“The Grand Challenge is designed to address really big, intractable questions in cancer. The idea is not to make small, incremental steps, but to make a huge leap forward.”
Thea Tlsty, PhD
$26 Million 'Grand Challenge' Project Will Probe Role of Inflammation in Cancer
Thea D. Tlsty, PhD, Professor of Pathology and a UCSF leader in cell cycling and signaling, received a $26 million Grand Challenge Grant from Cancer Research UK (CRUK) to lead an international team exploring how chronic inflammation causes cancer. Below, Tlsty talks about the 150-year-old pursuit of the inflammation-and-cancer question, and how very recent technological breakthroughs make possible this ambitious project.
Q. Congratulations on the Cancer Research UK Grand Challenge Grant. It is hugely competitive.
When you applied, how were you feeling about your chances of receiving funding?
A. The CRUK invited bold ideas from any investigator world-wide. We knew that obtaining this grant would be highly competitive, but we felt we had a great idea and novel approach to a very important question in cancer research.
Q. How did this project come about? How did you assemble the international team?
A. The CRUK identified a set of eight questions that are extremely difficult to address and extremely important in cancer research. When I saw the questions, the issue of chronic inflammation and how it might contribute to increased cancer incidence interested me the most, and I believed it had the potential for tremendous impact. My team at UCSF (Drs. Philippe Gascard, Deng Pan and Joseph (Tony) Caruso) discussed how to tackle this problem in a manner not previously done. Based on our ideas, we recruited the very best people from around the world to address the problem and join the team.
Q. What is the current understanding about chronic inflammation and cancer? How long have scientists been looking at it?
A. Scientists have known for almost 150 years that chronic inflammation plays an important role in cancer. The problem is that we do not understand how it contributes to the disease. As a field, multiple scientists have been studying this for several decades and progress is happening.
Q. What are the known or suspected causes of chronic inflammation in the cancers most closely associated with it?
A. Any area of the body that is exposed to chronic irritation or injury will develop chronic inflammation – and be at a higher risk for cancer. This can be due to acid reflux from the stomach into the esophagus and the resulting continued damage to the esophagus. An additional cause can be bacteria that damage infected tissue. For example, chronic infection with the bacteria Helicobacter Pylori is linked to stomach cancer. Similarly, chronic bacterial infection in the colon leads to Inflammatory Bowel Disease (IBD), and in some cases, colon cancer. Also, unresolved viral infections (such as hepatitis B in the liver) cause chronic inflammation that quite often leads to deadly liver cancer. The causes of chronic inflammation are numerous.
Q. What makes this project a Grand Challenge? How is it innovative?
A. Our proposed project qualifies for the Grand Challenge because it takes on the big questions of how chronic inflammation contributes to increased cancer incidence from the beginning of the process all the way to the lethal end. Not only that, we suspect that the process that happens in the esophagus is similar to the process that happens in the stomach, the colon, the pancreas, the liver, the lung, etc.
We believe that by understanding and comparing several of these chronic inflammation-associated cancers, we can find a common process that can be extended to numerous cancers falling into this category.
Our project will seek to find the commonalities and target them for prevention and intervention of these deadly cancers. Very few funding opportunities allow for such broad and ambitious goals from a team approach. Finally, most work in this area focuses on the cells that are transformed to cancer – epithelial cells. Our proposal makes use of the recent data that indicate that the microenvironment (called the stroma) surrounding the transformed cancer cells can play a critical role in whether a cancer will form or not and whether it will progress to lethal disease. Our group will seek to characterize the microenvironmental (stromal) signals associated with chronic inflammation and responsible for cancer progression in order to devise novel methods of modulating their contributions.
Q. Would a project like this have been viable five or ten years ago?
The question we are addressing, and the manner in which we are addressing it, could not have been attempted even five years ago. There have been several significant breakthroughs in how we think about cancer cells, plasticity of cell fates, tissue interactions, systems biology, mechanotransduction and stromal cells that make this project attractive at this time.
Additionally, powerful new technologies give this project tremendous potential to make significant advances. These include single cell RNA sequencing, as well as multiplex immunostaining and imaging that allow us to capture “neighborhood” characteristics in the tissue and to infer the signaling networks involved in cancer. Another is the reconstitution of human organs in microfluidic devices (organs-on-chip).
Q. The team includes four patient advocates. What is their role?
A. Patient advocates play several critical roles on our team. Some people become patient advocates because they are cancer survivors, while others do so because of loved ones who died of cancer. Our advocates educate our investigators about patients’ perspective of the diseases we study. They also educate fellow advocates and the patient community about our team’s novel approach to addressing these lethal diseases. Our advocates provide feedback on our initial ideas and evolving research plan. They help us surmount barriers to acquiring tissue specimens or critical information. Advocates are embedded in each sub-project and in the steering committee. We are fortunate to have such dedicated people who are passionate about solving the problems posed by these diseases.
Q. How have UCSF and the Helen Diller Family Comprehensive Cancer Center enabled or contributed to the direction of your work and this project?
UCSF and the Helen Diller Family Comprehensive Cancer Center provide an outstanding environment for studying lethal cancers, and they encourage us to tackle the most difficult questions. As this proposed project matured, several key people provided critical support. Drs. Jayantha Debnath, Scott Oakes, Avril Ma, Alan Ashworth, and Allan Balmain were among members from multiple departments and the Cancer Center who provided input from inception through our final application interview. Brilliant colleagues from surrounding companies and institutions in the Bay area also provided valuable critique and advice. The input provided by these colleagues improved our application tremendously.
Q. What is the duration of the project and where do you hope it will lead?
The funding from the CRUK Grand Challenge will last five years. We hope that our efforts will revolutionize the way we diagnose, slow, and even treat these chronic inflammation-associated lethal cancers.
This is a tall order, but we believe that we have assembled an outstanding team focused on delivering on these promises. We hope that five years from now our work will have made a big impact in the field.