The Harvard Tissue Atlas (HTA) gathers together multiple research projects into collections of single-cell data “atlases” that contain data from normal and diseased tissues from humans and animal models, with a particular emphasis on cancer. The goal of these atlases is to describe the myriad of interactions that occur between cells and acellular structures within tissues by combining image and omic datasets into molecular and physical maps. Many HTA projects are currently organized by the manuscript in which they were first described, but will be gathered together into larger Atlases soon.
Ludwig Tumor Atlas: A Focus on Drug Resistance
The Ludwig Tumor Atlas is a collaborative project involving US and European research laboratories that are part of Ludwig Cancer Research Centers and Branches and involves several types of solid cancer. Research at HMS is performed under the auspices of the Ludwig Center at Harvard Medical School. The overall aim of the Atlas is to investigate the molecular basis of intrinsic and acquired resistance to anti-cancer drugs and to develop disease management strategies and therapies that overcome or avoid such resistance. The Atlas can be view at Ludwig Tumor Atlas.
Drug resistance is the greatest single challenge facing contemporary cancer therapy. Despite extraordinary advances in cancer therapeutics, most patients eventually relapse and succumb to disease due to the development of drug resistance. The problem of resistance is complicated by tumor heterogeneity– both within a single tumor and across a population of patients. Tumors and their microenvironments are also plastic, changing through the course of disease and in response to drugs. High dimensional tissue imaging and single-cell genetics aim to characterize this heterogeneity at multiple spatial and functional scales to improve our understanding of the origins of drug resistance - this understanding is a necessary first step to overcoming resistance in patients. Data are commonly acquired in biopsies from patients prior to and during therapy, and then following relapse. Mouse models of disease are also an important part of this research. An explicit goal of the Ludwig Tumor Atlas is to create and validate image-based clinical tests for next-generation diagnosis and drug development.
- What are the relative roles of changes in the tumor microenvironment and cancer cells themselves in generating drug resistance?
- Are drug resistant states (and mutations) present prior to the initiation of therapy or are they induced by therapy?
- Are mechanisms that cause tumors to exhibit intrinsic resistance (drug insensitivity) similar to the mechanisms that make initially sensitive tumors drug resistant (acquired drug resistance)
- Which among these mechanisms might be targettable using new or existing drugs?
Ludwig Center at Harvard Medical School and the Ludwig Cancer Research Foundation
Melanoma Pre-Cancer and Progression Atlas
Melanoma is a highly immunogenic type of cancer treatable with minor surgery when localized to superficial layers of the skin but potentially lethal when it invades deep into the dermis and metastasizes. The Melanoma Pre-Cancer and Progression Atlas aims to identify the earliest molecular changes in pre-cancer and determine the sequence of events that ultimately leads to disseminated disease. This work is a component of the National Cancer Institute Human Tumor Atlas Network (HTAN)(a Cancer Moonshot Initiative) and Cancer Systems Biology Program.
Melanoma is an increasingly common type of cancer that often becomes metastatic when quite small, making melanoma a dangerous disease. Routine surveillance of the skin, followed by removal of lesions suspicious for cutaneous melanoma, is common in many developed countries. However, surveillance and staging are not perfect and some dangerous lesions slip through. Moreover, individuals with less access to healthcare do not benefit from regular monitoring and some times of melanoma (e.g. acral lentiginous melanoma) are underdiagnosed and undertreated, particularly in people of color. By improving our understanding of the sequence of molecular events that drive melanoma, the Melanoma Atlas will improve diagnosis, staging, and disease management.
Melanoma is noteworthy in that it can be treated both with targeted therapy (inhibitors of the RAF and MEK kinases for the ~50% cutaneous melanomas carrying BRAF mutations) and with immunotherapy (inhibitors of the PD-1 and CTLA-4 checkpoint proteins). Understanding precisely why these therapies achieve longer and deeper remission in some patients than others is not only relevant to understanding targeted and immunotherapy in general, but also to improving patient care–choosing among treatment options at the level of individual patients is not always straightforward. The importance of understanding the high responsiveness of melanoma immunotherapy is increasing since many other types of solid cancer have proven to be much more resistant to immune therapy.
- What are the earliest events in the development of melanoma precursors? How might these precursors be identified diagnostically and eradicated therapeutically?
- What are the key events in melanoma progression and why does the immune system successfully clear many pre-melanomas but fail to stop others?
- How can we use this information to improve our ability to recognize the subset of primary melanomas that are at high risk of progression to metastatic disease?
- What are the molecular events that allow some melanoma cells to escape therapy and survive as residual disease from which disseminated cancer can re-arise?
Funding: Research on precancers and primary melanoma is supported by the NCI Human Tumor Atlas Network (Grant U2C-CA233262). HTAN aims to generate, publicly-accessible data on the spatial, genetic and epigenetic features of common human cancers and precancers. Research on advanced and metastatic melanomas are supported by the NCI Cancer Systems Biology Program (Grant U54-CA225088). Additional support is provided by the Ludwig Center at Harvard Medical School.
NCI Human Tumor Atlas Network grant U2C-CA233262
Tuberculosis Granuloma Atlas
The Tuberculosis Granuloma Atlas aims to transform our understanding of TB granulomas by using spatially resolved profiling methods that reveal bacterial, lung and immune cell organization, states, and communication within granulomas of different types.
The Tuberculosis Granuloma Atlas aims to understand the biology of granulomas, sites of chronic lung inflammation shaped by the biology Mycobacterium tuberculosis (Mtb) and host immune responses. Within a granuloma, Mtb growth is often limited, but this provides a niche from which bacteria can subsequently disseminate. The project also aims to build capacity for digital pathology in low and middle income countries (LIMC) including the eventual deployment of Atlas viewers and analysis modules on cell phones. As part of the Atlas, LSP investigators are assembling a cloud-based Tuberculosis Data Resource that will consolidate a rich collection of imaging and genomic data on TB granulomas and make the data publicly available.
The Atlas is expected to launch in Summer 2022 and is part of a sustained effort by the Bill and Melinda Gates Foundation to understand and ultimately eradicate TB (Funded by Grant INV-027106).
- Bree Aldridge, PhD. Associate Professor, Molecular Biology and Microbiology, Tufts University School of Medicine
- Peter Sorger, PhD. Professor of Systems Biology, Harvard Medical School
Bill and Melinda Gates Foundation grant INV-027106
BRCA1/2 Cancer Atlas
The BRAC1/2 Cancer Atlas involves leading cancer centers across the US focused on collecting and analyzing diverse genomic and imaging on BRAC1/2 breast and ovarian cancers. The goal of the effort is to understand pre-cancer states, develop new diagnostics that detect cancer before it spreads, and improve disease management and prevention strategies.
The mutations that cause cancer often arise spontaneously in somatic tissues but some are heritable. Among these mutations in BRCA1 or BRCA2 (BReast CAncer gene 1&2) stand out as having relatively high prevalence and causing a substantial increase in a variety of cancers including those of the breast, ovaries, pancreas and prostate. BRCA1 and BRCA2 are involved in the repair of damaged DNA but the precise events that initiate tumor formation are not fully understood.
Funding: This research is funded by the Gray Foundation Basser Initiative. The Atlas is expected to launch in Summer 2022.
- Sandro Santagata, MD PhD, Associate Professor of Pathology, Brigham and Women’s Hospital and Harvard Medical School
- Peter Sorger, PhD. Professor of Systems Biology, Harvard Medical School
The Gray Foundation
The Omic and Multidimensional Spatial (OMS) Atlas
The OMS Atlas Center based at the Oregon Health Sciences University (OHSU) and led by Joe Gray is a component of the National Cancer Institute Human Tumor Atlas Network (HTAN), a multi-center program within the National Cancer Institute that emerged from the Beau Biden Cancer Moonshot Initiative.
The OMS Atlas Center based at the Oregon Health Sciences University (OHSU) and led by Joe Gray is a component of the National Cancer Institute Human Tumor Atlas Network (HTAN), a multi-center program within the National Cancer Institute that emerged from the Beau Biden Cancer Moonshot Initiative. Our team us a collaborator on the OMS Atlas focusing on the application of multi-dimensional CyCIF imaging methods to clinical trial samples.
The OMS is focused on elucidating mechanisms of therapy resistance in three clinical scenarios in which disease recurrence is a major concern: (a) hormone-receptor positive breast cancer (HRBC) undergoing treatment with a CDK4/6 inhibitor in combination with endocrine therapy, (b) triple negative breast cancer (TNBC) undergoing treatment with a PARP inhibitor and an immunomodulatory agent (c) castration resistance prostate cancer (CRPC) undergoing treatment with enzalutamide. Diverse imaging and omic methods are being applied to this analysis including several complementary ways to create spatial maps of cell types and states. These include multiplex immuno-histochemistry, CyCIF, Focused Ion Beam Scanning Electron Microscope (FIB-SEM).
Funding: The OMS Center at Harvard Medical School is funded by a Human Tumor Atlas Network grant U2C-CA233280 (Joe Gray PI) from the National Cancer Institute “Omic and Multidimensional Spatial (OMS) Atlas”.
NCI Human Tumor Atlas Network grant U2C-CA233280
David Liposarcoma Research Initiative
Liposarcomas originate from precursors of fat cells are one of 250 types of sarcoma and are relatively rare, but they have few effective treatments. The David Liposarcoma Research Collaboration is led by DFCI Investigator George Demetri and aims to transform the treatment of this rare, underfunded, and understudied disease. As part of this effort, the LSP is collecting highly multiplexed images of liposarcomas before and after treatment.
David Liposarcoma Research Initiative