DDNews Cancer Research Exclusive: A different take on dedifferentiation
SINGAPORE—Drosophila melanogaster, or fruit flies, have served as a popular organism for laboratory work for decades, due to their numerous genetic similarities to humans, ease of care and quick reproductive cycles. The latest discovery made with these flies comes from the Duke-NUS Graduate Medical School in Singapore, where researchers discovered a protein complex that disrupts dedifferentiation, which is known to lead to the development of tumors.
Differentiation is the process by which cells, such as stem cells, become more specialized, developing into specific cell types. On the flip side, dedifferentiation is the process by which progenitor cells, or mature cells, become ectopic neural stem cells, which cause tumors. For this research, the team studied neural stem cells, or neuroblasts, multi-potent cells that are pivotal to brain and nervous system function. Specifically, they focused on type II neuroblasts. These cells, like stem cells, divide, resulting in another neuroblast and a second cell—progenitor cells. Those cells can then differentiate into specific cell types, but progenitor cells are prone to dedifferentiating into neural stem cells and then ectopic neural stem cells, which in turn can undergo uncontrolled growth and lead to the development of brain tumors.
Dr. Hongyan Wang, associate professor of the Program in Neuroscience and Behavioral Disorders at Duke-NUS Graduate Medical School in Singapore, led the team for this research, utilizing the larval brains of fruit fly models. The team uncovered a protein complex, consisting of Brahma, HDAC3 and Earmuff, that plays a significant role in preventing progenitor cells from dedifferentiating.
“These three proteins function in different aspects of gene expression,” Wang explains. “Earmuff is a transcription factor that directly binds to its target genes to control their expression; Brahma and HDAC3 represent two major classes of chromatin remodeling factors, which partially unpack chromatin, a complex composed of DNA and histone proteins, to allow transcription factors and other proteins have access to the DNA. By working together, they regulate gene expression in intermediate progenitor cells to prevent them undergoing dedifferentiation back into a stem cell-like state in the fruit fly larval brain. By preventing dedifferentiation, they prevent brain tumor formation in fruit flies.”
Wang says her team has been researching dedifferentiation using a fruit fly model for about four years. She says they have not studied other tumor types using the fruit fly models, but notes that “similar mechanisms may be adopted by many other types of cancers, such as leukemia and breast cancer, in which dedifferentiation of cells can cause the production of cancer stem cells.”
Wang explains that “The mammalian counterpart of Brahma complex is SWI/SNF complex and their subunit genes are collectively mutated in around 20 percent of all human cancers.” However, given that most of the studied mutations are “inactivating mutations,” she notes that it is challenging to target them directly in terms of therapeutics.
As for why some cells differentiate normal while others are prone to dedifferentiate, Wang says the cause is “unclear.”
“It is known that several non-mammalian vertebrate species possess a remarkable capacity in natural dedifferentiation in response to tissue damage or lost, while mammals have a limited capacity of it,” she says. “For those cells that do not normally undergo dedifferentiation, they may be induced to undergo dedifferentiation. However, induced dedifferentiation is a double-sided sword. It can be utilized as a strategy to promote regeneration in mammalian tissues that normally lack this capability. On the other hand, this process may be adopted by cancers, if dedifferentiated cells become cancer stem cells.”
The next step for their research will be the identification of genes whose expression is regulated by the protein complex to prevent dedifferentiation.
“It is important to identify the pathways that this protein complex regulates, so that potential therapy can be developed,” she adds.
This study, titled “The Brm-HDAC3-Erm repressor complex suppresses dedifferentiation in Drosophila type II neuroblast lineages,” appeared online in eLIFE on March 11. The research received support from the National Research Foundation, Prime Minister’s Office, Singapore under its Research Fellowship (NRF-RF2009-02) and the Duke-NUS Signature Research Program, with funding from Singapore’s Agency for Science, Technology and Research and the Ministry of Health.