High mobility group (HMG) genes and cancer: an interview with Dr. Linda Resar, Johns Hopkins University School of Medicine

Linda Resar ARTICLE IMAGE

What are high mobility (HMG) genes and what role do they play in cancer?

High mobility group A genes are highly expressed in all aggressive cancers studied to date. These genes encode the high mobility group A (HMGA) proteins. In other words, these genes provide the genetic “code” necessary to produce HMGA proteins.

HMGA proteins are named “high mobility group” proteins because they are small and travel rapidly in polyacrylamide gels used in the laboratory to separate proteins (thus high mobility group).

They are chromatin remodelling proteins because they bind to DNA and other proteins in the nucleus (or the nuclear chromatin) to alter its structure and regulate expression of other genes.

The HMGA family of proteins are distinguished from other HMG proteins because they have “AT-hook” DNA binding domains that facilitate binding to chromatin at AT-rich regions.

Work from our laboratory indicates that HMGA proteins function as “Master Regulators” (or key regulatory proteins) in many cellular pathways that are needed for aggressive cancer cells to invade and metastasize or spread to distant sites. We also found that they are important for normal embryonic stem cell function.

What function do HMG genes have in stem cells and why do many researchers consider cancer cells the evil twin of stem cells?

Many genes important in normal embryonic development also become reactivated and lead to abnormal cancer cell growth when aberrantly “switched on” after birth. In fact, several key properties needed by developing embryos appear to be “hijacked” by cancer cells and these properties could enable cancer cells to evade therapy and spread to distant sites.

The defining properties of stem cell include: 1) unlimited self-renewal, or the ability to reproduce indefinitely, and, 2) plasticity, or the ability to form different tissues of the body.

These properties are essential for normal development, while in cancer, these properties are distorted and used to promote their growth and spread to distant sites.

For example, unlimited self-renewal, which is needed for normal embryonic stem cells to grow into mature organisms, gives cancer cells the ability proliferate in an uncontrolled fashion.

Emerging evidence also suggests that the stem cell property of plasticity enables cancer cells in one location to change shape, mobility, and other characteristics, which allows them to invade blood vessels, travel to distant sites, and then take root at these distant sites and form metastatic tumors, whereby the process begins again.

Other stem cell properties, which include high expression of detoxification enzymes and channel proteins to export toxins out of cells, helps to protect embryonic stem cells from toxic exposures during development. These properties, however, could also enable cancer cells avoid toxic effects of chemotherapy.

Thus, the stem cell properties shared by cancer cells have given rise to the idea that cancer cells can function as distorted embryonic stem cells, or the “evil twin” of normal embryonic stem cells.

You have been investigating HMG genes for two decades. What first prompted your interest in them?

I began studying HMG genes in the laboratory of Dr. Daniel Nathans. Although Dr. Nathans was awarded the Nobel Prize in Physiology or Medicine for discovering restriction endonucleases together with Werner Arber and Hamilton Smith, his group was investigating genes that are turned on by growth factors when I joined his laboratory in 1992 as a junior faculty member at Hopkins.

Not surprisingly, many genes that are activated by growth factors and regulate normal cell growth become “over-active” in cancer and contribute to the development of cancer. My first project in the Nathans’ laboratory was to study how the HMGA gene is regulated.

HMGA1 is among the “delayed early” genes that are activated by growth factors. These genes follow the initial wave of gene (immediate-early genes) turned on by growth factors.

After cloning the regulatory regions upstream of the HMGA1 gene, I discovered that HMGA1 is activated by the cMYC protein, another potent, cancer-causing protein or “oncoprotein”. This suggested that HMGA1 could also be important in cancer.

In my own laboratory, I began exploring the properties induced by HMGA1 and discovered that it also functions as a potent oncoprotein in cell and mouse models.

How has the understanding of HMG genes changed over this period?

It has become clear that HMGA1 is highly expressed in embryonic stem cells, adult stem cells (such as blood stem cells or intestinal stem cells) and all aggressive cancers studied to date. Together, these findings indicate that it plays a fundamental role in both normal development and cancer.

Our recent studies show that we can use genetic tools to silence this gene, which in turn leads to a dramatic change or “reprogramming” of the cancer cell into a cell that looks and grows more like a normal cell.

Work from my group has focused on understanding how this protein induces abnormal cancer growth when it is “switched on” in cancer cells. We have identified many pathways that are activated by HMGA and give rise to properties that are essential for cancer cells, also called hallmarks of cancer cells. Similarly, we are exploring how HMGA1 functions in normal stem cells.

Please can you outline the different types of HMG genes and the HMGA1 gene that your recent research concentrated on?

The HMGA gene family include the HMGA1 and HMGA2 genes. HMGA2, like HMGA1, is also highly expressed during embryogenesis and in normal embryonic stem cells, as well as in some adult stem cells (intestinal stem cells).

The HMGA2 gene has similar, potent oncogenic (cancer-causing) properties in cultured cells and is also overexpressed in aggressive cancer cells, although gene and protein expression studies suggest that it is less commonly overexpressed in cancer as compared to HMGA1.

For example, work from our group found high levels of HMGA1 protein in >90% of pancreatic ductal adenocarcinomas, and high HMGA1 correlates with poor differentiation status and decreased survival.

In contrast, HMGA2 protein levels were elevated in only about 40-50% of pancreatic ductal adenocarcinomas. High levels also correlate with poor differentiation and lymph node metastasis, which are markers of more advanced disease.

The pancreatic tumours in our study tended to have either high levels of HMGA1 or HMGA2, which suggests that a pancreatic cell requires only one of these proteins to become an aggressive cancer cell.

While both HMGA1 and HMGA2 are found in translocations in cancer, HMGA2 translocation events appear to be a more frequent in benign, mesenchymal tumors. Other HMG proteins share part of the name “high mobility group”, but differ in structural properties and function.

What did your recent research into HMGA1 and breast cancer involve?

In this study, we use potent genetic tools to “switch off” HMGA1 in aggressive breast cancer cells. We then investigated what happens to the appearance and behaviour of the cancer cells once HMGA1 was silenced.

We also investigated genes and molecular pathways that are regulated by HMGA1 in aggressive breast cancer cells.

What did your research find?

We found that switching off HMGA1 causes a dramatic change in the appearance and behaviour of the cancer cells. The “reprogrammed” cells changed from thin, spindle shaped cancer cells to cells with a plump, cuboidal shape; features that are present in normal epithelial cells.

We also discovered striking changes in the cancer cell behaviour, including a halting of the rapid cancer cell growth. The reprogrammed cells were no longer invasive and they lost many cancer cell properties, including the ability to grow as colonies in soft agar assays. In preclinical mouse models, they no longer formed tumours that could spread to distant sites.

Switching off HMGA1 also blocked cancer stem cell properties, such as the ability to grow as three-dimensional spheres. In addition, silencing HMGA1 depletes the tumour-initiator cells because tumours no longer formed when relatively small numbers of cancer cells were injected into the mammary fat pads of the mice.

We also found that HMGA1 regulates many genes that are expressed in normal embryonic stem cells or during development. In particular, genes expressed when embryos undergo an epithelial to mesenchymal transition during gastrulation were also regulated by HMGA1.

Gastrulation is a process that occurs early in normal development whereby a small, symmetric collection of cells (blastula) organizes into a 3-layered, asymmetric structure. These findings again support the hypothesis that cancer stem cells behave like dysregulated normal stem cells.

Do you think the results of this research will lead to a therapy being developed based on the principle of HMGA1 blockers?

We are now searching for therapeutic approaches to block the function of this protein.

If it was not possible to block HMGA1 itself, do you think it would be useful to block one of the pathways that HMGA1 affects?

We have also tried to block pathways downstream of HMGA1. For instance, we know that HMGA1 induces expression of the gene encoding the COX-2 enzyme, which can be blocked with inhibitors like aspirin or more specific COX-2 inhibitors, (called COXibs).

In our experimental models, we found that these agents impair the growth of tumours induced by HMGA1. Similarly, humans who take these agents regularly appear to have lower rates of many types of tumours.

We have also used inhibitors to the STAT3 protein, which is another downstream HMGA1 target that is important in cancer.

What are your future research plans?

Our major efforts are directed at developing agents to block this gene as well as gaining a better understanding of its role in normal stem cells, cancer stem cells, and cancer in general. We are particularly interested in developing novel technology, such as nanoparticles, to deliver HMGA1 inhibitors.

How important do you think HMG genes will be in the future of cancer therapies?

Because this protein functions as a master regulator in tumour progression and is highly expressed in all aggressive tumours, I predict that it will be an important target in cancer therapy.

Where can readers find more information on HMG genes and your research?

Our papers on HMGA1 genes and our research have been published and are available through pubmed or Google Scholar web searches.

About Dr. Linda Resar

Linda Resar BIG IMAGEDr. Resar is internationally recognized for pioneering studies on the role of High Mobility Group A (HMGA) Proteins in cancer and stem cells.

Dr. Resar was the first to discover that HMGA genes function as potent oncogenes and a seminal paper describing this work was featured in Science magazine’s STRIKE publication, which cites papers of major significance. 

Her laboratory also engineered the first transgenic mouse model demonstrating that HMGA1 causes cancer in vivo. Using this model and others, Dr. Resar has gone on to elucidate molecular mechanisms regulated by HMGA in human cancers. This work is important because HMGA1 is a key transcription factor enriched in all aggressive human cancers and embryonic stem cells.

She is currently an Associate Professor of Medicine and Oncology, and a faculty affiliate of the Institute for Cellular Engineering at the Johns Hopkins University School of Medicine. 

Dr. Resar has garnered continuous NIH funding over the past 21 years for her work in addition to funding from private sources, including the American Cancer Society and Leukemia & Lymphoma Society. She has published over 57 papers in the field.

As a result of her discoveries, Dr. Resar is the recipient of numerous prestigious awards including a Research Scholar Award from the American Society of Cancer (2001) as well as a Research Scholar Award from the Leukemia & Lymphoma Society (2005).

Dr. Resar was also awarded Innovator Awards from Alex’s Lemonade Stand Foundation (2008 & 2010) for established investigators in cancer research and she now serves as on the scientific advisory board member for this organization. 

In recognition of her groundbreaking contributions to this field, Dr. Resar was also the recipient of the CONCERN Foundation Cancer Research Award (1998), the J.P. McCarthy Fund Developmental Award for Blood Disease Research (2008), the Maryland Stem Cell Research Fund Exploratory Awards (2008, 2009, 2011), the Association for Research on Childhood Cancer Award (2011), and the Childhood Leukemia Research Association (2013).

Dr. Resar also serves on study sections for the Leukemia & Lymphoma Society, Department of Defense, Alex’s Lemonade Stand Foundation, the Medical Research Council in the UK, and the Italian Ministry of Health. 

In addition, she is a member of the editorial board for Current Molecular Medicine.  She was recently an invited speaker for the prestigious Distinguished Scientist Lecture Seminar at the National Cancer Institute in 2013.

Dr. Resar received her undergraduate degree from the University of Wisconsin in 1982 after an accelerated three year program and a medical degree with Honors in Research from the Medical College of Wisconsin in 1986. 

She completed both pediatrics training in addition to clinical and research fellowships in hematology-oncology at the Johns Hopkins University School of Medicine. 

In 1992, she received an American Society of Clinical Oncology Young Investigator Award and was recruited to the faculty of the Johns Hopkins University School of Medicine. 

Dr. Resar is board certified in Pediatric Hematology/Oncology, and she attends in the Hematology Clinic at the Johns Hopkins Hospital.

April Cashin-Garbutt

Written by

April Cashin-Garbutt

April graduated with a first-class honours degree in Natural Sciences from Pembroke College, University of Cambridge. During her time as Editor-in-Chief, News-Medical (2012-2017), she kickstarted the content production process and helped to grow the website readership to over 60 million visitors per year. Through interviewing global thought leaders in medicine and life sciences, including Nobel laureates, April developed a passion for neuroscience and now works at the Sainsbury Wellcome Centre for Neural Circuits and Behaviour, located within UCL.

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