By Paul Nicolaus
May 18, 2017 | It was the excitement surrounding a new treatment back in 2003 that nudged Muller Fabbri to leave his clinical career and home country of Italy behind. A 30-year-old medical oncologist at the time, he had just returned from a meeting where he heard a talk centered on a new option for pancreatic cancer.
It was clear that the development had already garnered plenty of attention. “And the big deal was that the new treatment was adding two weeks of survival,” he said. Frustrated that this type of incremental change was perceived to be outstanding, he looked himself in the mirror that day.
“Maybe you are about to make the biggest mistake of your life,” Fabbri said to the image staring back at him. After all, staying put and continuing to practice oncology was the safe bet. But he just couldn’t shake the desire to do something more. “This is when I made the decision to leave my country, to leave my career, and to embrace this new exciting adventure,” he said, “and I don’t regret it for a second.”
Fast forward nearly 15 years. Now an assistant professor at the Children’s Center for Cancer and Blood Diseases at Children’s Hospital Los Angeles and Department of Microbiology & Molecular Immunology at the Keck School of Medicine of the University of Southern California, Fabbri is a researcher on the forefront of the battle against cancer.
“Cancer is a very smart disease, incredibly smart,” he said, “but you know we can be smarter.” There is a need to clearly and fully understand how cancer operates to outwit the disease. “Once we know the mechanisms that it is working with we can actually exploit those to our advantage for new therapies.”
Two and Two Together
Even a decade ago the focus was on the cancer cell itself. “We were all doing our experiments in our flasks and in some cases with exciting results,” he said. But when these approaches were applied to a more complex model, usually a mouse, most of the time the results weren’t so exciting. It became apparent that the cells surrounding the tumor played a key role as well.
“I would say that this interaction between the cancer cell and its own tumor microenvironment is just witnessing at the cellular level that we are social,” Fabbri said. “It’s certainly intriguing that there is this communication between cells. They really are talking to each other.”
What was known is that the tumor microenvironment and cancer cells interacted by exchanging proteins called cytokines, and a lot of effort was poured into attempts to see which cytokines are exchanged and how this affects the biology of the tumor. As researchers began detecting microRNAs in blood and then in other biological fluids, Fabbri took note. Then a group in Sweden demonstrated that these microRNAs are contained in exosomes and can be moved from one cell to another.
“Putting two and two together–the fact that they can be detected in the blood and the fact that they can be shuttled from cell A to cell B–made me think of another group of molecules that do this in our body,” he said, “and these are hormones.” While the traditional mechanism of action for microRNAs is to regulate the gene expression by binding to specific messenger RNAs and preventing them from being translated into proteins, hormones work by binding to a receptor.
The goal, then, was to identify the receptor for microRNAs, and in a 2012 study, (DOI: 10.1158/0008-5472.CAN-12-3229) Fabbri revealed that microRNAs can bind to Toll-like receptor 8 (TLR8) and activate its downstream signaling, which identified a whole new layer of crosstalk between the tumor microenvironment and the cancer cell.
“The concept of the TLR family of receptors being able to recognize microRNA was entirely novel and suggestive of a new way for microRNA to communicate,” Neil Bhowmick, associate professor of medicine at Cedars-Sinai Medical Center, said of Fabbri’s study.
Cancer cells secrete microRNAs within exosomes. Two of the microRNAs released by cancer cells (miR-21 and miR-29a) can be taken by macrophages and then bind to their TLR8. This, in turn, leads to the activation of the NF-kB pathway and an increased secretion of cytokines and other exosomic microRNAs, which promotes cancer growth and resistance to chemotherapy.
It turns out the whole idea that the more immune cells that are present in the tumor, the better it is for the patient, is not necessarily true because cancer cells can inflate the immune cells to their advantage through this mechanism.
Next Steps
“My work is really trying to understand better and to help the scientific community better understand how the tumor microenvironment works,” Fabbri said. Although neuroblastoma, the most common form of extra-cranial solid cancer among infants, is the model used to publish his data, Fabbri is most interested in finding the basic mechanisms that all types of cancer share.
The findings that have been published so far, including a 2015 Journal of the National Cancer Institute paper (DOI: 10.1093/jnci/djv135) on the exosome-mediated transfer of microRNAs, have identified the mechanism and the molecules involved. The next step is to translate this discovery into something helpful for patients, and this goes in two directions.
On the diagnostic side, modulating the interaction between the microRNA and the receptor to exploit the exchange of exosomes and their microRNA content is a way to identify new biomarkers for tumors that are particularly resistant to chemotherapy or that might be sensitive to treatment.
Therapeutically speaking, tools are being developed to direct the content to the cell involved in this crosstalk. “And that is where my lab is working now,” Fabbri said. While still at the early stages of this discovery, if the data continues to show promise it is feasible that his current research could lead to clinical trials in the next 8 to 10 years.
“This is a tremendously exciting line of cancer research,” Susan Erdman said of Fabbri’s work. While the immune system is an important element of cancer prevention and treatment success, it is also challenging to harness for sustained benefit due to factors such as immune feedback loops, redundancy, and plasticity, explained the MIT research scientist. “Overall, the strategy has enormous potential.”
Bigger Picture
Fabbri’s work falls within a much bigger picture of research that really ramped up about a decade ago and includes the efforts of Bhowmick and Erdman. The Tumor Microenvironment initiative was launched by the National Cancer Institute (NCI) in 2006 and then reissued for another five years in 2010 to foster multi-institutional and transdisciplinary groups capable of growing the understanding of the role of the tumor microenvironment in cancer initiation, progression, and metastases.
The endeavor funded 20 centers in total (9 during 2006–2011 and 11 during 2011–2016) that formed the Tumor Microenvironment Network (TMEN). Also spanning that decade of research were 10 Collaborative U01 programs that brought together a TMEN investigator and researchers with expertise in other biological systems to form new projects. This was an opportunity to explore new questions, bring in additional expertise that wasn’t already part of the consortium, and expand the comprehensive scope of the initiative.
Bhowmick’s TMEN Collaborative U01 project examined the role of TGF-B signaling in osteoblasts and osteoclasts in the bone microenvironment and the effect on bone metastases, and Erdman’s focused on interactions between the GI tract microbiome and breast tumor stromal cells. Both researchers notice areas of overlap between Fabbri’s work and their own. For example, the concept of microRNA found in exosomes as a means of cell to cell communication can apply to many disciplines, Bhowmick pointed out.
And there are plenty of common denominators in local and systemic immunology relating to Erdman’s research (that focuses on how microbiota stimulate or inhibit the immune system to prevent or treat cancer) and Fabbri’s work. The microbial strategy explores the possibility of sustaining immune benefits by colonizing with beneficial microbes or stimulating with microbial products, she explained.
“Dr. Fabbri’s research has blazed new frontiers and is of huge interest to the tumor microenvironment research community,” Erdman added. “We don’t yet have all of the answers to help the body stay healthy, heal itself, and conquer cancer, but this research provides tractable targets, important clues, and missing puzzle pieces to broader NCI goals.”
Multidisciplinary Minds
These observed intersections and overlaps are emerging from a field that has had the chance to develop. When the NCI program first began over a decade ago, tumor microenvironment research was a fledgling discipline, explained Elisa Woodhouse, program director of the Tumor Biology and Microenvironment Branch in NCI’s Division of Cancer Biology.
Because of the amount of cell types and interaction involved, there was a sense at that time that a consortium of interdisciplinary researchers was needed to understand the biology of the tumor microenvironment and how that impacts the tumor. A network could bring investigators together and allow them to interact and decide what tools and resources were needed. This, in turn, could help nurture the emerging field. “And indeed, there is a lot of research now in the field. The field has matured,” she said, and “it continues to grow.”
“We’ve learned that there are reciprocal interactions between the tumor and the microenvironment and they are influencing each other and changing each other," Woodhouse said of the initiative and its decade of research and discoveries. "We’ve learned what much of that is, but the more we know, the more we’ll understand about cancer development, cancer progression, metastasis, and also therapeutic response.”
Although the initiative has come to an end, Woodhouse said this remains an active area of research. And while there have traditionally been two distinct disciplines – one focused on the study of the tumor vasculature, the ECM, and the pathophysiology of metastasis and the other concentrated on the role of the immune system and immunotherapy – these fields are beginning to come together.
The complexity of the many different cell types, aspects of biology, and questions being posed lends itself to a wide range of disciplines. As such, there is an ongoing need to reach out to and incorporate an array of scientific disciplines, such as engineering, imaging, nutrition, metabolism, and environmental science to meet the challenges posed. “And the more that they can come together,” Woodhouse said, “the more they can share information and put the pieces together.”
Paul Nicolaus is a freelance writer specializing in health and medicine. Learn more at www.nicolauswriting.com.