Cancer's Progress Detailed by 3D Genomic Maps

Researchers have long known that cancer alters its genome as it evolves. What has been less clear is how, when, and why genomic structures change as cancer progresses. A new Yale study published Aug. 18 in Nature Genetics reveals critical insights and potential biomarkers of stage-specific cancer development.

Using a technique called chromatin tracing, Yale researchers created detailed 3D maps of genome structures in individual cells in mouse models of lung and pancreatic cancers, driven by the cancer-causing gene KRAS. The maps reveal how chromosomes fold and genes are positioned in the cell nucleus. They also chart cancer’s route from pre-cancerous to advanced disease, even identifying different cancer cell states based solely on the 3D structure of their genomes.

“Importantly, using the unprecedented 3D genome maps, we developed new ways to better nominate cancer-driving genes. These are potential new drug targets for lung cancer, the top cause of cancer death worldwide,” says co-senior author Siyuan (Steven) Wang, PhD, associate professor of genetics and cell biology at Yale School of Medicine (YSM).

“On the basic genome biology side, we also discovered a completely new function for how the 3D genome is compartmentalized to enable single cancer cells to progress to more advanced states,” he says.

Co-senior author Mandar Deepak Muzumdar, MD, associate professor of genetics and of internal medicine (oncology) at YSM says: “Although cancers are thought to be quite heterogeneous, what is remarkable is that the global 3D structure of the genome evolves similarly in cancer cells within and across tumors in these models.

“By focusing specifically on these convergent, stereotypical changes, how they are regulated, and how they impact gene expression, we identified novel genes that delineate cancer prognosis and are crucial for cancer cells to grow,” says Muzumdar, who is a member of Yale Cancer Biology Institute and Yale Cancer Center.

The study suggests that the detailed data resulting from this method and its broad application could improve future cancer diagnostics and staging, as well as help identify new therapy targets by understanding what cancerous cells need to survive and thrive.

The study was led by Yale’s Department of Genetics at YSM, including co-first authors Miao Liu, PhD; Shengyan Jin, PhD; and Sherry S. Agabiti, PhD. Other contributors included numerous YSM departments, Yale Cancer Biology Institute, Yale Center for RNA Science and Medicine, Yale Liver Center, and Yale Computational Biology and Biomedical Informatics.

Using the advanced cancer 3D genome mapping methodologies established in this work, the researchers are next investigating additional subtypes of lung and pancreatic cancers and directly studying human patient samples, in collaboration with other investigators at the Yale Cancer Center.

“These 3D genome maps are just the tip of the iceberg,” say Muzumdar and Wang. “We are just getting started in using this new type of single-cell biologic information to uncover cancer’s untold secrets, aiming to improve treatment and clinical outcomes in the long-term.”

The research reported in this news article was supported by the National Institutes of Health (grants R33CA251037, R01CA292936, R01CA276108-02S1, 5T32GM007205, 2T32GM007499, R01LM013385, DP2CA248136, UH3CA268202, U01CA260701, R01HG011245, DP2GM137414, R01HG012969, 5T32GM00720, and P30CA0163595), AACR-Genentech NextGen Grant for Transformative Cancer Research (19-20-18-MUZU), Yale SPORE in Lung Cancer Career Enhancement Program award (P50CA196530), and Yale University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.