Gail Sonenshein, PhD.
Dr. Sonenshein is a member of the Find The Cause Research Consortium and a
Professor of Developmental, Molecular and Chemical Biology at Tufts University School of Medicine
FTC: How did you become a cancer researcher?
Dr. Sonenshein: I came to cancer research a little bit via the “Immunology backdoor”, as did our Consortium Chair, Dr. David Sherr. I went to M.I.T. as a Visiting Scientist to study how an antibody was made and how its synthesis was regulated. I was supported by a prestigious American Heart Association Established Investigator award, and worked with researchers in the labs of Malcolm Gefter and Nobel Laureate David Baltimore. We used a common mouse cell model, called a myeloma, which is a transformed (cancer) version of an antibody-producing B cell. The advantage of using the myeloma line was that these cells grow better than normal cells and only make one of the thousands of possible antibody (also known as immunoglobulin) molecules. Our research group was one of the first to successfully identify (clone) the mRNAs making the 2 types of chains in the antibody molecule: the Light (L) and Heavy (H) chains. This was in the incredibly exciting early days of gene cloning. With my knowledge of cloning, the L and H chain clones that we had isolated and a major publication in the highly visible journal Nature, I landed an Assistant Professorship in the Biochemistry Department at Boston University (BU) School of Medicine. In my own lab, we made several critical discoveries, one of the most important ones was that in the myeloma cells the H chain gene was not at all normal: it was rearranged. Importantly, the H chain gene was now connected to a specific cancer causing gene (or Oncogene) called c-myc. This gene rearrangement led both to increased production of a single antibody molecule and to uncontrolled growth. We then began studying the roles of oncogenes in normal cells and what happens to them to drive cancer. In retrospect, with that decision I began a lifelong study into cancer asking the questions: how do normal cells become cancerous, how are oncogenes regulated, what drives tumor cell growth and spread and how can we target those genes? More recently we are determining what are the roles of environmental carcinogens. Is there a faster way to detect the effects of carcinogen exposure so that we can prevent/intercept or detect cancers earlier, and can we develop a targeted therapy to treat breast cancer patients?
FTC: What compelled you to study breast cancer?
Dr. Sonenshein: The short answer is my overarching interest in women’s health. In the beginning, my lab was focused entirely on immune cell cancers. One day, I read an article in the NY Times about a new Residency program for young physicians in Women’s Health. I knew how important this training would be from a friend whose mother died of a heart attack after seeing her doctor multiple times because he didn’t know that heart disease can present differently in women and men. He missed the early signs. He sent her home with Tums, while in fact, she was having a heart attack. But as I was going to sleep, I thought that it really didn’t relate to me since I have a Ph.D. and will never see any patients. When I woke up the next day, I realized that it did relate to me since I care intensely about women’s health, but I was not using my skills and cancer knowledge to address any specific women’s health issue. After a few days of mulling this over, I decided that I would switch my lab over to working on breast cancer. I did some retraining with a sabbatical, and then as new students or postdoctoral fellows arrived in the lab, they were given a project on breast cancer. Since that time, my lab has worked on elucidating how breast cancer cells grow and spread, the role of environmental carcinogens in activating oncogenes, how breast cancer cells become resistant to chemotherapy, identification of druggable targets, and more recently on development of an antibody-based therapy. I also felt that BU Medical School should lead the country and develop a center for research on women’s health. I met with my Chair, the Dean, and women faculty across the campus. We decided that the center should be interdisciplinary and cover multiple health issues related to women. We started with a “Program in Women’s Health Research”, which launched a breast cancer working group that had a major focus on environmental carcinogenesis. Our group, which included Dave Sherr and David Seldin, was able to obtain support from the Avon Foundation. The results of our initial studies led to the awarding of a large multi-investigator (Program Project) grant from the National Institutes of Environmental Health Sciences. In part due to our funding successes, the Women’s Health Interdisciplinary Research Center (WHIRC) was officially launched in 2005 as a cross-campus center and I was honored to serve as its first Director.
Graduate School Portrait
Receiving The Tufts Inventors Award in 2019
FTC: Please give us an overview of your work and how it fits in with the work of the Consortium?
My main project is to develop an assay that will give an early warning signal of exposure to a cancer-causing chemical (carcinogen). The idea is based on two important pieces of information we obtained in our earlier work. 1) Genes that transform normal cells into cancer cells work in part via induction or inhibition of tiny messenger molecules called micro RNAs (miRNAs). 2) These miRNAs can be found in the serum of patients in levels commensurate with the transforming gene activity (i.e., either high or low). The strategy is to identify miRNAs induced by a common family of carcinogens and use this information in a liquid bioassay (blood draw) to determine whether a person has been exposed to one of those carcinogens. Members of the consortium are all using the same model system, developed by David Sherr, in which mice are treated with the environmentally common carcinogen called BaP and then examined right after exposure, midpoint after exposure but before tumors arise, and finally after tumors grow. Dave is also treating some mice with an inhibitor of a receptor that actively mediates the cellular changes for many common carcinogen, which allows us to confirm the signaling pathway. My lab has to date isolated miRNAs from untreated animals and at the midpoint after carcinogen exposure. Once we collect the final samples (post tumor development), we will be analyzing all samples together using a powerful molecular technique that allows us to identify every change in miRNA expression. We will then work with Stefano Monti to analyze the data statistically and identify a panel of prognostic miRNAs. A follow-up experiment will confirm the ability of the selected miRNAs to predict exposure to carcinogen. The power of the Consortium is that other changes resulting from carcinogen exposure, e.g., in the immune system, are being followed in the same mice. Since we are all studying the same model system but from different perspectives, we are able to cast a wide net and identify complimentary information that can be associated with cancer progression and used in prevention, detection, and/or treatment. A timeline to identify common links or pathways would not be obvious or readily achievable in work by a single investigator.
The Find The Cause Research Consortium
(Left to Right: Dr. Stefano Monti, Dr. Charlotte Kuperwasser, Dr. Gail Sonenshein, and Dr. David Sherr)
FTC: Where do you see science on prevention going in the next ten years?
Dr. Sonenshein: I believe that in the next 10 years scientists will develop several important new tools for prevention. Firstly, fast, inexpensive liquid bioassays that will be able to test in real time for carcinogen exposure will become available. We are already seeing papers that report on the identification of changes in expression of miRNAs that result from carcinogen exposure. Several of these act like oncogenes and their presence indicates potential problems ahead. Identification of these early changes will give time to seek out and hopefully block the molecular effects of the specific exposure and possibly intercept its action, thereby prevent tumor development. More rapid assays are also being developed to identify which compounds are carcinogens. Acceptance of such assays by the EPA would speed up the time needed to identify and prevent further exposure to these carcinogens, e.g., in the environment, or our food chain or in skin care products such as cosmetics.
FTC: How do investments from FTC impact your research?
Dr. Sonenshein: It is impossible to overstate how much FTC funding means for our work. As it has become more and more difficult to obtain government funding, the amount of preliminary data required to satisfy the review committees has grown to where you have to have completed almost half of the project to be seriously considered for funding. And given that prevention is the poor cousin to treatment with respect to the NIH funding pie, one needs even more data. To generate that amount of “preliminary data” requires substantial funding and FTC is doing just that. As a gardener, I have used the analogy of FTC providing the seed funding that can grow into a huge tree, which is very apt. Personally, I am extremely grateful to the FTC for their support.
FTC: On a personal note, you are a mother and a grandmother, and you shared in our recent scientific panel discussion that your niece was just diagnosed with breast cancer. To what extent does this impact your sense of urgency to move the science of prevention forward.
Dr. Sonenshein: I have lost many family members to cancer. My Mom and her brother died in their senior years. But my brother was only 49 and it is his oldest daughter who was recently diagnosed with breast cancer. In my family’s case, I believe there is a genetic issue. That said, I also believe the environment is likely playing a critical role given the divergence in ages and cancer types. So yes, these cancers light an internal fire for me. And yes, I worry about my daughter and son and my 2 grandchildren. So, it is very accurate to say that I am highly motivated to contribute and to make a difference in the science of prevention.
Dr. Sonenshein and family at the NYC Museum of Natural History, 2019