Research Interest

• Cancer research
• Solid tumour microenvironment
• Hypoxia
• Metastasis research
• Pre-metastatic niche
• Targeting hypoxic tumour cells in therapy
• Radiation biology
• 2013-present, National Mentor, The Terry Fox Foundation Strategic Initiative for Excellence in Radiation Research for the 21st Century (EIRR21) at CIHR
• This integrated Radiation Medicine training program for graduate students and post-doctoral fellows is based out of the University of Toronto, with 32 “local” mentors from Toronto, 3 national mentors from across Canada, and 3 international mentors. I am the national mentor representing the province of British Columbia

Most solid tumours contain cells that are poorly oxygenated, and these hypoxic tumour cells are refractory to a variety of cancer treatments including radiation therapy and chemotherapy. Not only are hypoxic cells the most difficult tumour cells to kill with conventional therapies, but hypoxia also promotes a more aggressive tumour phenotype. In the clinic, patients with primary tumours that contain large fractions of hypoxic cells have poor outcome, due in large part to limited treatment response and the presence of distant metastatic disease. My lab is interested in the role of tumour hypoxia (and the tumour microenvironment) in cancer therapy and in the development of tumour metastases.

Tumour Perfusion and Hypoxia

The extent of hypoxia in solid tumours can be measured by exogenous hypoxia markers (drugs that are bound and retained in hypoxic cells) and/or endogenous hypoxia markers (proteins that are increased in hypoxic cells). The oxygenation level of tumour cells can change as a function of time due to fluctuations in tumour perfusion, and this transient (or cyclic) hypoxia is poorly understood. We use positron emission tomography (PET), immunohistochemistry, and flow cytometry to quantify transiently hypoxic tumour cells with the goal of designing more effective therapeutic strategies to target (or exploit) tumour hypoxia. We also study the influence of ionizing radiation on tumour cell phenotype and invasion in models of breast and brain cancer.

Immune suppressive cells in solid tumour metastasis

The metastatic spread of cancer is associated with over 90% of cancer-related deaths. We have found that cytokines and other proteins secreted by tumours can stimulate the accumulation of immune modulatory cells in tissues prior to the arrival of metastatic tumour cells. Immune suppressive cells (e.g., myeloid-derived suppressor cells, macrophages, regulatory T cells) inhibit the cytotoxic function of effector T cells in several tissues, creating localized environments that allow metastasizing tumour cells to escape immune attack. Inhibition of immune suppressive cell recruitment and function leads to decreased metastatic tumour growth in the lungs, supporting therapeutic strategies to target immune suppressive cells in the clinic. We are also interested in how the immune system responds to tumour antigens and microenvironmental limitations to immune cell infiltration into solid tumours.

Bone marrow-derived cells in solid tumour metastasis

The metastatic spread of cancer is associated with over 90% of cancer-related deaths.  We have found that selected proteins secreted by tumours can stimulate the accumulation of bone marrow-derived cells (BMDCs) in tissues prior to the arrival of metastatic tumour cells.  BMDC accumulation may enhance the survival and growth of metastatic tumour cells, and predict future sites of metastatic tumour growth.  We are particularly interested in the accumulation and function of immune suppressive myeloid cells (myeloid-derived suppressor cells, macrophages) in metastatic target organs, and in therapeutic modification of tumour-secreted proteins and immune suppressive cells in metastatic-target organs to decrease metastatic tumour growth.

FUNDING

We gratefully acknowledge operating grant funding and stipend support from the following organizations:

Operating funds:

The Canadian Institutes of Health Research (http://www.cihr.gc.ca/e/193.html)

The BC Cancer Foundation (http://www.bccancerfoundation.com/)

The Canadian Institutes of Health Research: Institute of Cancer Research (http://www.cihr-irsc.gc.ca/e/12506.html)

The Terry Fox Foundation (http://www.terryfox.org) via The Canadian Cancer Society Research Institute (http://cancer.ca/Research.aspx)

Stipend and salary support:

Kevin Bennewith is a Michael Smith Foundation for Health Research Biomedical Research Scholar (http://www.msfhr.org/)

Jenna Collier is currently funded by a Walter C. Koerner Fellowship from the UBC Affiliated Fellowships Program (https://www.grad.ubc.ca/awards/affiliated-fellowships)

Jenna Collier and Liz Halvorsen were funded by Frederick Banting and Charles Best Canada Graduate Scholarships Master’s Awards from the Canadian Institutes of Health Research (http://www.cihr-irsc.gc.ca)

Natalie Firmino is currently funded by a Cordula and Gunter Paetzold PhD Fellowship from the UBC Affiliated Fellowships Program (https://www.grad.ubc.ca/awards/affiliated-fellowships)

Natalie Firmino and Brennan Wadsworth are Scholars in The Strategic Training in Transdisciplinary Radiation Science for the 21st Century (STARS21) Program (http://www.radonc.utoronto.ca/stars21)

Liz Halvorsen is currently funded by a Li Tze Fong Memorial Fellowship from the UBC Affiliated Fellowships Program (https://www.grad.ubc.ca/awards/affiliated-fellowships)

Liz Halvorsen and Brennan Wadsworth are currently funded by Four Year Doctoral Fellowships from the University of British Columbia (https://www.grad.ubc.ca/awards/four-year-doctoral-fellowship-4yf)

Brennan Wadsworth was funded by an Alexander Graham Bell Canada Graduate Scholarship Master’s Award from the National Sciences and Engineering Research Council of Canada (http://www.nserc-crsng.gc.ca/index_eng.asp)

Brennan Wadsworth was funded by a Northern Telecom Graduate Fellowship and a Jean MacDonald Graduate Fellowship from the University of British Columbia Affiliated Fellowship Program (https://www.grad.ubc.ca/awards/affiliated-fellowships)