Determining precise timing of cellular growth to understand the origins of cancer

Scientists from Vanderbilt University, led by Mirazul Islam, a graduate student mentored by Professor of Cell and Developmental Biology Ken Lau andProfessor of Medicine Robert Coffey, have laid the groundwork for understanding and predicting the natural transition between precancers and cancer. They showed that colorectal cancer is likely to arise from multiple normal cells in the intestinal epithelium, not just from a single cell.

This work lays the foundation for how this approach could be extended to record other aspects of cell activity, such as the timing of when signaling events occur. "We hope that adding a temporal axis enables a fundamental understanding of tissue development and disease," Lau said.

Although only a low percentage of precancers progress to cancer, the only current predictor of colorectal cancer progression is the size of polyps -- small clumps of cells that can become cancerous -- in the colon. The researchers developed the precise molecular "clock" to date that records the timing of cellular events at a single-cell resolution. This work, published in the journal Nature, helps decipher the origin of colorectal cancer.

Prior to Islam and Lau's work, researchers had used naturally occurring genetic alterations in cancers to track when cell changes occur, but the authors find that although "they provide only inferences of chronological order or clonality" they are not precise enough.

To fill the current gap in knowledge, Islam used a CRISPR platform to create a "genetic barcoding" approach that records the timing of cellular events and clonality in vivo. He tested this approach in both in a mouse model and a patient cell-derived model.

Using the strong patient resources at the Vanderbilt University Medical Center -- as well as the Human Tumor Atlas Network -- they collected one of the largest multi-omic atlasing datasets on human sporadic polyps to date and revealed that colorectal cancer originates from independent mutational events occurring in multiple healthy cells. The team posits that cancers transition from having genetically distinct cells (polyclonal composition) in the early precancer stage to genetically identical cells (monoclonal composition) in advanced stages. Understanding this process will help develop better predictors of the progression from precancer to cancer.

"Mirazul drove this entire project, from conception through execution," Coffey said. "But we couldn't have done this without our collaborators, particularly Mark Magnuson and Qi Liu." Magnuson, Louise B. McGavock Professor and professor of molecular physiology and biophysics, provided expertise in developmental biology. Liu, professor of biostatistics, and her group provided bioinformatics support.

Lau already has an eye toward the future. "We are applying this approach to understand the clonal dynamics in regeneration by identifying new cell populations with stem cell potential," he said.

The Human Tumor Atlas Network is a National Cancer Institute-funded Cancer Moonshot^SM initiative to construct 3-dimensional atlases of the dynamic cellular, morphological, and molecular features of human cancers as they evolve from precancerous lesions to advanced disease. Lau is a lead researcher on the HTAN project U01CA294527.

The paper "Temporal recording of mammalian development and precancer" was published in Nature in Oct. 2024.

Funding

This research received financial support from the Vanderbilt University Stanley Cohen Innovation Fund, the Human Tumor Atlas Network, the Translational and Basic Science Research in Early Lesions program and a Gastrointestinal Specialized Programs of Research Excellence from the National Cancer Institute, and the Digestive Diseases Research Center.