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Marian Waterman in front of brick building

Scientist who discovered protein involved in cancer metastasis named Alumni Fellow

By Srila Nayak

Alumna Marian Waterman, professor of microbiology and molecular genetics at the University of California, Irvine

Marian Waterman (B.S. ’81), professor of microbiology and molecular genetics in the School of Medicine at the University of California, Irvine (UCI), was honored with the 2018 Alumni Fellows Award at the OSU Alumni Association’s awards ceremony on October 18. The award recognizes eminent alumni who have distinguished themselves in their professions and communities.

At the beginning of her stellar career, while still a postdoctoral scholar, Waterman discovered a new type of gene regulatory protein, a transcription factor called Lymphoid Enhancer Factor 1 (LEF1). During pre-natal development, LEF1 is highly expressed in the majority of developing, proliferating tissues of the fetus. In adults, LEF1 is most highly expressed in white blood cells (B and T cells) and in tissues that continuously regenerate from stem cells (skin, intestine, bone, etc). Waterman, in addition to other cancer researchers who began to focus on LEF1, discovered that LEF1 is implicated in growth and metastases in a wide variety of cancers.

Waterman’s breakthrough discovery has had profound and far-reaching consequences for cancer research: Not only was LEF1 found to play a very important role in mediating Wnt signaling during normal tissue regeneration, but it also plays an important role in carcinogenesis in the intestine and many other types of tumors (especially in Leukemia, lung cancer, liver cancer, etc). How exactly LEF1 directs tumor cells to proliferate and metastasize is an ongoing area of research, not only for Waterman and her research mentees, but also for laboratories around the world now focused on finding ways to stop Wnt-linked cancers.

Waterman is a leading expert on LEF/TCF expression patterns, protein structure and activities, Wnt signaling, gene expression, as well as the basic science of cancers such as colorectal cancer and leukemia. An author of more than 100 research articles, Waterman is the Director of the Cancer Research Institute, the basic science arm of the Chao Family Comprehensive Cancer Center, as well as the Deputy Director of the Cancer Center.

Recently, Waterman and her colleagues received a $10 million National Cancer Institute grant to establish a new Center for Cancer Systems Biology at UC Irvine, a center focused on developing new approaches to understand the complexity of different types of cancers and develop better treatments.

Waterman received her bachelor’s degree in biochemistry/biophysics from Oregon State University in 1981, and her Ph.D. from the University of California, San Diego (UCSD). She was a postdoctoral scientist at the Salk Institute (1987-93) before joining the University of California, Irvine as an assistant professor, where she has remained and is currently a full professor.

What made you select Oregon State University for your undergraduate studies? Have you stayed in touch with any faculty?

Waterman: I am homegrown. I went to junior high and high school in Corvallis. After graduating from Crescent Valley High School, I went to Oregon State to study biochemistry and biophysics.

I am definitely still in touch with OSU faculty. They were influential in my career. I return home two to three times a year to check in with my parents who still live in Corvallis. I make a point of meeting with Dr. Christopher Mathews (emeritus professor and former chair of the Department of Biochemistry and Biophysics). I also check in with James Summerton of Gene Tools because he was at OSU when I was a student and I worked with him for a year. And I often check in with Kevin Ahern and Indira Rajagopal, two colleagues I knew during our graduate student days at UCSD.

What were the best things about being a biochemistry and biophysics student? Did those experiences shape and influence your career as a scientist?

Waterman: What was particularly special was that the department had a sense of community, and I think that was driven by the chair at the time, Christopher Mathews. By a sense of community, I mean that undergraduates had opportunities to work in research laboratories and were encouraged to attend research seminars. Actually, I started working in Dr. Mathews’ laboratory because I needed money for tuition, and for the last two years at OSU, I also needed money for basic living expenses. Eventually, he noted my interest in research and assigned me a small project. I met with him weekly to go over my experimental design and results. I want to point out how unusual this is. The chair of an academic department is very busy with multiple demands on his/her time.

“To meet weekly with an undergraduate is incredibly generous. But that was the culture of the department. Students mixed with faculty outside the classroom, in the laboratory, at seminars, at holiday gatherings—a nurturing environment for involving undergraduates in research and encouraging them to continue on an academic career track.

“I should add that the undergraduate classes for the biochemistry/biophysics major were quite rigorous; we were schooled in the fundamentals and that prepared me very well for graduate school.

What were some of your formative experiences at OSU?

Waterman: The formative experience for me was being given the chance to do experiments in Dr. Mathews’ laboratory. I also had the opportunity to do research with Jim Summerton – who was at the time developing the scientific framework for what would eventually become GeneTools. Dr. Summerton’s passion for his work and his creativity were influential. In both laboratories, I relished the chance to work on my own project where I generated my own data and worked to interpret the results. I realized I loved the process of discovery. Yes, the classes were really great but the formative experience was being given the opportunity to perform research in a laboratory.

How and when did you get started on cancer research?

Waterman: Moving into cancer research was not planned, it happened because of my discovery of the regulatory protein LEF1. After OSU, I applied to graduate programs in physiology and pharmacology because I was interested in the biochemistry of human health, particularly of the brain. I became a doctoral student at the University of California, San Diego, in the pharmacology and physiology graduate program. I studied how the production of hormones from the pituitary gland is regulated – research that had nothing to do with cancer.

Then I joined a laboratory as a postdoctoral fellow at the Salk Institute where I was assigned a project to understand how the HIV virus becomes active in T cells — a project also unrelated to cancer. However, work on this project led me to purify and discover LEF1, which I determined to activate expression of HIV1. LEF1 was an entirely new type of gene regulator. There was nothing known about how this protein worked. I took the LEF1 project with me to start my own research group as an assistant professor at the University of California, Irvine – aiming to study how LEF1 works in normal, uninfected T cells. About four years into developing my research program and obtaining grants to study this protein, a laboratory in Germany discovered that LEF1 played an important role in a pathway called “Wnt.” At the same time, other research groups were reporting that Wnt might be a driver of certain forms of cancer such as colon cancer.

A light bulb went off. Those two new discoveries changed my research program overnight. Instead of writing grants to understand how LEF1 works in T cells, I began writing grants to understand how LEF1 works in colon cancer. Because I was one of the few experts on LEF1 and the related TCF proteins, I established a presence in an international community that studies Wnt signaling in embryonic development and cancer — a presence I have maintained for 21 years.

My story is the typical story in science, where serendipity leads to new discoveries and pretty soon you find you are researching something you never expected you would ever think about. In my opinion this is one of the most exciting and addictive aspects of scientific research.

Can you describe some of your scientific breakthroughs?

Waterman: One important contribution was to define LEF1 and the related TCF proteins as a novel gene regulatory family (LEF/TCFs). There are four LEF/TCFs and we defined what those proteins are like structurally, what activities they are capable of, where they can be found in cells, what regulates their expression, what other proteins they directly bind to, etc. Another important contribution was to discover that the expression of LEF1 appears in colon cancer. That was a landmark paper.

More recently, we have been studying the genes that are regulated by LEF/TCFs and ascertaining how these genes work together to drive cancer. We have shown LEF1-activated genes trigger signals to the microenvironment that cause blood vessels to grow in and around the tumor so it can grow. We have also shown that LEF/TCFs drive cancer cells to adopt certain forms of metabolism, to use glucose in ways that enable them to grow faster. In more recent studies, we have been working to understand how LEF/TCFs drive cancer stem cells to be invasive and metastatic.

Have you seen the effects of your research on cancer treatments or other applications?

Waterman: Not directly. For more than 20 years since the discovery of a link between Wnt and cancer, many groups and all the big pharma companies have tried to develop new drugs that directly block Wnt signaling. To date, all attempts have failed. Partly because drug development is complex and expensive, but also, drugs that block Wnt signaling have significant side effects that are revealed in clinical trials. If there were a cancer-specific aspect to Wnt signaling that could be targeted that would be ideal. But so far, we and other groups have observed that Wnt signals in tumors are driving normal processes to be overactive — activities that are not very cancer-specific. The challenge is to discover differences that can be specifically targeted without harming normal cells.

For that reason, my research program is focused on first principals — the basic science of LEF/TCFs and how they mediate Wnt signaling in normal colon stem cells vs. colon cancer cells. The colon, in fact the entire intestine, is a fascinating tissue to study because it is one of the most dynamic and fastest growing tissues in the body, even more than skin. Every week the intestine has a new lining because Wnt signaling is driving stem cells to proliferate and replenish it. How LEF/TCFs direct such incredible rates of stem cell proliferation without causing cancerous overgrowth is important to understand. Once we understand how normal growth is constrained and directed, we can understand how aberrant Wnt signaling drives overgrowth, and invasive, metastatic properties in colon cancer.

Where I have had influence in changing the practice in clinical settings is in my role as deputy director of the Chao Family Comprehensive Cancer Center. I help develop programs to bridge collaborations with doctors and basic scientists with the goal of developing clinical trials that test new ideas of diagnostics and treatment. So, I am participating in the clinical realm in that way but my own research is quite basic.

How do you balance your administrative and leadership roles with your other responsibilities: research, teaching and family?

Waterman: It is very challenging. While my husband and I were raising a family, I focused my energies on my kids, my group research and my teaching. Now that my kids are grown, I have been devoting more energy to leadership and furthering larger initiatives. I now have the bandwidth to take on responsibilities such as the deputy directorship of the Chao Family Comprehensive Cancer Center, a National Cancer Institute center, and also directorship of the basic science arm of the Cancer Center that we call the Cancer Research Institute. These two responsibilities are linked. A high level of organization in my personal and professional life is key to handling all these responsibilities.

In April 2018, two of my colleagues and I were awarded a $10M grant to establish a new Center for Cancer Systems Biology at UCI. I am very excited about this center and its potential impact on innovative cancer research.

Reports suggest that fewer students are studying the basic sciences, such as biology, chemistry, mathematics and physics. For science students, the attrition rate can be pretty high. How would you emphasize the importance of studying the fundamental sciences to students and the value of sticking with science?

Waterman: I feel very strongly about this. Our world is complex and beautiful and terrible all at the same time and it is changing fast. Despite all the amazing discoveries of scientists and physicians that have come before us, the incredible fact is that we still do not understand very much about our world. Working towards an even deeper understanding will allow us to forge a better way forward to be on this planet and a better way towards health and longevity. This means we need basic scientists!

As far as encouraging students to “stick with science” and develop a career in science, I have served as chair of a national grant review panels at NIH and American Cancer Society, and I can quite confidently say that these funding agencies place great value and devote significant investment in basic science. We know from experience over the last several hundred years of scientific inquiry that fundamental new knowledge about how our world works is the fertilizer for applied science: developing new devices, new diagnostics, and new drugs. In other words, without basic science, the well of new ideas dries up quickly. I would advise students who are excited by our amazing world and interested in understanding how it works to consider a career in basic science.

“There will always be a place for basic scientists. A workforce that is focused only on applied science is unsustainable.”

Women continue to be underrepresented in STEM (science, technology, engineering and medicine) academic jobs. Can you talk about the factors that have played a role in your success as an academic?

Waterman: I am extremely fortunate. My parents were very supportive of me as a woman and a mother, and they encouraged me to pursue my career goals. My parents-in-law were also supportive in the very same way. My husband Harry Mangalam has been the most supportive in terms of promoting my career above his by following me whenever I had a job opportunity — I owe a great deal of my success to him.

I am a mother of two wonderfully talented kids. They are grown now, pursuing their own careers, but my husband and I shared responsibilities in raising them. Even though it was exhausting to do everything at once, to build an academic career and raise a family, it was beyond rewarding.

I have many women colleagues both in the medical school and in the main campus who are married to academic professionals. Almost without exception, they sought out a social network, mentorship by other women faculty, and they took a faculty position at a place like UC-Irvine that provides family support in terms of nearby childcare and subsidized faculty housing to help them save time commuting to campus. Therefore, they worked to establish an academic career where there were support structures in place and raising a family was logistically easier. I think this can make a tremendous difference to women in academic careers.

What was it like growing up in your family and how did you become interested in science?

Waterman: We moved to Corvallis when I was just starting junior high. My parents did not have opportunities to go to university, and they both worked extremely hard to make ends meet and support their three children. My parents were very positive and supportive and they encouraged us to do our best in academics, to go to university and to pursue careers. All three of us heeded their advice. My sister is a senior associate with an architectural firm in San Francisco, designing corporate spaces for companies, including Google and law firms. My brother is chief financial officer of The Kitchen, a farm-to-table restaurant now placed in 19 cities across the United States.

As for how I became interested in science: I was always interested in human health and biology in the natural world. When I was a student at Crescent Valley High School, our biology class had a laboratory section where I enjoyed doing experiments. I also did well in mathematics and biology courses. Obviously, one is attracted to subjects one does well in.

What did your parents do for a living?

Waterman: My father worked for the Union Pacific Railroad as a shipping clerk and my mother was a homemaker and then a bank teller. After my father quit the railroad, we moved to Corvallis. Both my parents, in the final part of their professional lives, worked at Summit Information Systems. My father was a mailroom shipping clerk and my mother was in the accounting department. I should add that my mother has been a piano teacher for 67 years and just retired from teaching this year.

Both my parents were able to attend OSU’s alumni awards ceremony and this meant a lot to me. My brother flew in as well. I come from a tight-knit family. I was just so honored that they could be there during this special moment.

How do you feel about your alumni award and recognition by your alma mater?

Waterman: I think this honor is the culmination of the efforts of a lot of people who have invested in my career – and the award is as much theirs as it is mine. Multiple people spent time mentoring me and giving me chances at OSU. They helped shape my career path and I am taking this opportunity to acknowledge that and thank them for it. I am very proud of my alma mater.

Do you wish to share any final thoughts with our readers?

Waterman: It has been a thrill and a privilege to pursue a career in scientific research and academia. If there is anything to emphasize, it is a message of strong encouragement for women, and all people from different walks of life interested in science, to continue their pursuit of a career in scientific research because it can be done and because our world needs them. I am not special, and if I can get this far so can anyone else.