invasion and metastasis, which are the major cause of human cancer death. The proteolytic activity of MT1-MMP promotes cellular invasion and requires this protein to be localised to invasive membrane protrusions called invadopodia. Here, we have explored the role of Rab27a in MT1-MMP secretion in breast cancer cell line MDA-MB-231. Depletion of this Rab GTPase silenced the effects of MT1-MMP-dependent gelatin degradation and 3D collagen invasion. Furthermore, Rab27a was found to be associated with MT1-MMP exocytosis-related proteins, such as IQGAP-1 and Exo84. Finally, we also showed that the regulation of MT1-MMP trafficking by Rab27a was not in biosynthetic pathway but through MT1-MMP recycling to the plasma membrane. In conclusion, we suggest that Rab27a is a novel regulator of MT1-MMP recycling in breast cancer cells. High grade serous ovarian cancer (HGSC) remains the most lethal gynaecological cancer despite advances in surgery and chemotherapy. OPCML is a glycosyl phosphatidylinositol (GPI)-anchored protein and it is downregulated in many types of cancers, including HGSC, where 84% of cases show loss of OPCML expression. Previously, our group identified that OPCML negatively regulates a specific repertoire of receptor tyrosine kinases (RTKs) by interacting with the extracellular domains of the RTKs causing a reduction in cell growth, migration and invasion. However, it has been poorly understood whether this happens on the cell surface (where OPCML is localised) or in endocytic vesicles after the two proteins are internalised together. In this study, using an ovarian cancer cell line SKOV3, we have identified that OPCML is internalised via a caveolin-1-dependent pathway, where dynamin and cholesterol were also found to be important. After the uptake, Rab5 and Rab7 appeared to be involved in the trafficking of OPCML. We could also observe active recycling and degradation of OPCML after the endocytosis. Finally, we tested the effect of OPCML on RTK distribution and trafficking. The result showed that activated AXL redistributes to caveolin-1-positive structures from clathrin-associated membranes in the presence of OPCML.
Supervisor: Recchi, Chiara ; Gabra, Hani Sponsor: Kwanjeong Educational Foundation (Korea)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral