Cancer is more than just tumor cells driven by gene mutations.
Cancer is like an ecosystem filled with evolving populations of tumor cells that interact with and enlist support from neighboring non-tumor cells, including agents of the immune system. Over time, tumor cell populations diversify into distinct lineages harboring different mutations and modifications. This complexity is why cures have remained so elusive.
The Human Tumor Atlas Network (HTAN) is a massive effort to map the complex ecosystems of cancer – and pave the way for advances in prevention, early detection and treatment. HTAN is part of the National Cancer Institute Cancer Moonshot Initiative. The components of the network and how they are coming together are detailed in a new perspective article in the journal Cell by HTAN principle investigators including Joe Gray, Ph.D., Gordon Mills, M.D., Ph.D., Jeremy Goecks, Ph.D., and George Thomas, M.D. in the Knight Cancer Institute.
The atlas network currently includes ten interdisciplinary research centers, each focused on specific tumor types. They are building three-dimensional atlases of cancers and their transitions from pre-malignancy to malignancy, from primary tumor to metastasis, and from pre-treatment to post-therapeutic response. The project will give researchers tools to explore tumor ecosystems in multiple dimensions and visualize their structure, composition, and interactions at distinct points in tumor evolution. The point is to help researchers find new and better predictive biomarkers and reveal cell types, cell states, and cellular interactions that can be targeted for therapy, the perspective authors said:
“In pre-cancers, HTAN should help identify the genetic, epigenetic, and environmental factors involved in the earliest steps of malignancy, such as non-cell-autonomous factors distinguishing successful from unsuccessful immune surveillance. In later stage cancers, atlases should help us to understand the difference between immune-infiltrated and cold tumors; the drivers of metastasis, which could be more readily discernable with spatial data than with purely genomic data; and the impact of tumor heterogeneity and ecosystems on therapeutic response and resistance. A better understanding of these mechanisms will inform new predictive models and prognostic biomarkers, signatures, and diagnostics that can ultimately be deployed at point of care to improve the outcomes of cancer patients. It will also improve the development of preventive strategies, therapeutic agents, and drug combinations that can effectively target these processes at multiple steps in the malignant process.”
Unlike previous large-scale cancer genomics programs, HTAN atlases will give researchers a view of the tumor microenvironment and the cellular interactions occurring there. While most previous efforts focused on primary tumors with limited treatment and outcome data, HTAN emphasizes repeated sampling over time, from pre-cancer to advanced tumors and metastases, tied to comprehensive clinical data. The atlases will spatially connect cancer genomics and histopathology, the two primary means of diagnosing cancer and informing therapy, the authors said.
The HTAN Research Center at OHSU is focused on developing an Omic and Multidimensional Spatial Atlas of Metastatic Breast Cancers. The team includes collaborators from Harvard Medical School and the MD Anderson Cancer Center. The project is benefitting from the clinical infrastructure built for the SMMART platform, which enables rapid analysis of longitudinal tumor samples from individual patients, including targeted and whole exome sequencing, RNA transcriptional profiling, protein expression analysis, and multiscale spatial analyses of molecular and cellular interactions.
More information on all of the funded HTAN research projects can be found on the NCI Cancer Moonshot website.
The Human Tumor Atlas Network: Charting Tumor Transitions across Space and Time at Single-Cell Resolution by Orit Rozenblatt-Rosen, Aviv Regev, Philipp Oberdoerffer, Tal Nawy, Anna Hupalowska, Jennifer E. Rood, Orr Ashenberg, Ethan Cerami, Robert J. Coffey, Emek Demir, Li Ding, Edward D. Esplin, James M. Ford, Jeremy Goecks, Sharmistha Ghosh, Joe W. Gray, Justin Guinney, Sean E. Hanlon, Shannon K. Hughes, E. Shelley Hwang, Christine A. Iacobuzio-Donahue, Judit Jané-Valbuena, Bruce E. Johnson, Ken S. Lau, Tracy Lively, Sarah A. Mazzilli, Dana Pe’er, Sandro Santagata Alex K. Shalek, Denis Schapiro, Michael P. Snyder, Peter K. Sorger, Avrum E. Spira, Sudhir Srivastava, Kai Tan, Robert B. West, and Elizabeth H. Williams. Cell, April 16, 2020.