If you ask me, one of the cooler aspects of science has to do with the larger research narratives that laboratories produce—sure, an individual study can detail a surprising result or provide a valuable resource, but the steady, unyielding march of scientific progress is often measured in years, decades, or even lifetimes. Today’s story comes to us from the Eisenman Lab in the Basic Sciences division at Fred Hutch, who continue to write the evolving scientific narrative concerning an oncogene called MYC and its role in cancer. Their recent preprint, helmed by staff scientist Dr. Brian Freie, could just as well have been adapted into a romantic drama starring MYC, its loving but mysterious partner MAX, and their extended families.
If you’re a regular Science Spotlight reader and ‘Eisenman Lab’ or ‘MYC’ sound oddly familiar to you, you’re not crazy. In a previous study published in Genes and Development (which you should read about here), Freie and Eisenman created a novel mouse model to test the cancer-causing potential of a specific mutation in MYC, a master regulator of cell growth and frequent member of ‘Cancer’s Most Wanted’ lists. They were surprised to find that a single amino acid substitution in MYC was enough to predispose mice to blood cancers, highlighting the precise regulation of MYC that our cells maintain to keep their growth in check.
This time, Freie and Eisenman turned their attention to a new character whom we didn’t mention last time: MYC’s partner-in-crime, MAX. In cells, MYC and MAX bind together to form a heterodimer, and this complex is actually what binds DNA and does most of the things that MYC is known for. And—in true soulmate fashion—MYC and MAX feel each other’s loss. “We had previously shown that in absence of MAX, MYC protein levels are strongly downregulated,” notes Eisenman, “however, it’s also been shown that mutations in MAX appear to drive a collection of neuroendocrine cancers, prompting questions about how (or whether) these cancers depend on MYC for their growth.” MYC upregulation drives cancer, MAX loss downregulates MYC, and… MAX loss also drives cancer? Something wasn’t adding up here.
To test whether MAX loss alone is enough to drive cancer, Freie and Eisenman collaborated with researchers from the MacPherson lab in the Human Biology Division to create a mouse model in which they could induce MAX inactivation specifically in neuroendocrine tissues (including the thyroid, pituitary and adrenal glands). After inducing MAX inactivation, the team were interested to find that indeed, MAX loss caused the formation of pituitary adenomas in mice receiving the induction but not in littermate controls. As these tumors took a long time to develop (over 600 days!), the team also found that crossing this model with mice lacking the tumor suppressors RB and p53 accelerated tumorigenesis. Overall, these results confirmed MAX as a bona fide tumor suppressor in neuroendocrine tissue.
MAX is gone, MYC is heartbroken—what are these tumor cells to do? Here, Freie and Eisenman note that—although MYC and MAX play leading roles in this drama—they are also part of an extended family of evolutionarily related proteins, aptly named the MYC transcription factor network. “Another member of this network that is similar to MAX is a protein called MLX, which can’t bind MAX or MYC, but does dimerize with other proteins in the network called MondoA and MNT,” notes Freie, “so we wondered whether some of these proteins might sustain oncogenic signaling in MAX-null tumors.” The team used a technology called ChIP-seq to measure genome-wide MLX, MNT, and MondoA occupancy in their MAX-null tumors, revealing a substantially altered landscape of DNA interactions in this network. Indeed, MondoA appeared in spots where MAX normally bound DNA, while MNT dimerized with MAX to repress a collection of genes—in the absence of MAX, this repression was lost. Surprisingly, the team also found regions of DNA bound by MondoA and MNT in the absence of MLX (which was thought to be necessary for their binding to DNA).
Thus, it appears that—in the absence of our leading roles MAX and MYC—the other members of the MYC network play a game of musical chairs to keep the house in order. But does this game have functional consequences for tumors? By showing that MAX-null thyroid tumors are differentially sensitive to perturbations of MLX, MondoA, and MNT, the team suggests that it does. “What we found in these MAX-inactivated tumors can best be described as a functional rearrangement of the MYC transcriptional network,” notes Eisenman. “It really stands in contrast to the classical model that MYC overexpression drives tumorigenesis and highlights the remarkable plasticity that this well-studied pathway has—plasticity that will need to be better understood as we continue trying to target this pathway to treat the variety of cancers it’s implicated in.” One step at a time, science marches on.
The spotlighted work was funded by the National Institutes of Health and supported by the Genomics and Bioinformatics and Comparative Medicine Shared Resources at Fred Hutch.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium members Drs. Robert Eisenman and David MacPherson contributed to this study.
Freie, B., Ibrahim, A. H., Carroll, P. A., Bronson, R. T., Augert, A., MacPherson, D., & Eisenman, R. N. (2024). MAX inactivation deregulates the MYC network and induces neuroendocrine neoplasia in multiple tissues.
Science Spotlight writer David Sokolov is a graduate student in the Sullivan Lab at the Fred Hutch. He studies how cancer cells modify their metabolism to facilitate rapid proliferation and accommodate tumor-driving mitochondrial defects. He's originally from the east coast and has bachelors' and masters' degrees from West Virginia University. Outside of the lab, you'll find him enjoying the outdoors, playing music, or raising composting worms in his front yard.
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