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MIGRATION, INVASION AND METASTASIS
www.beatson.gla.ac.uk/laura_machesky
Cancer metastasis is a huge challenge for cancer research, as it
is often the main barrier to effective treatment. We aim to gain
insights into mechanisms of metastatic spread by determining
the roles of key actin cytoskeletal proteins, such as the actin
filament nucleation machinery and the bundling protein
fascin-1, in cancer cell invasive and migratory behaviour.
Group Leader
Laura
Machesky
FRSE
Research Scientists
Amelie Juin
Nikki Paul1
Karthic Swaminathan
Ben Tyrrell
Iben Veland2
Scientific Officer
Heather Spence
Clinical Research Fellows
Hayley Morris
Graduate Students
Loic Fort
Vasileios Papalazarou3
Emma Woodham
1
Pancreatic Cancer Research Fund
University of Copenhagen/
Danish Research Council
2
CRUK Glasgow Centre,
joint with Manuel Salmeron-Sanchez, University of Glasgow
3
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The actin cytoskeleton is important not only
for cell strength and migratory capacity but
also for adhesion-dependent survival,
membrane trafficking and establishment of
polarity. Additionally, it plays a key role in how a
cell interacts with and remodels the extracellular
environment. The extracellular matrix
contributes to the development and
homeostasis of organs and tissues, and in
tumours matrix and stroma provide key support
for growth, invasion and metastasis. We aim to
understand how various actin regulators control
interaction with matrix and how tumours
subvert both the actin cytoskeleton and the
surrounding tumour stroma to gain advantages.
Role of actin nucleating proteins in cell
migration, invasion and membrane trafficking
The Arp2/3 complex is the major inducer of
actin filaments in response to extracellular
signals. The Wiskott-Aldrich Syndrome protein
family (including WASP/N-WASP, Scar/WAVE,
WASH, WHAMM and JMY) transmit signals to
the Arp2/3 complex to trigger actin assembly.
Each of these proteins is regulated differently
and one of our aims is to understand the
mechanisms of regulation and the involvement
of these proteins in invasion and metastasis of
cancer as well as their normal cellular functions.
WASP family proteins regulate actin assembly in
multiple essential and pathological cellular
processes, such as endocytic trafficking,
protrusion of lamellipodia and filopodia, cell
division, and assembly of invasive structures
such as podosomes and invadopodia. Postdoc
Ben Tyrrell is studying the role of the WASH
protein complex in production of actin
networks on endocytic vesicles to regulate cell
signalling and motility in three-dimensional
matrix. Postdoc Iben Veland is funded by the
SCIENTIFIC REPORT 2015 CANCER RESEARCH UK BEATSON INSTITUTE
Danish Research Council to investigate the
role of WASH proteins and associated adapter
proteins in invasive migration, and delivery of
matrix metalloproteases and receptors into
invasive pseudopods. PhD student Loic Fort is
working in collaboration with Jose Batista in
Robert Insall’s group to discover new regulators
of the Scar/WAVE complex and determine
their role in migration and invasion.
Role of actin regulatory proteins in
colorectal and pancreatic cancers
N-WASP is established as a key driver of
formation of invadopodia and of cancer cell
invasion in vitro, but much less is known about
its potential role in vivo. This year, MRC-funded
clinical research fellow Hayley Morris continued
her study of N-WASP in colorectal cancer (in
collaboration with Owen Sansom). She finds a
role for N-WASP in the early conversion
between polyps and carcinoma. Postdoc
Amelie Juin is studying N-WASP in pancreatic
ductal adenocarcinoma (PDAC). High levels of
N-WASP have recently been correlated with
poor outcome in human patients with PDAC
(Guo et al, 2014) pointing to N-WASP as a
potentially interesting new target for this cancer.
We will determine whether the role of N-WASP
in invadopodia translates into differences in
tumour formation, progression and spread.
Thus far, we find a strong impact of N-WASP on
invasion and metastasis and are working to
discover the mechanisms by which the actin
cytoskeleton confers invasiveness and
metastatic capability to pancreatic cancer cells.
Student Loic Fort and Pancreatic Cancer
Research Fund postdoc Nikki Paul are studying
how fascin upregulation affects the initiation of
pancreatic cancer from the precursor lesions
Figure 1. Melanoblasts in mouse embryo skin are marked with dopachrome tautomerase (DCT, green) 2 . H&E staining of a mouse PDAC tumour showing regions Figure Figure
early tumours and track cells escaping from
intraepithelial
and BrDu (red) to i1ndicate proliferaBon. Nuclei are s(pancreatic
hown in blue (DAPI), revealing also neoplasia).
surrounding Nikki leads
Melanoblasts
in mouse
Of dense desmoplasBc stroma (pink staining, black arrows). Photo keraBnocytes in the developing skin. Photo credit: Eour
mma ongoing
Woodham efforts to develop
the tumours.
and
test fascin-1
embryo skin are marked with
Amelie Juin inhibitor compounds togetherCredit: with Martin
dopachrome tautomerase (DCT,
Role of extracellular matrix in migration
Drysdale’s Drug Discovery team. We continue
green) and BrDu (red) to indicate
and invasion of tumours
to explore the mechanisms by which fascin
proliferation. Nuclei are shown
in blue (DAPI), revealing also
PDACs contain a dense fibrous stroma rich in
contributes to invasiveness and metastatic
surrounding keratinocytes in the
collagen, fibronectin and other components
spread of pancreatic cancer.
developing skin. Photo credit:
(Fig. 2). This is thought to serve both as a barrier
Emma Woodham
Figure 2
H&E staining of a mouse PDAC
tumour showing regions
Of dense desmoplastic stroma
(pink staining, black arrows).
Photo Credit: Amelie Juin
Role of actin regulatory proteins in
melanoblast migration and melanoma
We previously showed that loss of Rac1 causes
major defects in melanoblast migration and
proliferation during development (Li et al, 2011).
We continue to investigate the roles of RhoA
and Cdc42 in melanoblasts (Fig. 1) with PhD
student Emma Woodham and postdoc Ben
Tyrrell, together with Cord Brakebusch (BRIC,
University of Copenhagen). Emma has found a
major role for Cdc42 in melanoblast migration
and proliferation and is currently working with
primary cultured melanocytes to unravel the
molecular mechanisms. Postdoc Karthic
Swaminathan studies the role of the major
actin nucleation promoting complex Scar/
WAVE in melanoblast migration and
melanoma metastasis. He and student Loic
Fort are also setting up a model to study
melanoma metastasis (in collaboration with
Jim Bear, University of North Carolina) where
we will use intravital imaging to view events in
to chemotherapeutic treatment and an inducer
of more aggressive behaviour of the tumour
cells. We have a new CRUK Glasgow Centrefunded PhD student, Vassilis Papalazorou,
co-supervised by Manuel Salmeron-Sanchez
(Engineering Department, University Glasgow),
to study how matrix stiffness and composition
affects tumour migration and invasion. Together
with postdoc Amelie Juin, we are studying the
mechanisms of matrix remodelling by cancer
associated fibroblasts as well as the effects of
this matrix on cancer cells using engineered
matrix with defined stiffness and composition.
Our goal is to better understand the crucial
properties of desmoplastic stroma so that
PDAC treatments can be improved in the future.
Publications listed on page 88
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MIGRATION, INVASION AND METASTASIS