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DESCRIPTION OF PROJECTS.
The projects summarized below will allow the trainees to translate the skills of the Training
Program and to develop a thorough knowledge in basic, clinical and translational research. The
proposed topics include advanced imaging in disease and novel technology developments,
patient-based translational research through novel technologies and unique resources, functional
genomics, genetics, basic cancer research, apoptosis and new treatments, and developmental
biology. There is ample room for creativity and innovation, especially in the development of
novel technologies, software, bio-markers, and possible treatment protocols. All approaches are
unique in that they tackle current challenges in health sciences through innovative methods and
complement them with the strong expertise of each mentor in a transdisciplinary manner.
Projects that involve foreign mentors will be rotations or short- vs. long-term projects that are
carried out in collaboration with Canadian mentors. The Program Coordination Committee will
assure the best possible training environment for the trainees in the program.
1. Advanced molecular imaging.
Mechanisms of disease: Imaging in disease and new technology developments.
a) Infrared spectroscopy and spectral imaging in Alzheimer’s disease. K. Gough.
Trainees will be involved in the application of vibrational spectroscopic imaging of the
molecular compositions of normal and diseased tissue. They will gain knowledge in the analysis
of focal collagen distribution in cardiac tissue and will evaluate the effects of diet on collagen in
bone healing following spinal surgery and on glomeruli in stroke-prone mouse kidney. They will
develop skills in mapping of molecular changes that occur in human autopsy brain tissue of
Alzheimer's patients using FTIR and Raman spectromicroscopy. They will visualize abnormal
B-sheet protein distribution in transgenic mouse models for Alzheimer's disease. In addition,
spectral and infrared imaging will be utilized in comparison in tissue analysis for the first time
(in collaboration with S. Mai).
b) Structural and functional genomics in three dimensions, high resolution methods,
nonoscale electrophoresis and molecule detection, and nano-articles. Y. Garini
Modern research is an interdisciplinary science that either tries to explain biological phenomena
with physical models, develop novel physical tools for biological studies or both. We are
exploring novel Bio-physics electro-optical and imaging methods and its utilization in subcellular biology and genetics. We develop methods that are based on nano structures, near-field
and far-field optical microscopy, scanning probe microscopy and digital imaging. The projects
we work on include:
Structural and functional genomics: By using DNA probes and microscopy-based methods,
we explore the structure of the nucleus and the organization of the genome. Working in
collaboration with Sabine Mai we showed the telomeres change their 3D organization along the
cell-cycle and that c-Myc possesses the ability to reorganize the genetic information. As part of
this project, we have developed a unique analysis package for 3D telomere probes.
Developing a novel high-resolution method: By using metal structures with periodic patterns,
it is possible to achieve optical features that are smaller than the conventional diffraction limit.
We explore the near-field characteristics of nano-structures and develop a mid-field microscope
that will allow high-resolution measurements of biological samples.
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Nanoscale Electrophoresis and single molecule detection: We develop a new electrophoresis
fluidic chip for detecting and manipulating single molecules. We use quantitative imaging and
numerical flow simulation to analyze the electroosmotic flow in two-dimensional nanofluidic
device.
DNA - Protein interaction method by using metal nano-particles: The study of DNA-proteins
interactions is important for cellular processes. We develop a novel tool based on tethered
particle motion and metallic nano-beads. The method will allow the study of DNA-protein
interactions.
c) Three-dimensional nuclear imaging of telomeres, centromeres and chromosomes in normal
and tumor cells. S. Mai
Using three-dimensional (3D) imaging, trainees will examine the positions of telomeres,
centromeres and chromosomes in nuclei of normal and tumor cells. Trainees will learn how to
prepare cells and tissues for 3D imaging, and how to perform fluorescent in situ hybridization
(FISH) followed by 3D imaging and analysis. Trainees will focus on nuclear remodeling, the
underlying mechanisms and investigate the impact of nuclear remodeling on cellular
transformation. Short-term, long-term and workshop experience in this field are offered to
interested applicants.
Previous data suggest a cell-cycle-dependent and cell type-specific movement of telomeres and
centromeres. Moreover, the organization of the telomeres in nuclei of tumor cells is different
from that in normal cells. Recent data show that centromeres are significantly altered during
cellular transformation of mouse lymphocytes. The movement of chromosomes is under
investigation. It appears that they can alter their positions in response to oncogene-activation.
The study models include primary B cells, primary fibroblasts, mouse plasmacytoma, human
Burkitt's lymphoma, Hodgkin’s lymphoma, colon carcinoma, colon carcinoma, and breast
cancer. This work is done in collaboration with Yuval Garini (Bar-Ilan University), Dr. William
Foulkes (McGill University) and Dr. Hans Knecht (University of Shrebrooke).
2. Patient-based translational research through novel technologies and unique resources.
a1) Genomic analysis of prostate cancer preneoplasia and current chromosomal
rearrangements. J. Squire
The extraordinary advances in human genome research coupled with the recent progresses in the
use of high resolution microarrays, which permits the simultaneous study of DNA alterations of
several thousands of genes in one experiment, now allow us to use genomics and in silico tools
to study the genetic basis of cancer origin and progression. In this project, we are using
oligonucleotide array CGH (Agilent platform) to study a large collection of retrospective and
prospective prostate cancer tumour samples, and correlate these findings with tumor stage,
response treatment and to overall patient survival. Our recent progress has centered on the
discovery that ~50% of prostate cancer tumors have tiny genomic deletions affecting the PTEN
gene (Yoshimoto et al 2007). The long term goal of this project is to understand the genomic
mechanisms implicated in tumor origin, progression and treatment response in prostate cancer.
Trainees will learn how to perform array CGH analyses (depending of rotation or project) and
will be shown how to use interphase FISH to study tissue microarrays. Training will take place
in Toronto.
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a2) Array CGH analysis and the study of genomic instability in osteosarcoma. J. Squire
This research laboratory uses array comparative genomic hybridization (CGH) screening
methods and fluorescence in situ hybridization (FISH) to search for genetic and chromosomal
changes in the bone tumour osteosarcoma that are associated with disease onset or poor response
to treatment. We have developed molecular approaches to studying the degree of chromosomal
instability in this tumour and are studying potential molecular mechanisms that are causative role
for such changes and for variable diseade outcome. Much of our research involves the use of
patient tumours rather than laboratory cell lines so that findings will be directly applicable in
diagnosing and treating cancer in the clinic.Trainees will learn how to perform array CGH
analyses and will be shown how to use the contemporary in silico genomics tools to analyze their
data. Training will take place in Toronto.
b) Defining molecular markers to improve diagnosis and disease management in breast
cancer using tumor bank resources including the Manitoba Breast Tumor Bank.
P. Watson on leave of absence from the Manitoba Institute of Cell Biology.
Rotations, short-term and large-scale projects are possible in the study of the biology of
preinvasive breast disease and the mechanism of development of the invasive phenotype. Our
current understanding of this critical early stage in the process of progression towards lethal
metastasis is limited. We have developed the capability to address this critical problem from a
novel perspective through combined microdissection and molecular approaches applied to the
unique tissue format of the NCIC-Manitoba Breast Tumor Bank, to conduct direct comparisons
of gene expression in human preinvasive and invasive cell populations within the same tissue
specimen. We have identified for the first time several novel or previously unexplored genes,
expressed in early preinvasive stages of breast tumors including lumican, psoriasin, and with
collaborators the carbonic anhydrases, which have potential as clinical markers of risk in preinvasive in-situ breast cancer. Trainees will be involved in the development of clinically relevant
markers that will improve the current diagnosis and management of breast cancer.
c) Mechanisms of lung cancer progression and drug resistance in Non-Hodgkin's Lymphoma.
M. Mowat. The proposed project can be either short-term (rotations or small-scale projects) or
long-term. 1) Roles of p53 and Blc-6 and p14ARF in drug resistance in non-Hodgkin's
Lymphoma. Our earlier work had shown a correlation of p53 over expression with lack of
response to chemotherapy or early relapse in NHL. Multi-color FISH will be performed on
patient material to determine if loss of heterozygosity of the p53 and ARF or translocation of
Bcl-6 genes is predictive of response to CHOP chemotherapy.
d) Oncogenes in cellular transformation, cell cycle and apoptosis. T. Fest.
Only people with a good background on B-cell immunology and/or B-cell tumors will be
considered in this program.
Naïve B cells that leave the bone marrow carry functional BCR that may bind an antigen, in a Tcell-dependant immune response, leading to a strong B-cell activation. These later undergo
clonal expansion after selection in structures called germinal centers (GC) where
immunoglobulins are modified by class-switch recombination and somatic hypermutation. One
of the main recent emerging concepts is that the GC B-cell transition represents a pivotal stage in
the pathogenesis of lymphomas. The dual function of cell proliferation and apoptosis in the
context of this GC reaction represents an interesting event that will be studied in B cells as well
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Appendix: PROPOSED PROJECTS
as in some cells that constitute the microenvironment. Specific stroma cells called follicular
dendritic cells support B-cell proliferation implicating bidirectionnel interactions between the B
cells and the microenvironnment, which induce high numbers of modifications in multiple
signaling pathways. c-Myc protooncogene seems to play an important role in the physiological
context and obviously in tumorigenesis. In addition, genomic instability may easily be promoted
during the GC reaction sustaining tumor promotion. Standard karyotypes, spectral karyotyping
and FISH will be performed in this study in order to analyze genomic instability. Apoptosis will
be explored through different techniques including morphological and molecular evaluation.
Moreover, cell cycle checkpoints and the DNA repair machinery will be analyzed, and
microarrays will be utilized to explore different cell compartments involved in the germinal
center reaction.Trainees will be involved in a variety of modern technologies used in research
into cell cycle regulation, DNA repair, oncogenesis, and apoptosis. Trainees will carry out
projects in France and Canada, based on the unique resources in the laboratories of the mentors
and on the directions established by the Program Coordination Committee.
3. Functional Genomics.
Functional genomics. G. Hicks. The proposed projects allow all levels of training (rotations,
small scale, large-scale and exchange programs). 1) Embryonic stem cell mediated mutagenesis.
Using tagged sequence mutagenesis, we have begun to generate an ES cell resource library
where every gene in the mouse ES cell genome will be disrupted. Through random insertion of
the gene trap vector into the genome, genes are both tagged and invariably mutated. Advanced
technologies used in this program include embryonic stem cell culture and manipulation, large
scale genomics applications and bioinformatics. Scientific areas of expertise encompass
transgenic and micro-injection and manipulation of the mouse genome. Training opportunities
are available for interested trainees. 2) Genetic Modeling of Disease. Current disease modeling
encompasses cancer, cardio-vascular, neuro-degenerative, genetic disease syndromes and
musculo-skeletal diseases. Advanced technologies used in this program include the development
of transgenic mice by both nuclear and blastocyst injections, random and targeted mutagenesis,
cryo-preservation of sperm and embryos and ethical approaches to animal husbandry. Scientific
areas of expertise encompass the development of transgenic technologies, disease modeling in
mice, and the pathophysiology of analyzing animal phenotypes.
4. Basic cancer research
a) Cellular transformation and histone modification. J. Davie. Rotation projects and/or projects
will be offered. Four projects are proposed. 1) Histone H3 phosphorylation and oncogenemediated cellular transformation. The activation of Ras-mitogen activated protein kinase
(MAPK) pathway by oncoproteins results in the phosphorylation of histone H3, which results in
the chromatin remodeling and expression of a specific subset of genes. Dr. Davie’s laboratory
has identified the MSK1 kinase as the responsible kinase for the interphase H3 phosphorylation.
Trainees will be involved in the determination of the subcellular location of phosphorylated
histone H3 using deconvolution microscopy. They will also acquire knowledge about chromatin
remodeling that has led to new strategies of therapies and treatment in leukemias and other
cancers. 2) Dynamic histone acetylation and transcriptionally active chromatin. Transcribed
chromatin is bound to the nuclear matrix and associated with dynamically acetylated histones.
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The histone acetyltransferase associated with the matrix include CBP, PCAF and SRC-1. Histone
deacetylases 1, 2, and 3 but not 4 are nuclear matrix bound. Trainees will be involved in
determining whether the bound enzymes catalyze the dynamic acetylation of transcribed genes
and mediate a dynamic attachment of transcribed chromatin with the nuclear matrix. Other
possible project include; 3) Estrogen receptor: nuclear matrix acceptors in human breast cancer,
and 4) Isolation of estrogen-responsive genes in human breast cancer cells.
b) Molecular mechanisms of hormone dependence and progression in human breast cancer.
L. Murphy. Three projects are proposed for the Training Program. 1) The role of estrogen
receptor beta and its variant isoforms in both normal and neoplastic breast tissue. Trainees will
address the hypothesis that estrogen receptor-beta (ER) and/or its variants modulate
ERactivity, either directly or indirectly, and alteration of the relative activities of the two
estrogen receptor families is involved in the altered estrogen signal transduction that occurs
during human breast tumorigenesis and breast cancer progression. One specific hypothesis
addressed in this aspect of my research is that ER-beta and its variant isoforms may have a role
in regulating the mitotic apparatus in target cells. Since these receptor proteins are altered in
expression during breast tumorigenesis and possibly breast cancer progression, it is possible they
have a role in the development of aneuploidy and genetic instability. The level of aneuploidy as
determined by FISH analysis using centromeric probes for chromosome 1, 7, 8, 16 and 17, is an
absolute requirement for addressing this hypothesis, and depending on the results more specific
information about chromosomal structure will be required. A high level of collaboration with the
Genomic Centre for Cancer Research and Diagnosis is essential to this aspect. 2) Mechanisms of
Hormone Independence in Human Breast Cancer: Beyond the Estrogen Receptor - Cogs,
Wheels, Kinases and their Role in Hormone Independence. Trainees will be involved in
understanding how one attempts to elucidate mechanisms responsible for altered estrogen action
that occurs during breast tumorigenesis and the progression of invasive human breast cancer
from a hormone dependent to a hormone independent phenotype with the accompanying
development of resistance to endocrine therapies. They will addresses the hypothesis that altered
expression of estrogen receptor (ER) coregulators and altered expression of pathways involving
MAP kinase activation have a role in altered estrogen action that occurs during breast
tumorigenesis and the progression of invasive breast cancer from hormone dependence to
independence and the development of endocrine resistance. 3) Refined Molecular Profiling and
Stratification to Determine Cancer Risk and Prognosis of Human Breast Lesions. Alteration of
genes is known to be the underlying molecular basis for all disease including cancer. Recently
several technologies to determine many altered genes in small, well defined human biopsy tissue
samples have been developed which ultimately will allow the achievement of the goal of
classifying breast cancer and breast lesions accurately at the individual patient level. Using DNA
microarray hybridization units and scanners, real-time PCR equipment, laser capture
microdissecting, trainees will learn how to analyze high throughput gene expression of multiple
human breast tissue samples to achieve gene expression profiling of human breast lesions. The
collaboration with the GCCRD, will allow us to significantly increase and expand the nature of
our molecular profiling analyses of tissue samples, and enhance training opportunities.
c) Functional anlysis of TLS in genomic instability and DNA repair: G. Hicks. TLS (also
known as FUS) is translocated with the gene encoding the transcription factor ERG-1 in human
myeloid leukemia. Loss of TLS results in wide spread genomic instability. The involvement of a
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Appendix: PROPOSED PROJECTS
nuclear riboprotein in these processes is unprecedented and suggests a novel activity for TLS that
is required for genome maintenance. We rationalized that identifying the type of genomic
instability present in these TLS-/- mice will allow one to understand the function of the normal
TLS protein, and by extension, how the loss of this activity contributes to the transformation
process. Advanced technologies used in this program include molecular cytogenetics, confocal
and real-time subcellular imaging, and genetic manipulation of the genome. Scientific areas of
expertise encompass molecular genetics, mechanisms of DNA repair and cancer biology.
Training opportunities are available for trainees of the proposed program (short or long-term
projects, rotations and exchange programs).
d) Genomic instability and c-Myc. S. Mai. Each proposed project can be designed such that it
is applicable for short-term (and rotation) or for long-term projects as well as for exchange
projects. 1) c-Myc-dependent changes in replication initiation. c-Myc deregulation alters the
usual replication patterns found in cells and contributes to the initiation of genomic instability.
The analysis of affected loci will allow us to design a map of susceptible loci that contribute to
the onset of genomic instability and neoplasia. Trainees will be involved in the analysis of
specific loci that undergo changes in replication patterns. They will learn which controls to use
and how to determine replication patterns and their alterations. They will become familiar with
methods of modern molecular cytogenetics and molecular biology; they will use in vivo
replication studies and identify c-Myc-dependent changes. 2) Genomic instability in
experimental tumorigenesis. In appropriate mouse models, trainees will examine the onset and
progression of tumorigenesis. Three mouse models are currently explored in the laboratory.
Trainees will learn how to study the development of these tumors with a focus on the earliest
genetic changes that occur during tumor initiation. Focus is on c-Myc-dependent tumor
development. 3) Three-dimensional organization of the nucleus in normal and tumor cells.
Trainees will learn the applications of 3D imaging to understand the principles of nuclear
organization of chromosomes, centromeres and telomeres. We offer appropriate cell models for
this study (for details see 1.c)).
e1) Role of relaxin on breast cancer tumor growth and invasiveness. S. Hombach-Klonisch.
RESEARCH HYPOTHESIS: Relaxin acts as a novel morpho-functional regulator of cytoskeletal
and associated systems leading to altered cell movement and cell polarity in breast cancer cells.
This action depends on the presence of estrogen receptors (ER).
The in-vitro studies include the establishment of stable Relaxin over-expressing transfectants of
ERα-negative and ERα-positive human breast cancer cell lines using a lentiviral expression
construct. The migratory behaviour and cytoskeletal dynamics in relaxin-expressing cancer cells
will be studied in 3D-culture conditions using fluorescence microscopy. Particular emphasis will
be on the metastasis-promoting calcium-binding protein S100A4 which was identified in my lab
as novel relaxin target molecule in breast cancer cells. In-vivo carcinoma growth and metastasis
will be studied in nude mouse xenografts. Developing primary tumor and metastases specimens
will be analysed with particular emphasis on (a) angiogenesis, (b) hypoxia, (c) collagen content,
(d) extracellular matrix modulating enzymes and (e) novel relaxin target molecules (e.g.S100A4,
cath-L, cath-D). Immunofluorescence and immunohistochemical imaging techniques and
transmission electron microscopy will be used to analyse these tumor samples.
e2) Impact of environmental pollutants on epithelial cell polarization and function in the
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female reproductive tract. S. Hombach-Klonisch.
RESEARCH HYPOTHESIS. Exposure to environmental pollutants of the PAH-group
(polyhalogenated aromatic hydrocarbons) during critical time windows of pre-natal development
or steroid hormone-dependent post-natal epithelial cell differentiation results (a) in disturbances
of epithelial organization affecting reproductive physiology and (b) in long-term alterations of
developmental programming and tissue patterning resulting in the inability of the tissues to
respond to physiological endocrine stimuli.
We will investigate, on the cellular and sub-cellular level, the interference of environmental
pollutant chemicals with epithelial cell structural organization, the interaction with the stroma
and the dynamics of directional vesicular transport important for maintenance of polarization and
secretory and resorptive function. Novel immortalized epithelial cell models of the female
reproductive tract, which were developed in my lab and were shown to express functional steroid
hormone and dioxin receptors, will be used for these polarization studies. Our unpublished data
reveal several molecules involved in vesicle docking and trafficking to be altered by dioxin-type
chemicals. The short-term goals of this project are to identify alterations in vesicle trafficking
involved in endocytosis and exocytosis functions using fluorescence microscopy and
immunogold electron microscopy techniques on polarized epithelial cells. The long-term goals
are to identify genome dynamics induced by prenatal exposure to environmental chemicals
which result in trans-generational changes in steroid hormone responsiveness and reproductive
function. We will investigate changes in the number and content of extrachromosomal elements
(EEs) present in the endometrium of pre-natally exposed mice. We will use microarray
comparative genomic hybridization of fluorochrome-labeled probes of extracted EE to
metaphase chromosomes from primed mouse lymphocytes to determine the chromosomal sites
contained within the EE and copy number changes. Our long-term goal is to determine the genes
located on EE in defined cell types of female reproductive tract organs whose regulation is
associated with heritable biological malfunctions.
5. Apoptosis and new treatments.
a) Mechanisms of apoptosis and development of novel treatment protocols in cancer. S.
Gibson. The proposed projects can be either short-term or long-term. 1) The mechanism of
MEKK1 induced apoptosis. MEKK1 is a serine/threonine kinase that causes apoptosis in many
different cell types. Kinase inactive MEKK1 inhibits apoptosis in response to detachment or
genotoxic agents. Trainees will be involved in studies designed to determine the MEKK1 signal
transduction pathways leading to apoptosis using imaging and deconvolution in conjunction with
molecular approaches. 2) The mechanism of epidermal growth factor receptors protection against
death-receptor-induced apoptosis. In many epithelial-derived cancers such as breast, the
epidermal growth factor receptor is overexpressed correlating with poor prognosis. Treating
epithelial cancer cells with EGF blocks apoptosis. Trainees will be involved in studies that
examine this effect. The study will involve advanced imaging and microarrays. 3) The potential
of TRAIL as a molecular based treatment for chronic lymphocytic leukemia (CLL). CLL is
currently an incurable form of leukemia. Tumor necrosis factor related apoptosis-inducing ligand
(TRAIL) is proposed as a potential treatment for cancer. TRAIL binds to the death receptors
inducing apoptosis. TRAIL kills cancer cells more efficiently than normal cells. In combination
with chemotherapeutic drugs, TRAIL gives a synergistic apoptotic response. CLL cells are
sensitive to TRAIL induced apoptosis when compared to normal lymphocytes. Trainees will be
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Appendix: PROPOSED PROJECTS
involved in the analysis of this synergistic response studying DNA condensation, DR4 and DR5
expression and changes in mitochondrial functions using advanced imaging and analysis. They
will new gain insights into chemotherapeutic-induced apoptosis and resistance to their action and
will gain knowledge about the development of new targets for chemotherapy and treatment of
cancer.
b) Genetic control of drug induced apoptosis. M. Mowat. The project involves cloning of genes
associated with control of drug induced apoptosis and to study the functional role of these genes.
To isolate apoptosis mutants, Dr. Mowat’s laboratory has carried out sequence-tagged
mutagenesis using a retrovirus vector. Several mutant cell lines defective in apoptosis have been
isolated. The viral integration sites are used to clone the genes. To learn the subcellular
localization of the gene products, trainees will be involved in detection of proteins using
immunofluorescence (in focus image analysis and deconvolution). Colocalization of the epitope
stained protein products with organelles markers will confirm their distribution to these sites. To
determine functions of these genes in vivo, we will generate knock-out mice or obtain gene
knock out ES stem cell libraries at the Mammalian Functional Genomics Centre.
6. Developmental Biology.
Neuronal differentiation during development and pediatric malignancies. D. Eisenstat.
1) The primary aim of Dr. Eisenstat’s research program is to facilitate our understanding of the
processes of differentiation of neuronal cells through changes in the internal milieu and external
environment of the neuron. Trainees will be involved in these studies as outlined below. They
will gain an improved understanding of two key candidate regulatory molecules identified
through my earlier work: glia maturation factor (GMF) and the DLX class of homeobox
transcription factors. The actin depolymerizing factor glia maturation factor (GMF) interacts
with the internal cytoskeleton of neurons and glia and is localized to the axonal compartment and
growth cones of differentiating neuronal cell populations. The DLX homeodomain proteins are
transcription factors expressed in differentiating neurons of the developing forebrain and retina.
The ultimate goal is to develop novel therapeutic approaches complementing current treatment
strategies by modifying differentiation programs in pediatric malignancies, including
neuroblastoma, retinoblastoma and brain tumors. Four projects (rotations and or larger scale
projects) are suggested as part of this Training program. 1) Glia maturation factor (GMF) – its
role in neuronal differentiation and in neuroblastoma. 2) Role of Dlx homeobox genes in retinal
development and retinoblastoma. 3) Identification of downstream targets of Dlx homeobox genes
using chromatin immunoprecipitation. 4) The use of F.I.S.H. technology in the molecular
classification of pediatric and adult oligodendrogliomas. Students (high school, undergraduate,
graduate) and fellows (PDF and clinical) have exposure to knockout/transgenic mouse models,
primary cell culture and patient tumor samples and utilize molecular, cellular and cytogenetic
approaches to these diseases. Important collaborative links to the Genomic Centre of Cancer
Research and Diagnosis, include Molecular Cytogenetics/FISH (brain tumors, neuroblastoma),
digital imaging and deconvolution software (nuclear and cytoplasmic sublocalization of
homebox gene targets) not available elsewhere in Manitoba or Canada.
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