Dr Elena Rainero
Room: B2-04 Florey building
Brief career history
Extracellular matrix internalisation in breast cancer invasion
The extracellular matrix (ECM) is a complex network of secreted proteins which not only provides tissue support, but is also involved in the control of several cell functions, including migration and oncogenic transformation. The tumour microenvironment has a pivotal role in modulating cancer initiation, progression and metastasis, while cancer cells in turn modify the composition and properties of the ECM, demonstrating a bi-directional interaction between tumour and stroma. Our research addresses cell-ECM interaction from a novel and exciting angle, investigating how the internalisation of ECM components control breast cancer cell invasion.
Using a combination of different approaches, we aim at characterising how ECM internalisation controls cancer cell migration and invasion in 2 dimensions (2D), 3 dimensions (3D) and in vivo systems.
Extracellular matrix internalisation in epithelial remodelling
Most of our organs are built from epithelial cells. They are supported extracellularly by a complex network of secreted proteins collectively known as extracellular matrix (ECM). The ECM is commonly viewed as “dead space” that provides a static scaffold for organ shape and acts as an obstacle for migrating cells. However, new data strengthen the idea that there is a dynamic interplay between cells and the ECM, which actively orchestrates how cells and organs acquire their shape. Therefore, a better understanding of how cells dynamically remodel their ECM environment and how the cell-ECM interplay contributes to epithelial remodelling will shed new light on fundamental mechanisms underlying the shaping of organs.
The mammary gland has a tree-like structure, whereby a single monolayer of epithelial cells surrounds the lumen of the ducts. The formation of new branches, or branching morphogenesis, is controlled by hormones and growth factors, including Hepatocyte Growth Factor (HGF). Moreover, the extracellular matrix (ECM) has been shown to have a key role in this process. Our data indicate that, upon HGF stimulation of normal mammary epithelial cells (MECs), tubule formation is associated with ECM remodelling and uptake, suggesting that ECM endocytosis might contribute to branching morphogenesis.
We aim at characterising the endocytic pathway(s) responsible for ECM uptake, focusing on the integrin family of ECM receptors, and assessing the contribution of ECM uptake to branching morphogenesis in 3D environments
Undergraduate and postgraduate taught modules
Postgraduate PhD studentship
Supervisor: Dr Elena Rainero
Funding status: Competition funded project European/UK students only
This project is eligible for a department scholarship. These scholarships are awarded on a competitive basis – find out more on our funding webpage.
This project is also open to self funded students
This project focuses on the interaction between cancer cells and the tumour microenvironment, analysing the role of the extracellular matrix (ECM) modifying enzyme ADAMTS5 in ovarian cancer cell invasive migration. In particular, we will dissect how ADAMTS5 protein is upregulated in ovarian cancer cells and the molecular mechanisms through which the cleavage of the ADAMTS5 substrate versican promotes cancer cell invasion. Ovarian cancer is the most lethal gynaecological malignancy.
Mostly because of late stage diagnosis, the 5-year survival rate is <30%. The major cause of death is associated with the presence of therapy-resistant metastasis. Given the fact that >70% of ovarian cancers are diagnosed at late stage, it is essential to understand what the molecular mechanisms controlling metastasis formation are in order to develop novel strategies for the maintenance of this deadly disease. The tumour microenvironment, including the ECM, has a pivotal role in modulating cancer initiation, progression and metastasis. In particular, Versican (VCAN), a proteoglycan of the lectican family, has been shown to be upregulated in brain tumours, melanomas, osteosarcomas, lymphomas, breast, prostate, colon, lung, pancreatic, endometrial, oral and ovarian cancers and high VCAN expression correlates with reduced overall survival in ovarian cancer patients. VCAN is cleaved by a family of zinc-dependent metalloproteases, A Disintegrin And Metalloproteinase Domain with TromboSpondin type I module (ADAMTS), composed of 19 members of secreted proteases, including ADAMTS5. ADAMTS5 has been shown to increase cell invasive potential in glioblastoma, lung cancer, colon cancer and laryngeal cancer cells. Vesicular trafficking is essential for the polarised distribution of transmembrane receptors and secreted molecules and it is controlled by Rabs, small GTPases of the Ras family.
It is not surprising that alterations in Rab expression and function have been associated with cancer. In particular, epithelial specific Rab25, a member of the Rab11 family, has been shown to promote ovarian cancer cell migration and invasion. Consistent with this, high Rab25 expression correlates with poor prognosis in ovarian cancer. Preliminary data from the lab indicate that Rab25 induces ADAMTS5 expression, and the catalytic activity of ADAMTS5 is required for Rab25-induced cancer cell migration and invasion through 3D environments.
Therefore, we hypothesise that Rab25-expressing ovarian cancer cells upregulate ADAMTS5 expression when in contact with fibroblast-generated ECM. This in turn stimulates their migratory and invasive ability, eventually promoting metastasis formation. This project specifically aims at answering the following questions:
Despite the incidence and mortality of ovarian cancer, the mechanisms controlling metastasis are not fully understood. The outcome of this project will deepen our understanding of the interplay between cancer cells and the ECM, highlighting whether ADAMTS5 can represent a novel target for the development of new ovarian cancer therapies.
Keywords: Cancer / Oncology, Cell Biology / Development
For informal enquiries about the project or application process, please feel free to contact me.
To find out more about this project and how to apply see our PhD opportunities page:
- Rainero E (2016) Extracellular matrix endocytosis in controlling matrix turnover and beyond: emerging roles in cancer. Biochemical Society Transactions, 44(5), 1347-1354. View this article in WRRO
- Rainero E, Howe JD, Caswell PT, Jamieson NB, Anderson K, Critchley DR, Machesky L & Norman JC (2015) Ligand-Occupied Integrin Internalization Links Nutrient Signaling to Invasive Migration. Cell Reports, 10(3), 398-413. View this article in WRRO
- Christoforides C, Rainero E, Brown KK, Norman JC & Toker A (2012) PKD Controls αvβ3 Integrin Recycling and Tumor Cell Invasive Migration through Its Substrate Rabaptin-5. Developmental Cell, 23(3), 560-572.
- Rainero E, Caswell PT, Muller PAJ, Grindlay J, McCaffrey MW, Zhang Q, Wakelam MJO, Vousden KH, Graziani A & Norman JC (2012) Diacylglycerol kinase α controls RCP-dependent integrin trafficking to promote invasive migration. The Journal of Cell Biology, 196(2), 277-295. View this article in WRRO
- Dornier E, Rabas N, Mitchell L, Novo D, Dhayade S, McKay G, Sumpton D, Pallares M, Nixon C, Blyth K, Macpherson I, Rainero E & Norman JC () Glutaminolysis drives membrane trafficking to promote cancer invasion. Nature Communications. View this article in WRRO