The human genome consists of 6 billion " letters" of sequence. These form different " words" that need to be organized in the right order to make a " story" . Each " story" gives rise to a particular cell type. Since each cell type consists of a different " story" our genome needs to be organized in many different ways to make the right story readable. Although the order of the " letters" in our genome is typically unchanged across cell types, different stories can be generated by folding our genome in such a way that the " words" for a particular " story" align. " Words" not required in a given cell type are typically masked. Disease development commonly stems from changes in the " story" of normal cells. For instance, mutations or genetic variations will change the " letters" or " words" of a normal " story" to promote cancer development. These genetic defects cannot readily be corrected and are often considered irreversible. Normal " stories" can also changed to cancer " stories" by modulating the legibility of " words" without affecting their " letters" . This occurs through epigenetic events that will affect how the genome is folded or how particular " words" are masked. This is not a static process. Specific drugs can alter epigenetic events, inferring that cancer " stories" can be rendered indolent. Dr. Lupien's research is centered on identifying the changes in " word" masking and genome folding that operate in cancer cells and to reveal their underlying molecular biology. The ultimate goal is to develop new and improved strategies to hinder cancer development.
Two thematic objectives drive Dr. Lupien's leading-edge research. The first consists of delineating the functional consequence of mutations and genetic predispositions in cancer by identifying the " words" that are targeted by these genetic defects. Each " story" relies on " words" aligning to form " sentences" . These sentences consist of " words" of different nature that correspond to different functional elements of the genome, such as " nouns" (genes), " verbs" (promoters) and " adjectives" (enhancers). Mapping epigenetic events discriminates " nouns" from " verbs" and " adjectives" that are legible or masked across the genome. Using this principle the Lupien Lab recently demonstrated that genetic predispositions to breast and prostate cancers were preferentially found in regions on the genome that harbour enhancers (the adjectives). These genetic predispositions can modulate the degree of these " adjectives" thereby affecting expression of target oncogenes or tumour suppressor genes (the nouns) to promote cancer development. For instance a normal sentence such as " express more gene A" would be changes in cancer to " express less gene A" . We are currently applying this methodology to reveal the functional nature of mutations that accumulate in tumors throughout their development or as they acquire resistance to drug treatment.
The second thematic objective focuses on identifying the alterations in genome legibility or folding occurring in the course of cancer development. This is achieved by comparing maps of epigenetic events from normal versus cancer cells. By focusing on epigenetic events that discriminate the nature of " words" , the Lupien Lab can identify the " stories" specific to cancer cells. This was recently applied to colorectal cancer where epigenetic mapping revealed significant differences in the enhancers (adjectives) used in normal colorectal crypt versus cancer cells were detected. This approach can also help identify the mechanisms that promote cancer progression. Recent work from the Lupien Lab focused on breast cancer compared epigenetic maps from cancer cells responsive or resistant to hormonal (endocrine) therapy. Results revealed significant differences in all types of " words" that were masked and legible between drug responsive and resistant breast cancer cells. This revealed a " story" specific to hormonal therapy-resistant breast cancer cells that identified a pathway promoting resistance. On-going research is expanding this work to clinical samples.
New Investigator, Ontario Institute for Cancer Research (OICR)