A team of researchers at the University of California, San Francisco was selected to receive a five-year, $25 million Cancer Grand Challenges award to investigate the very early stages of cancer development. The team, called PROMINENT (PROMotion to INform prevENTion), aims to discover what triggers normal cells to become cancerous with the goal of finding ways to prevent tumor formation. They will explore how carcinogens and other mutation-forming factors help turn a normal cell into a tumor cell.
“As a research community, we’re on the verge of a major leap forward in our understanding of the factors that contribute to the risk of cancer, which could help to find new, informed ways to stop cancer before it even starts,” said co-leader of the team, Allan Balmain, PhD, at UCSF’s Helen Diller Family Comprehensive Cancer Center (HDFCCC). Researchers from the International Agency for Research on Cancer and the Research in Biomedicine Barcelona will also co-lead the team.
Although the accumulation of mutations in cells has long been assumed to trigger tumorigenesis, recent studies suggest a much more complex relationship—cells often carry many known cancer-causing mutations yet remain phenotypically normal. These cells, despite their remarkable genetic similarities with cancer cells, do not form tumors.
The UCSF team will study how cells and tissues maintain ‘normal’ phenotypes while otherwise harboring oncogenic mutations and how they transition to become a tumor.
The PROMINENT study will examine cells exposed to carcinogens that accumulate cancer-driving mutations but otherwise do not immediately form tumors. Their hope is to unravel the mechanisms that trigger the mutation-laden cells to develop into cancerous tumors. Ultimately the team hopes to create a roadmap linking the travel of the mutated cells on their journeys to become malignant and form tumors.
To get at these fundamental challenges, the team will rely on several resources, including a tissue bank of more than 4,000 mouse samples across all stages of carcinogenesis, and a large, annotated collection of pairs of tumor and healthy tissue samples provided by more than 5,000 people across 20 countries.
Serial biopsies of normal tissues will also be collected from people participating in intervention studies focused on obesity and smoking. A range of genomic and screening techniques will be used, including human organoid culture and CRISPR-Cas9 gene editing. All data will be collected in a central repository and analyzed with molecular-evolution and machine-learning models to identify the molecular signatures and mechanisms of cancer promotion.
At the conclusion of the study, the PROMINENT team hopes to answer four major questions:
- What are the environmental, lifestyle or endogenous risk factors that promote the selection of pre-initiated cells in normal tissue?
- Which cells carry initiating mutations, where are they located, how are they selected for during aging, and what is their relationship with normal and cancer stem cells?
- Which mechanisms promote the first signs of neoplastic growth, and what additional changes cause transition to full malignancy?
- What intervention can prevent the earliest stages of neoplastic cell selection by tumor promoters?
In addition, they plan on studying a collection of a novel group of compounds, which they refer to as ‘promolytics’, for their role in preventing or reversing the promotion step.
