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Science Spotlight

MGA & MYC: mega-sized players in cancer progression

From the Eisenman Lab, Basic Sciences Division and the MacPherson Lab, Human Biology and Public Health Sciences Divisions

Cancer seems, at first glance, an easy disease to explain – a form of cellular dysfunction leading to the uncontrolled proliferation and spread of diseased cells until they overwhelm the tissues in which they arise, vital organs, and ultimately the body. But despite these long-understood basic principles common to all types of cancer, the disease has been among the most difficult for science to grasp, and among the most challenging to solve. In the past two decades, as major improvements in genetic sequencing have made it possible to identify the mutations at the heart of a wide range of cancers, the fallacy of cancer’s simplicity has been laid bare. Researchers have identified hundreds of cancer-causing mutations, mixed and matched in dizzying numbers to generate each individual tumor. Cancer, it turns out, is a thousand different diseases in one, each with its own mutational landscape, its own quirks, its own treatment needs. But lest the enormous complexity of this disease get you down, take heart, for even within this mutational maelstrom lie the signatures of all cancers’ basic natures. However varied it may be, cancer remains a disease fundamentally based on cellular growth, proliferation, and survival. And some genes play such an influential role in these processes that they are mutated again and again in a wide range of different cancers.

One such major driver of cancer progression – the MYC transcription factor – has been a primary focus of research by Dr. Bob Eisenman, a professor in the Basic Sciences Division at Fred Hutch and member of the UW/Fred Hutch Cancer Consortium. “Given the critical role of transcription factors in the control of development and in driving cellular functions, it is not surprising that transcriptional regulators can function as potent tumor supressors or oncogenes,” his group writes. This is because mutating transcription factors - genes that act to turn on or off many other genes – can in one fell swoop dysregulate entire networks of genes controlling cellular functions. In MYC’s case, hyperactivation leads to “rampant proliferation and tumor progression.” But, they point out, “MYC does not function in isolation: it is part a larger network of transcription factors [called the MYC network] that cooperate with or antagonize MYC activity.” In a new paper in eLife, Postdoctoral fellow Dr. Haritha Mathsyaraja and Dr. Eisenman worked in close collaboration with Fred Hutch and Cancer Consortium members Dr. David MacPherson, as well as Drs. Alice Berger, A. McGarry Houghton, and William Grady, to identify the role of one such MYC network member in tumor progression and invasiveness.

The transcription factor MGA (pronounced mega) is a known antagonist of MYC function. Additionally, Dr. Eisenman explains, “MGA was found to be mutated in a wide range of cancers, including lung adenocarcinomas and colon carcinomas, suggesting the possibility that MGA might act as a tumor suppressor”. To understand the role that MGA inactivation plays in cancer progression, the authors mutated this gene in a mouse model of lung cancer. The presence of the MGA mutation led to significant increase in tumor growth,  worsening of tumor grade, and animal survival, confirming this gene’s role as a tumor suppressor. To dig deeper into how the loss of MGA affected tumor growth, the group generate a cell line from their mutant mice to perform in vitro analysis. They first carried out RNA-sequencing analysis to identify genes whose expression changed upon MGA inactivation, and identified several, many of which were previously identified as MYC targets, involved in cell division and cell invasion. Intriguingly, the group also identified several upregulated genes that are normally controlled by non-canonical polycomb (ncPRC), a repressive complex. They then performed tandem-affinity purification and found that MGA interacts with multiple members of the ncPRC complex, and that in the absence of MGA this complex appears to be destabilized.

While ncPRC has been studied in embryonic stem cells, its association with MGA led the authors to ask what role it might be playing in tumor cells. To answer this question, they performed CHIP-Seq to find where in the genome this complex binds in control cells and MGA-inactivated tumor cells. “MGA [and ncPRC] were seen to bind several thousand promoters”, they noted. “Moreover, we noted a marked reduction in [ncPRC] binding” in cells lacking MGA. Finally, they mutated members of the ncPRC complex and found that these mutations affected the expression of many of the same genes as the MGA mutation, indicative of the close working relationship between MGA and ncPRC.

Finally, the authors expanded their examination of MGA to ask whether it plays a role in tumor progression in other contexts. They first examined human lung cancer samples and found that loss of MGA was associated with increased expression of many of the same genes as in their lung cancer model and increased invasiveness in cultured human lung cancer cells. They then deleted MGA in cultured human colon organoids and found that this again caused the upregulation of many of same set of genes and accelerated tissue growth. Although the authors pointed out some intriguing differences in how MGA-depleted cells act between their lung and colon models, differences that deserve further study, these data indicate that disruption of MGA may play similar roles in colorectal cancer as in lung cancer. This observation highlights the fact that, although in many ways each cancer should be viewed as its own disease entity, in some ways they’re not so different after all.

The genetically-engineered MGA mutant mouse model developed in this study provides “a biological system in which we and others can study MGA tumor suppression in considerable detail,” Dr Eisenman says. “Our model systems will permit us to further elucidate MGA activity at very early stages of tumor formation and interaction with the microenvironment.” Additionally, he notes, “Our work has identified subgroups of genes whose expression is altered upon inactivation of MGA in both lung adenocarcinoma and in transformed colon organoids… We are interested in determining whether inappropriate expression of these genes induces DNA damage and genomic rearrangements that promote oncogenesis”

model of MGA function
Model for how MGA works with PRC and the MYC network member MAX to regulate gene expression. Image provided by Dr. Bob Eisenman.

This work was supported by the National Institutes of Health, the Cancer Prevention and Research Institute of Texas, the William and Ella Owens Medical Research Foundation, the Brotman Baty Institute, the Cottrell Family Fund, the Geiger Family Foundation, the Listwin Fund, the Hartwell Foundation, the Prevent Cancer Foundation, and the Fred Hutchinson Cancer Research Center.

Fred Hutch/UW Cancer Consortium members Bob Eisenman, David MacPherson, Alice Berger, A McGarry Houghton, and William Grady contributed to this work

Mathsyaraja H, Catchpole J, Freie B, Eastwood E, Babaeva E, Geuenich M, Cheng PF, Ayers J, Yu M, Wu N, Moorthi S, Poudel KR, Koehne A, Grady W, Houghton AM, Berger AH, Shiio Y, MacPherson D, Eisenman RN. (2021) Loss of MGA repression mediated by an atypical polycomb complex promotes tumor progression and invasiveness. eLife 10:e64212.