We are constructing a multi-dimensional atlas of pre-melanoma focused on understanding genetic and epigenetic events that transform melanocytes into invasive tumors. Melanoma is a cancer of increasing prevalence that is curable with minor surgery if detected early but life-threatening when it metastasizes. Melanomas metastasize when still small, making early detection essential but challenging. Our atlas will delineate the precise sequence of events leading up to pre-melanoma through detailed spatial analysis of cell-autonomous events such as oncogene mutation and non-autonomous events such as escape from immune surveillance. The atlas is based on highly-multiplexed tissue imaging and single cell sequencing and focused on samples in which the full sequence of events from atypia to invasive melanoma can be visualized in a single specimen. The atlas will serve as a publicly accessible resource for research scientists, physicians, and patients and improve our ability to (i) highlight lesions likely to progress to cancer, (ii) identify high-risk patients to inform decisions on surgery, (iii) identify low-risk patients to reduce unnecessary procedures, (iv) design improved procedures for routine screening of all individuals, and (v) inform treatment options when surgery is insufficient. Complementary studies with similar goals (but not supported by HTAN) are studying later stage melanomas.
Dr. Peter Sorger, Otto Krayer Professor of Systems Pharmacology at Harvard Medical School, leads the PATCH Center and is director of a shared research laboratory (the Laboratory of Systems Pharmacology; LSP) in which much of the PCA work is based. The LSP is a multi-investigator lab focused on improving the fundamental science used to develop therapeutic drugs, evaluate them in clinical trials, and identify patients most likely to benefit. Research in the Sorger lab focuses on mammalian signal transduction and oncogenesis in several types of cancer, including melanoma, using a mix of experimental and computational approaches. The laboratory developed the cyclic-immunofluorescence (CyCIF) method being used to construct the PCA pre-melanoma atlas as well as the software tools being used to analyze the resulting images, and the Open Microscopy Environment (OME) that is being used to manage PCA image data also was started in the lab. This pre-melanoma atlas is part of a larger digital histology effort, the Harvard Tissue Atlas, also led by Dr. Sorger.
Dr. Sandro Santagata is an Associate Professor in Pathology at Harvard Medical School and a Neuropathologist in the Department of Pathology at Brigham and Women’s Hospital and the Department of Oncologic Pathology at Dana-Farber Cancer Institute. He is a member of the Ludwig Center at Harvard, the Harvard Program in Therapeutic Science (HiTS), and the HMS Laboratory of Systems Pharmacology (LSP). Dr. Santagata applies novel tissue imaging methods, including tissue-based cyclic immunofluorescence (CyCIF), to understand the spatial and molecular phenotypes of human cancer. Using clinical trial specimens, he measures and models therapeutic responses in tumors and their microenvironment. Drs. Santagata and Sorger co-direct all aspects of the Harvard Tissue Atlas, of which the pre-melanoma atlas is an essential component.
Dr. Jon Aster is the Chief of Hematopathology at the Brigham and Women’s Hospital and the Dana-Farber Cancer Institute and co-leads the Lymphoma and Myeloma Program of the pan-Harvard Dana-Farber/Harvard Cancer Center (DF/HCC). He also serves as Director of the DF/HCC Specialized Histopathology Core Laboratory and is a member of the Harvard Ludwig Cancer Center. His research is focused on Notch signaling in T-cell acute lymphoblastic leukemia (T-ALL) and other cancers. Notch receptors participate in a signaling pathway that controls differentiation and other fundamental cellular processes in a context-specific fashion. The Aster lab has demonstrated that Notch signals can induce T-cell development from bone marrow progenitors and has shown that T-ALL cells depend on continued Notch signaling for growth. Dr. Aster is leading a pilot project in the PATCH Center to develop atlases of hematological pre-cancers and an effort to use multiplex tissue imaging data to improve medical education in pathology.