Download How a virus can orchestrate cancer

BIOMEDICAL
How a virus can
orchestrate cancer
Professor Martin Bisaillon investigates the intricate ways that viruses modify the genetic patterns
of the human cells they infect – and how this gives rise to a range of deadly cancers
What inspired your focus on the role of human
viruses in cancer?
Cancer is still a leading cause of death
worldwide. Like most individuals, I have lost
members of my family to this devastating
disease. After working for a decade on viral
and cellular enzymes, I decided to use my
knowledge and experience to try to improve
our comprehension of the molecular causes
of cancer. Every day is a very challenging,
exciting and humbling experience because I am
constantly learning new things.
We also recently provided the first
comprehensive portrait of global changes
in the RNA splicing signatures that occur
in both hepatitis B virus- and hepatitis C
virus-associated liver cancer. We identified
modifications in the alternative splicing
patterns of transcripts encoded by more than
2,500 genes, such as tumour suppressor genes,
transcription factors, splicing factors and
kinases. The results also reveal widespread
alternative splicing changes in liver cancer that
impact cell metabolism and proliferation in a
way that likely contributes to tumourigenesis.
Why is a multidisciplinary approach vital to
the success of your research?
The most satisfying part of my work is working
with the members of my research group.
Each is unique and brings different skills to
the group. Multidisciplinarity is crucial for the
success of our research. For instance, in the
Why is it so important to explore the links
between human viruses and cancer?
An estimated 15 per cent of all human cancers
worldwide may be attributed to viral infections,
representing a significant portion of the global
cancer burden.
THBV
NNoV
INTERNATIONAL INNOVATION
profilin
in HBV-­ass
(HCC). Heatmap representa
transcrip ts for RNA-­sequenc
samplsplicing
e s. The
Global profiling of alternative
heat map shows
event modifications in hepatitis
B virusfor HBV-­associated
associated hepatocellular carcinoma
HCC. Eac
tissue sample , and each line
(HCC). Heatmap representations of
isoform ratios for cellular
transcripts
event.
HBV-­a ssociated HCC
for RNA-sequencing data obtained
tis
comparative healthy tissues (N
from 377 tissue samples. The heat map
What are your most interesting discoveries
about the molecular mechanisms that viruses
use to induce cancer?
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1. Global
modifications
Establishing a link between a virus and
cancer is challenging due to the long delay
between infection and tumour development.
Many complex genetic changes must occur in
infected cells before cancer can develop. Our
recent studies are investigating some of the
changes that occur in order for a normal cell to
become cancerous.
We have recently demonstrated that viruses
can modify the alternative splicing of cellular
messenger ribonucleic acids (mRNAs).
Alternative splicing is a central mechanism of
genetic regulation which ultimately increases
both the variability and diversity of proteins,
by changing their composition through
differential choice of the exons to be included in
mature mRNAs.
Figure
shows the splicing levels of various
transcripts for HBC-associated HCC.
Each column represents the data
from one tissue sample, and each line
represents a specific alternate splicing
event. HBV-associated HCC tissues
(THBV) are shown in red, and the
comparative healthy tissues (NNoV) are
shown in green.
0 10 20 3 0 4 0 5 0 6 0 7 0 8 0 9 0 100
PSI
past few months, we have been using the
expertise of bio-informaticians to analyse
large-scale data, something that we have
never done before. All the members of
the lab are now getting training in this
fascinating field, and are seeking to apply the
notions to their respective research projects.
Can you summarise some of the most
significant findings from your previous
studies on viral enzymes and antivirals?
My laboratory has been actively involved
in the development of antivirals and/
or in the characterisation of known viral
inhibitors for the past decade. We have
used a variety of strategies and approaches
to understand how specific molecules
can inhibit the replication of viruses. For
instance, we demonstrated a completely
novel mechanism by which the broadspectrum antiviral nucleoside ribavirin can
inhibit virus replication. Using vaccinia virus
as a model, we showed that the antiviral can
directly serve as a substrate for an enzyme
which is involved in the synthesis of the
cap structure found at the 5’ ends of viral
mRNAs. Viral mRNAs capped with ribavirin
are not efficiently recognised by the cellular
translational apparatus, thereby inhibiting
virus replication.
Could you highlight the work of your
laboratory with high school and
college students, and explain how this
benefits both the students and your own
research group?
Our laboratory has always welcomed many
students from high schools and colleges to
provide them with an opportunity to work in
a research lab. This is a great opportunity for
us to show them how exciting science can be
and, hopefully, lead them to realise that they
can pursue a career in the field.
Our students frequently make a real
contribution to our lab. For example, the
work of two past high school students –
Sabrina Bouchard and Geneviève Larivée
– resulted in a publication last year where
they elucidated the mechanism of action
of an antiviral. Moreover, the presence of
these students in our lab provides a great
opportunity for our graduate students to
supervise them and share their knowledge
with them.
The molecular
mechanisms of viral cancers
Biochemistry researchers at the University of Sherbrooke,
Canada, are revealing the bases of essential viral and fungal
colonisation processes, with the aim of identifying targets for
combatting prevalent infectious diseases and the genetic damage
they induce
THE RELATIONSHIP BETWEEN a viral
infection and the development of cancer was
first discovered by the virologist Francis Peyton
Rous in 1911. Though it took decades for his
discovery to be formally recognised, it is now
widely accepted that viruses are responsible
for a significant percentage of human
cancers worldwide.
In most cases, whether or not a viral infection
will persist and lead to a particular kind of
cancer depends on environmental factors or an
intrinsically weak immune response, as well as
the nature of the virus itself. The Epstein-Barr
virus – the first virus to be characterised as
causing tumours in humans – is implicated in
many gastric cancer cases; in fact, the annual
burden is estimated at 80,000 new cases a
year. Other examples are the hepatitis B and
C viruses (HBV and HCV, respectively, which
are the leading causes of the most common
liver cancer), the Human T lymphotrophic virus
type 1, which is linked to T-cell leukaemia,
and strains of human papillomavirus (HPV),
now known to be responsible for most
cervical cancers.
HPV and hepatitis infections in particular are
at epidemic proportions globally, affecting
hundreds of millions of people. So as targets
for inhibiting the transmission of viruses are
discovered, vaccination can be seen as part
of standard healthcare practice to reduce the
likelihood that cancer will develop later in life.
Indeed, vaccinating young people against HPV
and HBV is now the norm in many countries.
EXPLORING PROTEIN INTERACTIONS
Professor Martin Bisaillon, head of the
biochemistry department in the medical and
health sciences faculty of the University of
Sherbrooke in Québec, conducts research
into the molecular mechanisms that drive
interactions between enzymes and their
ligands, paying particular attention to infectious
agents. To study these interactions, Bisaillon’s
laboratory employs a multidisciplinary
approach, using the proteins involved in the
creation and maturation of the messenger
RNAs (mRNAs) of viral and fungal organisms,
such as West Nile virus, HBV, HCV, vaccinia
virus, influenza virus and the Candida albicans
yeast, since their mRNAs undergo many
modifications during transcription before being
translated into enzymes.
As Bisaillon details, many viral mRNAs
undergo a number of co-transcriptional
modifications. Each modification involves many
proteins and a vast network of interactions. In
addition to exploring the enzymatic reactions
involved, Bisaillon’s team examines these
structural modifications, and investigates
the thermodynamics of the processes that
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MOLECULAR MECHANISMS USED BY VIRUSES TO
INDUCE CANCER
OBJECTIVES
• To understand the molecular mechanisms that
dictate the interactions between enzymes and
their ligands
• To explore the biochemical properties of infectious
agents that interact with RNA, metal ions and/
or nucleotides
• To discover how enzymatic activities essential for
viruses/yeast can be inhibited
• To understand how viruses cause cancer
KEY COLLABORATORS
Dr Brian Geiss, Colorado State University, USA
Dr Jean-Pierre Perreault, Université de
Sherbrooke, Canada
Dr Guy Boivin, Université Laval, Canada
FUNDING
Canadian Institutes of Health Research
Natural Sciences and Engineering Research Council
of Canada
Fonds de recherche du Québec – Santé
Centre de recherche du centre hospitalier universitaire
de Sherbrooke
Faculté de médecine et des sciences de la santé de
l’Université de Sherbrooke
CONTACT
Martin Bisaillon
Professor and Head of Biochemistry Department
Faculté de Médecine et des Sciences de la Santé
Université de Sherbrooke
Pavillon de Recherche Appliquée sur le Cancer (PRAC)
3201 Jean Mignault
Sherbrooke, Québec J1E 4K8
Canada
T +1 819 821 8000 ext. 75287
E [email protected]
http://bit.ly/1l9pLMO
MARTIN BISAILLON is an expert
in Biochemistry and viral enzymes.
He obtained a PhD in Microbiology
and Immunology at the Université
de Montréal in 1999. He then
completed his post-doctoral training at the SloanKettering Institute in New York City before directing a
research team in the pharmaceutical industry aimed
at developing antiviral agents. He is currently Chair
of the Biochemistry Department at the Université
de Sherbrooke.
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INTERNATIONAL INNOVATION
operate during mRNA synthesis
and maturation. From this work,
the researchers hope to identify a
means of inhibiting the enzymatic
activities of yeasts and viruses
towards the development of new
antifungal and antiviral therapies
to ward off infectious diseases.
Being able to inhibit essential viral
enzymatic activities is key to winning
the fight against persistent infections
THE ROLE OF VIRAL POLYMERASES
Viruses are now known to contain many
enzymes that carry out polymerase activity,
enabling the replication and transmission
of genetic information and the transcription
of viral genomes. Although divergent in size
and structure, they all catalyse the addition of
nucleotides on nucleic acids. However, viral
polymerases often assemble nucleotides
erroneously during polymerisation, which
leads to cumulative changes in the viral
genome and, consequently, antiviral resistance.
Bisaillon’s team undertakes precise kinetic
analyses to characterise how this happens at
the molecular level during the incorporation
of nucleotides, with a special emphasis on
what takes place when certain inhibitors are
added. For instance, one of their early studies
revealed the molecular basis of the inhibition
of HCV replication and proliferation by ribavirin,
a commercially-available antiviral drug,
showing that it interacts directly with the HCV
RNA polymerase.
More recently, the team has uncovered the
intricacies of the catalytic mechanisms used by
the hepatitis virus RNA polymerase, including
identifying the many amino acids involved
in the binding of cofactors, nucleotides and
proteins. Bisaillon now hopes to develop new
approaches for targeting these essential
functions, particularly in regard to the HCV RNA
polymerase and the human cytomegalovirus
(which is associated with herpes) DNA
polymerase, to inhibit their replication and thus
their burden of infection.
STUDIES OF THE VACCINIA AND WEST
NILE VIRUSES
Another strand of work in Bisaillon’s laboratory
concerns how the vaccinia virus and the
West Nile virus replicate upon infection.
The smallpox virus – variola – disfigured,
blinded and killed millions of people until its
eradication was announced in 1979 – during
the 20th Century alone, it is estimated that
the death toll from smallpox was anything
between 300 and 500 million. To date, smallpox
remains the only human infectious disease
that has been eradicated globally; variola
continues to be studied because of the risk
that residual samples may be weaponised for
bioterrorism purposes.
Vaccinia virus is closely related to variola –
indeed, vaccinia was the basis of the vaccine
for smallpox that successfully accomplished its
eradication. West Nile virus, on the other hand,
is a mosquito-borne infection that can lead to
encephalitis or meningitis. While Bisaillon’s
laboratory investigates the proteins of these
viruses to obtain greater understanding of how
the proteins interact with various ligands, they
also are evaluating the molecular bases that
determine elements such as the specificity
of the West Nile virus RNA polymerase for
nucleotides. So far, the team has identified
numerous nucleotide analogues that have
the ability to inhibit the West Nile virus RNA
helicase, paving the way for their future
application as antiviral agents.
VIRUS-INDUCED CANCER
Recently, Bisaillon has been exploring the
molecular mechanisms used by viruses to
induce cancer, in order to understand the
structural modifications they drive and the
thermodynamics of the reactions involved in
the process: “Five years ago, I would never
have imagined that I would be working on
cancer,” he reflects. “The amazing thing with
research is that you never know where it will
take you.”
Bisaillon’s recent work has led him to believe
that being able to inhibit essential viral
enzymatic activities is key to winning the fight
against persistent infections. He is confident
that his findings will contribute to future
successful therapies for cancers arising from
viral infection, and considers that they could
ultimately underpin direct remedial treatment
of tumours. “Certainly, we believe that our
recent results could eventually lead to the
development of novel biomarkers for the
detection of virus-induced cancer cells,” he
says. “We also envisage the use of molecular
tools to correct aberrant alternative splicing
events and/or to induce the expression
of therapeutic splice variants to ‘cure’
cancer cells.”