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Muller Fabbri, M.D., Ph.D.: The microRNA journey and the future of cancer therapy

cancer cell

Children’s National Hospital welcomes Muller Fabbri, M.D. Ph.D., as associate director for the Center for Cancer and Immunology Research at the Children’s National Research Institute. In this role, he will build and lead the Cancer Biology Program while developing and conducting basic and translational research. Dr. Fabbri will also develop multidisciplinary research projects with various clinical divisions, including oncology, blood and marrow transplantation, pathology and hematology.

Dr. Fabbri shares his journey working with microRNAs, how his work is advancing the field and his vision for the Center for Cancer and Immunology Research at Children’s National.

Q: You have been working with microRNAs for quite some time. How are you exploring the role of microRNAs in cancer?

A: It was well established within the scientific community that a gene, which is a piece of DNA, becomes a piece of RNA and then becomes a protein. This thought process was pretty much a one-way flow of information that we had, going from DNA to protein as part of a cell function. But, almost 30 years ago, it was discovered that this is not entirely true because what happens is that some of these genes that are transcribed into RNA do not become a protein. Instead, they stay as RNA. Some of these RNAs are tiny and have short sequences, which is why they are called microRNAs.

I work primarily on microRNAs and non-coding RNAs and my research studies focus on the role that microRNAs play in cancer. I can take a cancer cell and a healthy cell and observe how these microRNAs are expressed in the two different cell populations. In this way, the microRNAs expressed in cancer cells are profoundly different from the microRNAs expressed in healthy cells.

We conducted a series of studies to observe what happens to a cancer cell if we restore normal levels of certain microRNAs like the ones you would see in a normal cell. We discovered that by restoring some of these microRNAs levels it led to the death of the cancer cells, suggesting that this approach may be used as a cancer treatment. This is one of the research areas that I will further develop at Children’s National as I seek to understand the mechanisms that control microRNA expression and subsequently affect cancer cell proliferation. With this information, we can target these mechanisms and create drugs that interfere with this function and, hopefully, stop cancer cell growth.

Q: Can you tell us about that eureka moment with your best friend during a lunch break?

A: This was a bit of a crazy idea. I will never forget. I shared a theory during a lunch break with a friend. I dared to ask, what if microRNAs worked like hormones? MicroRNAs can be detected in the blood of patients with cancer, and they can be transferred from one cell to another inside of little vesicles called exosomes. If you think about it, I further asked, what other molecules in our body behave like that — i.e. are secreted, circulate in the blood and then transferred to a target cell? My friend replied, “well, those would be hormones.” To which, I added, yes, exactly! Then, why do we not think of RNAs as hormones? And I quote him now, “you are crazy, but if it works it is huge.”

I felt that I had some validation from my best friend, so I decided to invest in this crazy idea, carving extra time on the side while working on my “safe” projects. It was one of those rare cases in science, where in a little over a year, we showed for the first time that microRNAs do not only work the traditional way, but they can also work as hormones. They do have a receptor protein to attach to, and by binding to this protein, they trigger a response in a cell that can be pro-tumoral or anti-tumoral.

Even today, if you open a textbook of endocrinology, under the chapter of hormones, it mentions that there are only two categories, proteins and lipids. Well, it turns out there is a third category, which is nucleic acids because of RNAs.

Q: You mentioned other research areas of interest as it relates to cancer cell biology. What are they?

A: The other line of research that I am developing stems from the original observation that I made in 2012. Cancer cells release tiny vesicles that I like to compare to envelopes containing a written message — the RNA and microRNA. These vesicles released in the surrounding environment contain a message captured by immune cells, known as macrophages. Macrophages act as scavengers in our bodies. In cancer, macrophages are supposed to digest and destroy the cancer cell. However, it turns out that they also have the proper receptor to receive and read the message enclosed in the vesicles. Then, something shocking happens. The macrophage stops fighting the cancer cell and starts producing proteins called cytokines that promote cancer growth. This finding means that we are 180 degrees apart from what we thought at the beginning. A lot of macrophages in the cancer are good news for the patient because they are supposed to kill cancer cells, but because of this mechanism, a lot of macrophages can be bad news since they can also help the cancer cell grow.

My contribution to this discovery was to investigate how the macrophage response is mediated. I discovered that macrophages operate, at least in part, by expressing receptors that bind to microRNAs released by the cancer cell, thereby favoring cancer growth. In the pediatric cancer field we discovered that because of this microRNA–receptor interaction, the pediatric tumor neuroblastoma becomes resistant to chemotherapy. Therefore, one of the strategies we are working on now is to interfere or impair these negative communications between the cancer cell and immune cell. We want to disrupt these communications so the macrophage cannot read the message from the cancer cell anymore and instead keeps doing its job to fight the cancer. We hope that we can leverage this approach to develop novel cancer treatments or create strategies that improves immune cell function in the presence of the patient’s current therapy to enhance an anti-cancer treatment response.

Q: What is your vision for the Center of Cancer and Immunology Research?

A: I am very excited about what I saw at Children’s NationalI was delighted to talk to many faculty members, and I recognized the immense talent within the Center. I would like to help elevate and enhance the cancer biology program focused on solid tumors, and augment the work being done in this space by the cell therapy program. The clinicians are clearly eager to collaborate with the basic scientists including the sharing of samples and ideas, which is not typical of many scientific environments. My other goal is to ensure that the Cancer Biology Program plays a central role in acquiring an NCI-Designated Cancer Center recognition often given to institutions that stand out in scientific leadership and clinical research. Finally, I want to create the first national center that develops extracellular vesicles as an innovative treatment strategy for cancer. Importantly, I think that we have all the resources and connections at Children’s National that are necessary to realize this vision!

 

‘Trojan horse’ macrophage TNF-alpha opens door for HIV-1 to enter kidney epithelial cells, causing nephropathy

macrophage

Like a Trojan horse, the macrophage sits atop the epithelial cell with HIV hidden inside, opening a doorway into the kidney cell for high levels of HIV-1 to enter.

When nephrologist Patricio Ray, M.D., began investigating human immunodeficiency virus (HIV) as a renal fellow, children infected with the virus had a life expectancy of no more than seven years, and kids of African descent curiously were developing a type of HIV-related kidney disease.

HIV-associated nephropathy (HIVAN) is a progressive kidney disease seen in people who are both HIV-positive and of African ancestry. Kids who carry a modified protein that protects them against sleeping sickness are 80 times more likely to develop this type of kidney disease. Due to the kidney damage, they can have abnormal amounts of protein in their urine, focal segmental glomerulosclerosis, and microcystic tubular dilation, which can lead to enlarged kidneys and chronic kidney failure.

“No one understood how HIV could affect kidney cells that lack the receptors expressed in T cells and white cells,” recalls Dr. Ray, Robert Parrott Professor of Pediatrics at Children’s National Health System. Virologists said kidney epithelial cells that lacked CD4, a major receptor where HIV attaches, could not be infected with the virus. Nephrologists, meanwhile, were seeing that HIV infection was damaging these cells.

It’s taken two decades to unravel the medical mystery, aided by urine samples he coaxed kids to donate by offering them the latest music from New Kids on the Block in exchange for each urine bottle. Many of the kids died years ago, but their immortalized cells were essential in determining, through a process of elimination, which renal cell types were capable of being infected by HIV-1.

The paper represents the capstone of Dr. Ray’s career.

“This is how difficult it is to get an important contribution in science,” he says. “It’s 20 years of work involving the excellent contributions of many people, but that’s why research is called research. In the end, it’s all a learning process. But, it’s amazing how the puzzle pieces begin to fit. When the puzzle fits, it’s good.”

Dr. Ray, in collaboration with lead author Jinliang Li, Ph.D., and four additional Children’s National co-authors, published a paper November 3 in the Journal of the American Society of Nephrology that establishes a new role for transmembrane TNF-alpha, that of a facilitator that makes it easier for the HIV virus to enter certain cell types and replicate there.  Like a Trojan horse, the macrophage sits atop the epithelial cell with HIV hidden inside, opening a doorway into the kidney cell for high levels of HIV-1 to enter.

As a starting point, the research team cultured podocytes from the urine of kids with HIVAN. Through a number of steps, they isolated the unique contributions of the HIV envelope, heparan sulfate proteoglycans as attachment receptors – the glue that binds HIV to podocytes – and the essential role played by TNF-a, a 212-amino acid long type 2 transmembrane protein, in regulating at least two processes, including viral entry and fusion. They used a fluorescent marker to tag HIV-1 viruses, so it lit up bright green. Thus primed with transmembrane TNF-a, the podocytes were susceptible to HIV-1 infection when exposed to high viral loads.

Additional research is needed, such as in vitro work to help understand how HIV traffics within the cell, Dr. Ray says. Those insights could winnow the list of existing therapies that could block key steps, such as attachment to the viral envelope, which could help all people of African descent carrying the genetic mutation, including underserved kids in sub-Saharan Africa.

Another open research question is that certain cells located in the placenta and cervix express TNF-a, and may be more likely to be infected by HIV. Blocking that process could help prevent pregnant HIV-positive mothers from transmitting illness to their offspring.