What is it about?

In 1920s, Drs. Gordon and Kosswig independently found that some interspecies hybrid between ornamental fish species platyfish and swordtail developed cancer. In 1950s, Dr. Anders argued this spontaneous tumorigenesis is due to segregation of two loci, named Tu (Tumor) and Diff (Differentiation) in platyfish. !n 1989, Dr. Schartl identified an oncogene that served as the driver (Tu) of the spontaneous tumorigenesis. Since then lots of effort were put into the identification of the gene that regulate the oncogene. In 2010's Drs. Schartl, Walter and Warren sequenced the platyfish genome, establishing necessary genomic resources to facilitate the dissection of this oncogenic genetic interaction. We report final conclusion of the search of Diff, the endogenous regulator of Tu, the driving oncogene.

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Why is it important?

The Dobzhansky–Muller (DM) model describes interactions between diverged genes account for hybrid incompatibility and is a central theory explaining genetic mechanisms underlying speciation. This study reports the second vertebrate system (the only other example is mouse gene prdm9), with clearly defined interacting loci, that supports the DM model. In addition, our study also shows that cancer can serves as a mechanism accounting for speciation. More importantly, platyfish genome encodes an autonomous oncogene that is similar to human epidermal growth factor receptor (EGFR), disregulation of which is associated with a plethora of human cancer. However, interestingly, platyfish do not develop cancer. We identified a genomic region within the platyfish genome (Diff) that suppress the EGFR function. Characterizing the mechanism how Diff suppress the oncogenic function of EGFR can lead to new strategy in controlling this driver oncogene.

Perspectives

We know EGFR is a driver of cancer formation, but we still don't fully understand how EGFR regulates the downstream proliferation pathways and induces a tumor, and therefore don't know how to control these effects. So what is intriguing about the platyfish is that they have a mutant EGFR that is just like some of the oncogenic versions of human EGFR, but don't develop tumors. EGFR function is fully suppressed in platyfish until its co-evolved suppressor is removed. Platyfish have a naturally developed mechanism blocking the EGFR. We can utilize this model to develop novel therapy—small molecule or gene therapy to mimic what is happening in the platyfish. Characterizing molecular mechanism of Diff regulation of EGFR, and forwarding new drug-able target for cancer treatment is the long-term impact of this model following what we have accomplished so far.

Yuan Lu
Texas State University San Marcos

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This page is a summary of: Oncogenic allelic interaction in Xiphophorus highlights hybrid incompatibility, Proceedings of the National Academy of Sciences, November 2020, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2010133117.
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