Clarence Yapp, Leiter lab, Harvard Medical School, and his colleagues created a 3D reconstruction of colorectal cancer that revealed previously unknown structural features of the illness and how they relate to each other.
At the age of 45, in the United States, an endoscope equipped with a light and a camera is used to examine the colon for any cancer signs. Although colorectal cancer grows slowly, it may be treated through surgery if caught early. Unfortunately, it becomes more difficult to treat if left untreated for too long.
Despite the availability of this highly visual screening technique, individual patient treatment decisions remain largely guided by traditional histology — pathologists examine tumor slides under a microscope.
A Harvard Medical School research group has combined histology with cutting-edge single-cell imaging techniques to create massive 2D and 3D spatial maps of colorectal cancer. The maps, described in Cell, include extensive molecular information on the cancer's structure as well as its development and interactions with the immune system.
Shannon Coy, Santagata lab; Shu Wang and Yu-An Chen, Sorger lab, Harvard Medical School
"Our approach opens a molecular window into 150 years of diagnostic pathology," said co-author Peter Sorger, the Otto Krayer Professor of Systems Pharmacology at HMS. "We now can see the whole elephant in one go."
The maps are part of a team's effort to make atlases for different cancer types that would be freely available to the scientific community as part of the National Cancer Institute's Human Tumor Atlas Network. Earlier, the researchers used a similar technique to create in-depth maps of early-stage melanoma, but maps for other cancers are already being developed.
Pathologists examine a tumor sample stained with hematoxylin and eosin (H&E) under a microscope and pick out key features to determine the grade and stage of the cancer. This information is used by oncologists to plan a treatment regimen, which usually involves surgery, medication, and radiation.
"Our existing colorectal cancer maps originate in pathology," says co-author Sandro Santagata, HMS associate professor of systems biology and associate professor of pathology at Brigham and Women's Hospital.
The researchers hope to learn more about how colorectal cancer develops and progresses. Jia-Ren Lin, Harvard Medical School,
Traditional histology has its limitations, namely, it does not capture a cancer's molecular makeup or physical structure, making it difficult to fully utilize the knowledge gained in the last 50 years.
"Histology is extraordinarily powerful, but we often don't know what it means in modern molecular terms," Sorger said.
Researchers used histology and single-cell molecular imaging data to create detailed 2D maps of large areas of colorectal cancer, according to the first author in the Laboratory of Systems Pharmacology at HMS.
Santagata said the maps reveal "exciting architectural features that had never been seen before," as well as molecular changes associated with these features.
Clarence Yapp, head of the Harvard Medical School's Sorger lab, has developed a multifaceted and extensive network of channels and caverns (red and pink) that allow cancer cells to form finger-like projections.
The maps revealed that a single tumor may have more and less aggressive sections as well as more or less malignant-looking regions, resulting in histological and molecular gradients where one section of a tumor transitions into the next.
“There is a wide range of characteristics of colorectal cancer within each tumor,” Santagata said. Scientists may now examine what drives these differences within individual tumors.
The maps illustrated that immune environments differed enormously within a single tumor.
"Tissue immune cells were as different across a single tumor as among tumors," Sorger said. This is important because tumor-immune interactions are what you are trying to target with immunotherapy.
"This gives us a whole new appreciation of how varied and flexible the tumor environments are — they are complex communities, and we are now better equipped to observe how they develop," Santagata said.
Scientists previously identified what they thought were 2D pools of a mucus-like substance called mucin with cancer cells floating inside. However, in the new study, the 3D reconstruction revealed that these mucin pools are actually a series of caverns connected by finger-like projections of cancer cells.
'We now have a clear, clean picture of these tumor structures,' Santagata said. 'Because we can see them in 3D, we have a crisp, clean view of the structures, and we can now study why they exist, how they form, and how they influence tumor evolution.'
Yu-An Chen, Sorger lab, Harvard Medical School, offers an overview of colorectal cancer samples used to create 2D and 3D maps.
The purpose of these colorectal cancer maps remains the same as that of all of the other cancer atlases that they are working on: to advance research and improve diagnosis and treatment. Precision medicine, which involves tailoring treatment to a patient's cancer, is becoming increasingly crucial part of therapy, yet it can only go so far with pathology and genetics.
"We're currently working with Brigham and Women's and the Dana-Farber Cancer Institute to investigate how our methods might be applied in a clinical setting," says the big translational story.
Santagata said the new technique allows us to obtain a whole new layer of molecular and structural features that we believe will provide diagnostic and prognostic information and enhance our ability to target these cancers.
The researchers want to expand their abilities to perform 3D reconstructions of tumors and continue adding new imaging technologies to their maps. They also want to collect a larger sample of colorectal cancer samples for mapping and to investigate the basic biology of the disease that their maps have identified.
The Sorger/Ferg project is a unique collaboration between pathologists, engineers, and computational scientists: As imaging data rolled in, the computational scientists used machine learning to identify interesting findings that they presented to the pathologists, and the pathologists identified key features that should be combined with machine learning.
'I think it's an exciting glimpse of how these computation techniques might be applied in medicine in the future, rather than seeing them as replacements for each other,' Sorger said.
Because they are common cancers with unmet medical needs that include large, solid tumors and require significant treatment decisions, the researchers opted for melanoma and colorectal cancer as their starting points. They want to train other scientists to use imaging techniques to create their own cancer maps, which would open the way for more atlases.
"A new era in molecular pathology is beginning, and this is a thorough examination of a tumor that is demonstrating how remarkable the findings may be," Santagata said. "A new era in molecular pathology is beginning, and this is a thorough examination of a tumor that is demonstrating how remarkable the findings may be," said Santagata.
Jia-Ren Lin, Shannon Coy, Clarence Yapp, Maulik K. Nariya, Cody N. Heiser, Ken S. Lau, Sandro Santagata, and Peter K. Sorger, 19 January 2023, Cell. DOI: 10.1016/j.cell.2022.12.028
The National Institutes of Health, Ludwig Cancer Research, the Gray Foundation, and the David Liposarcoma Research Initiative sponsored the research.
Sorger serves on the boards of directors of Glencoe Software and Applied BioMath, the research advisory board for RareCyte, NanoString, and Montai Health, and is a consultant for Merck. Chen is a consultant for RareCyte.
