Invasion and Metastasis
Cell migration is fundamental to diverse aspects of the development and life of multicellular organisms. Angiogenesis, the immune system and neuritogenesis, to name but a few, all rely on the correct movement of cells to their destination in tissues in time and space.
During the progression of tumours, cells that were previously stationary re-acquire the ability to move through the adjacent tissue, a process known as cancer cell invasion. Cancer cell invasion often eventually leads to tumour cells entering the bloodstream (extravasation) and finally the colonisation of secondary tissues where metastatic secondary lesions of the primary tumour are formed.
We are aiming to understand the mechanisms that enable cells to move in a three dimensional tissue environment in health and especially during tumour progression. Work in our lab is currently funded by the Breast Cancer Now, North West Cancer Research Fund, the Wellcome Trust and the BBSRC.
Please find a describtion of our current projects in Reserach Interests 2 and 3.
Actin mediated receptor recycling and cancer cell invasion
Actin contributes to vesicular trafficking, acting as a molecular scaffold, providing force to deform membranes, facilitating vesicle abscission or propelling a vesicle through the cytoplasm and recent studies highlight important connections between the directed trafficking of receptors and the impact on cell migration and actin dynamics. A number of newly described actin nucleation promoting factors, such as the vesicle associated protein WASH, reveal unexpected roles of actin in membrane traffic and suggest that the cell dedicates a significant proportion of its regulation of actin dynamics to controlling trafficking. We are currently identifying the biological functions of vesicular actin in receptor trafficking. Our research can show that WASH mediated actin binding of receptors on endosomal membranes dictates their trafficking route towards recycling to the plasma membrane, away from ESCRT complex mediated receptor degradation pathways. This has important implications for receptor kinase driven tumors, like Her2 positive breast cancer, since the mechanism that recycles Her2 to the cell surface is pivotal for tumor progression and deregulated in drug resistance. We hope that by investigating WASH mediated receptor recycling we will find novel ways to target Her2 positive breast cancer.
Force in Migration: Mechanisms of invasive cell migration
As soon as normal tissue organization within a tumour breaks down cancer cells are thought to be able to migrate out by degrading the surrounding extracellular matrix or moving along channels in the tissue. Irrespective of the degradative ability, all cancer cells have to be able to migrate efficiently in a directional manner to complete the first step of the metastatic cascade -the invasion into surrounding tissues. Cell migration on a two-dimensional (2D) surface, mostly cell culture dishes, has been studied extensively and is driven by a well characterised mechanism involving basal adhesion sites called focal adhesions, actin driven protrusions called lamellipodia and actomyosin contractile forces. In contrast, the mechanisms of directional protrusive migration in drastically different three-dimensional (3D) tissue environments are not understood on a molecular level.
One of the major roadblocks to successful 3D matrix migration of cancer cells is the need to deform and move the nucleus forward when migrating in geometrically confined tissue with dense cross-linked extracellular matrix (ECM). For effective 3D matrix migration the outer nuclear membrane needs to be coupled to the cytoskeleton through a family of proteins called Nesprins. The n-terminal domains of Nesprins bind to the cytoskeleton whereas the c-terminal KASH domains bind SUN domain protein in the nuclear intramembrane space to transduce force into the nucleus and affect the nuclear cytoskeleton. Actomyosin based force transmission into the nucleus has been shown to affect both the expression profile of nuclear structural components, like lamin A/C and also to initiate oncogenic global changes in gene transcription though tension sensitive transcription factors like YAP/TAZ and Twist.
Nothing is known about how ECM-adhesion complexes regulate nucleo-cytoplasmic force coupling (NFC) in invasive cancer cell migration and how this affects cell migration in 3D environments. It is a central unanswered question in tumour cell biology, how interactions with tumour and normal tissue ECM are relayed into tension dependent signals that are required for invasion of cancer cells.
We are investigating the composition and function of 3D matrix adhesion sites in invasive cancer cells to decipher how nuclear force coupling drives invasive cell migration and metastatic cancer progression.
Wellcome Trust Four-year PhD Studentship 2016
WELLCOME TRUST (UK)
October 2016 - April 2021
Force in Migration: The Mechanism of Nuclear Force Coupling driven invasive cell migration
MEDICAL RESEARCH COUNCIL
February 2019 - September 2022
Bench fees for Mariah Nawwab Abdullah
ROYAL EMBASSY OF SAUDI ARABIA CULTURAL BUREAU IN LONDON (UK)
October 2017 - September 2020
Wellcome Trust Four-Year PhD Studentship with the Cellular and Molecular Physiology PhD Programme
WELLCOME TRUST (UK)
October 2014 - September 2018
Regulation of actin mediated endocytic recycling in invasive Her2 positive breast cancer
NORTH WEST CANCER RESEARCH INCORPORATING CLATTERBRIDGE CANCER RESEARCH (UK)
December 2014 - December 2017
Plasticity of epithelial cell boundaries governed by EGF and actin remodelling.
BIOTECHNOLOGY & BIOLOGICAL SCIENCE RESEARCH COUNCIL
November 2014 - October 2017
Stretching the supply routes: ErbB2 gene amplification and endocytic recycling in metastatic breast cancer
BREAST CANCER NOW (UK)
January 2015 - January 2019
In search of the pacemakers: Investigating the addiction of ErbB2/Her2 receptor tyrosine kinase expression levels on endocytic recycling
ROYAL SOCIETY (CHARITABLE)
March 2014 - March 2015