For decades, scientists and doctors have been searching for the mechanisms underlying the formation of cancers.  Accumulating studies have revealed that each cancer type (e.g. gastric cancer, lung cancer, leukemia, lymphoma, etc) is very unique. Many oncogenes are exclusively expressed in specific types of cancers. One long-standing question in the field is – how an oncogene “chooses” a particular cellular context to exert its oncogenicity (termed “tissue-specific oncogenicity”)?

Now, researchers from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS) have taken a significant step forward with a novel zebrafish cancer model as a platform to study the mechanism of cancer and elucidate tissue-specific oncogenicity. The research team led by Associate Professor Takaomi Sanda utilized zebrafish, an emerging animal model, in combination with the latest single-cell sequencing technology. This system enables the exploration of otherwise physiologically impossible phenomenon and study the characteristics of an oncogene in depth.

The researchers tested this idea using the IRF4 oncogene that is specifically expressed and regulates gene transcription in several types of mature lymphomas, reported by the same group and others. Although a plethora of basic and clinical studies have reported that IRF4 plays a central role in those cancers, the creation of animal models to analyze the oncogenicity of IRF4 has not been successful. The research team in CSI Singapore first expressed IRF4 in all subsets of lymphocytes and let it “choose” the lineage and stage at which to initiate cancer. Using single-cell sequencing techniques, they identified such “cell-of-origin” of cancers based on gene expression profile that characterizes cell identity.

Interestingly, they found that the expression of IRF4 is lethal to the immature stage of T-lymphocytes, but can initiate the expansion of a rare subset of T-lymphocytes expressing T-cell receptor (TCR)-? via affecting the cell fate decision of lymphocytes. Using single-cell sequencing technology, they also discovered several novel genes that are potentially involved in cancer formation, which have not been previously studied. They also demonstrated the applicability of the zebrafish models for drug testing conferring several advantages over other animal models.

“Master transcription factors such as IRF4 can affect cell fate. If such factor accidentally meets specific context, it may lead to cancer,” explained Associate Professor Sanda, who is also from the NUS Department of Medicine.

Ms Stella Amanda, a CSI Singapore research assistant who worked on the project, hopes that this model leads to further advancement of our understanding on oncogenes and to the development of therapeutic strategy. “Our zebrafish model would be useful for high throughput drug screening to “fish out” potential therapeutics,” she said.

Dr Tze King Tan, a CSI Singapore research fellow who worked on data analysis in this project, emphasizes the strong potential of single-cell sequencing technology. “Single-cell technology is the new era in science and grant in-depth perception on cancer development and therapeutics on single cell level,” he said.

The paper on this work was published in the journal Nature communications this month and was selected as one of the late-breaking abstracts at the prestigious Annual American Association for Cancer (AACR) meeting.