The biological checks and balances that keep fruit flies small and make blue whales big are the same in all animal species, according to a study by Hopkins researchers published last week in Cell. The study's results also demonstrate that disregulation of these processes likely plays a role in the growth of tumors.
How organs know when to stop growing is a question that has long kept biologists up at night. It is known to be a fundamental process of human development, so understanding it is a crucial part of the ongoing attempt to completely understand the body. Even more pressing is the belief that knowing more about the mechanisms controlling organ size could have therapeutic potential in treating cancer, a disease in which organ size is notably not under control.
Inroads into understanding size control have only been made in the last few years. The discovery of a key signaling pathway in fruit flies called the Hippo kinase cascade provided the first evidence of an intrinsic mechanism regulating organ size.
Like most signaling cascades, the Hippo pathway ultimately affects the rate of transcription of certain genes. In the case of size control, this is accomplished by adding a phosphate group to a transcription factor - normally localized to the nucleus - called Yorkie. The addition of a phosphate group is a biological tag telling other molecules in the cell to grab Yorkie and shuttle it out of the nucleus. Inactivated Yorkie can not promote the transcription of its associated genes, most of which inhibit cell death. Dying cells mean organ growth is suppressed, so the activity of Hippo is a critical part of the pathway.
Nonetheless the clear-cut nature of the Hippo pathway is only meaningful if you happen to be a fruit fly. Though previous studies have failed to find an analogous mechanism in mammals, most scientists have indicated a protein called YAP as the most likely candidate for a mammal version of Yorkie. The site where the phosphate group is added to each protein is identical.
To settle the debate, the Hopkins team, led by Duojia Pan of the School of Medicine's Department of Molecular Biology and Genetics, directly tested whether YAP inactivation was essential for growth suppression. Due to its central role, YAP gave the Hopkins team a superbly convenient experimental variable. In one case implanting a mutant version of YAP (one that could not be inactivated) into fruit flies caused overgrowth in many structures. A second case involved creating mice whose YAP-expression levels in specific organs could be controlled by the experimenters.
Inducing the overexpression of YAP in the liver caused it grow to four times its normal size. Amazingly the growth was entirely reversible, with the livers returning to normal size only two weeks after YAP overexpression was stopped. It is important to note that long-term overexpression led to the formation of large tumors over nearly the entire surface of the liver.
The researchers hypothesized that the massive and almost immediate expansion of liver size was due to YAP's rather unconventional properties. Most cancer-related proteins hijack the cell's reproduction cycle but simultaneously stimulate cell death. YAP, on the other hand, both promotes cell proliferation and suppresses cell death, a potential "double-whammy" explanation for the observed quintupling of organ size.
The main conclusion here is that YAP both dictates organ size during development and is critical in maintaining that size during life. The Hopkins group also confirmed previous hypotheses that, rather than monitoring every marginally large cell, the organ-size checkpoint functions instead at the tissue level. Alone, increased cell growth or cell proliferation can't affect an organ's size. Only when the Hippo cascade is disturbed in some way will organ size change.
Unsurprisingly higher-than-normal levels of YAP have been found in many types of tumors. suggesting that disrupting the Hippo pathway is one way tumors manage to get around the body's size control checkpoints. This provides a promising target for further research.
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