$26 Million ‘Grand Challenge’ Project Will Probe Role of Inflammation in Cancer

UC San Francisco Professor Thea Tlsty, PhD, is a winner of the “Grand Challenge” competition sponsored by Cancer Research UK (CRUK), an ambitious international funding initiative that aims to answer some of the biggest open questions in cancer. Tlsty’s international team will receive £20 Million (U.S. $26 million) to uncover how chronic inflammation causes cancer.

“The Grand Challenge is designed to address really big, intractable questions in cancer,” said Tlsty, Professor of Pathology and former director of the Program in Cell Cycling and Signaling at the UCSF Helen Diller Family Comprehensive Cancer Center. “The idea is not to make small, incremental steps, but to make a huge leap forward”

CRUK launched the Grand Challenge in 2015 to bring together scientists from around the world and from different disciplines to find solutions to cancer’s toughest challenges. Phase 1 of the program ended in 2017, with four winning teams selected from a pool of 57 applicants. Phase 2 proved even more competitive, with three winning teams selected from 134 entries.

“I’m not aware of any funding opportunities anywhere in the world that can begin to integrate this many international cancer experts on projects of such clear importance,” said Edward Harlow, PhD, member of the Grand Challenge Advisory Panel and the Virginia and D.K. Ludwig Professor of Cancer Research and Teaching at Harvard Medical School. “These teams have been brought together to tackle many of the biggest challenges we currently face in cancer research. We can see from the progress already achieved how powerful it is to support collaborations of this scale.”

Chronic Inflammation Drives a Quarter of All Cancers

Tlsty will lead a team that includes scientists, clinicians and patient advocates from the U.S., Canada, Israel and the U.K. Their efforts will focus on understanding how chronic inflammation drives some of the most aggressive forms of cancer. 

Inflammation is a normal part of the body’s immune response and occurs when white blood cells release protective molecules in response to cellular damage, foreign substances or infectious pathogens. 

“Inflammation is often the first line of defense after injury or infection,” Tlsty said. “But it turns out that chronic inflammation is directly responsible for several lethal cancers that result in 25 percent of cancer deaths worldwide. That’s over 2 million people who die of chronic inflammation–associated cancer each year.”

Though chronic inflammation causes a variety of cancers, Tlsty’s team will focus on four — certain types of esophageal, lung, stomach and colon cancer. These cancers are especially aggressive and, according to Tlsty, by the time patients receive a diagnosis, it’s usually too late. Tlsty believes that her team’s efforts will drastically improve outcomes.

Common Culprit Links Inflammation-Associated Cancers 

Each inflammation-associated cancer appears to have its own unique cause. Esophageal cancer caused by severe acid reflux disease, which irritates and inflames the esophagus, seems entirely unrelated to stomach cancers caused by the bacteria H. pylori, which inflames the gastric lining and also causes peptic ulcers.

Despite these apparent differences, Tlsty argues that a common process underlies each of these chronic inflammation-associated cancers — a process that has been largely ignored.

“These cancers are a collaboration between what’s happening with cells called epithelial cells and what’s happening in the surrounding cells and proteins known as the stroma,” said Tisty. “Most people studying chronic inflammation–associated cancer only look at the epithelial cells that turn into cancer.”

Epithelial cells — which line the surface of organs, including the esophagus, lung, stomach and colon — are the cells that are transformed into cancer in response to chronic inflammation. But chronic inflammation also injures stromal cells, which play an important part in whether epithelial cells become malignant.

“If I take epithelial cells normally incapable of generating tumors and put them next to stromal cells from a cancerous area, the injured stroma sends signals that turn these epithelial cells into cancer. But if I take epithelial cells from the most horrible cancer imaginable and surround it with healthy stroma, the tumor-forming capacity of these epithelial cells will be suppressed. Cancer arises from conversations between epithelial and stromal cells and there is now significant evidence suggesting that the stroma is dominant,” explained Tlsty. 

Tlsty’s team will employ cutting-edge techniques — including single-cell sequencing, immune cell engineering, multiplex staining and organs-on-chips — in order to listen in on the conversations between epithelial and stromal cells and identify the messages that cause cancer. Tlsty believes that this will eventually allow clinicians to predict whether a patient with chronic inflammation will develop cancer, years before the cancer emerges. She also hopes that her team’s discoveries will lead to drugs that interfere with these “conversations” and prevent cancers from forming. 

“The bottom line is that I don’t think we should approach these as different types of cancer. I think it’s one cancer process. If we understand the mechanism behind that process, we may be able to prevent one in four cancer deaths,” Tlsty said.

Members of Tlsty’s team include:

• Kole Roybal, PhD, UCSF
• Garry Nolan, PhD, Stanford University
• Uri Alon, PhD, Weizmann Institute of Science
• Lorenzo Ferri, MDCM, PhD, McGill University
• James Goldenring, MD, PhD, Vanderbilt University School of Medicine
• Sui Huang, MD, PhD, Institute for Systems Biology, Seattle
• Donald Ingber, MD, PhD, Wyss Institute for Biologically Inspired Engineering at Harvard University
• Stuart McDonald, PhD, Barts Cancer Institute, Queen Mary University of London
• Morag Park, PhD, Goodman Cancer Research Centre at McGill University
• Doug Winton, PhD, Cancer Research UK Cambridge Institute
• Desiree Basila, patient advocate
• David Chuter, patient advocate
• Deborah Collyar, patient advocate
• Ann Russell, patient advocate

UC San Francisco (UCSF) is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. It includes top-ranked graduate schools of dentistry, medicine, nursing and pharmacy; a graduate division with nationally renowned programs in basic, biomedical, translational and population sciences; and a preeminent biomedical research enterprise. It also includes UCSF Health, which comprises three top-ranked hospitals – UCSF Medical Center and UCSF Benioff Children’s Hospitals in San Francisco and Oakland – as well as Langley Porter Psychiatric Hospital and Clinics, UCSF Benioff Children’s Physicians and the UCSF Faculty Practice. UCSF Health has affiliations with hospitals and health organizations throughout the Bay Area. UCSF faculty also provide all physician care at the public Zuckerberg San Francisco General Hospital and Trauma Center, and the SF VA Medical Center. The UCSF Fresno Medical Education Program is a major branch of the University of California, San Francisco’s School of Medicine.