JANUARY 23, 2023, NEW YORK – A Ludwig Harvard team led by Peter Sorger and Sandro Santagata has combined histology with cutting-edge single-cell imaging technologies to create large-scale 2D and 3D maps of colorectal tumors. The maps, described in Cell, layer extensive molecular information over histological features to generate new information about the structure of such tumors, as well as how they form, progress and interact with the immune system.
“Our approach provides a molecular window into 150 years of diagnostic pathology—and reveals that many of the elements and structures traditionally thought to be isolated are actually interconnected in unexpected ways,” said co-senior author Peter Sorger, who is an investigator at the Ludwig Center at Harvard and the Otto Krayer Professor of Systems Pharmacology in the Blavatnik Institute at Harvard Medical School (HMS). “An analogy is that before, we were just looking at the tail or the foot of the elephant, but now, for the first time, we can start to see the whole elephant at once.”
The maps are part of the team’s broader efforts to create atlases for different cancer types as part of the Ludwig Tumor Atlas project. Their maps are also freely available to the scientific community through the National Cancer Institute’s Human Tumor Atlas Network. Previously, the researchers used a similar approach to create in-depth maps of early-stage melanoma, and maps for other tumor types are in development.
The researchers combined histology with single-cell molecular imaging data acquired through a multiplexed imaging technique called cyclic immunofluorescence, or CyCIF. They used this information to create detailed 2D maps of large regions of colorectal cancer. Those maps were then stitched together to form a large-scale 3D reconstruction of tumors.
“Our maps include information on almost 100 million cells from large pieces of tumors and provide a rather unprecedented look at colorectal cancer,” said Santagata, who is an investigator at the Ludwig Harvard Center and an HMS associate professor of systems biology and associate professor of pathology at Brigham and Women’s Hospital. They allow researchers to start asking key questions about differences between normal and tumor tissues and variation within a tumor, he added, and reveal “exciting architectural features that had never been observed before, as well as molecular changes associated with these features.”
The maps showed that a single tumor can have more and less invasive sections, and more and less malignant-looking regions—resulting in histological and molecular gradients where one part of a tumor transitions into the next. Differences abound between distinct neighborhoods of a given tumor. Immune environments, for example, vary as dramatically within a single tumor as they do between tumors.
The maps also provided new insights into the architecture of the tumors. Scientists have previously identified what were believed to be pools of a mucus-like substance called mucin with clusters of cancer cells floating inside. The 3D reconstruction revealed, however, that the mucin pools are, in fact, a series of caverns interconnected by channels, with finger-like projections of cancer cells.
Ultimately, the goal of these colorectal cancer maps is the same as it is for all the cancer atlases the team is developing: to advance research and improve diagnosis and treatment.
The media release from which this summary is derived is available here.