Title: SPECIFICANCER: Dissecting the tissue specificity of cancer drivers
Funder: Cancer Research UK

Abstract: Cancer is not a single disease, but rather a collection of diseases that exhibit both common and distinct properties at the molecular and cellular levels. The heterogeneous nature of cancer is reflected in the distinct genetic perturbations that arise in each form of the disease. A major unanswered question is why cancers that arise in different organs, or even different kinds of cancer from the same organ, select for mutations in distinct drivers. One possibility is that this is a passive process: some genes could drive cancer in a particular tissue, but for a variety of reasons are never mutated in the relevant cell type. Alternatively, as we believe, driver tissue specificity is an active process: the epigenetic state of cells dictates that only certain genetic perturbations are capable of driving cancer in that tissue. Through large-scale genetic screening experiments, we have discovered that normal cells derived from distinct tissues exhibit profoundly different responses to genetic perturbations that impact proliferation and survival. These differential responsiveness patterns underlie tissue specific drivers of cancer and impact recurring somatic copy number alteration (SCNA) patterns. We believe that the lack of mutations in certain tissues is as telling about the oncogenic properties of a given gene as are the common presence of mutations in other tissues. As such, the core approach of the SPECIFICANCER program is to compare the molecular and cellular manifestations of gene perturbations in tissues where mutations naturally occur and in tissues where they do not. This approach begins with gain and loss of function screens for drivers of proliferation and survival in 2D and 3D cellular models derived from different primary tissue sites. We will also explore whether cancer vulnerabilities are influenced by the epigenetic state including combinatorial changes due to multiple drivers. In parallel, we will use genetically engineered mouse models to explore the tissue-specific cancer promoting properties of mutations affecting RAS/MAPK, WNT, and PRC2. In these studies, global transcriptional, epigenetic, and proteomic measurements will be used to understand the molecular mechanisms that define tissue specificity and responsiveness to drivers. This work will generate a functional map of tissue specificity that will allow us to better interpret cancer genomics and to develop therapeutic paradigms based on the tissue-specific biology of cancer genes. We hope to improve the basic understanding of what drives cancer and to provide a rational foundation for therapeutic choices made by physicians and patients.

Lay abstract: Cancer is not a single disease, but rather a collection of diseases that exhibit both common and distinct properties at the molecular and cellular levels. The heterogeneous nature of cancer is reflected in the distinct genetic perturbations that arise in each form of the disease. A major unanswered question is why cancers that arise in different organs, or even different kinds of cancer from the same organ, select for mutations in distinct drivers. One possibility is that this is a passive process: some genes could drive cancer in a particular tissue, but for a variety of reasons are never mutated in the relevant cell type. Alternatively, as we believe, driver tissue specificity is an active process: the epigenetic state of cells dictates that only certain genetic perturbations are capable of driving cancer in that tissue. Through large-scale genetic screening experiments, we have discovered that normal cells derived from distinct tissues exhibit profoundly different responses to genetic perturbations that impact proliferation and survival. These differential responsiveness patterns underlie tissue specific drivers of cancer and impact recurring somatic copy number alteration (SCNA) patterns. We believe that the lack of mutations in certain tissues is as telling about the oncogenic properties of a given gene as are the common presence of mutations in other tissues. As such, the core approach of the SPECIFICANCER program is to compare the molecular and cellular manifestations of gene perturbations in tissues where mutations naturally occur and in tissues where they do not. This approach begins with gain and loss of function screens for drivers of proliferation and survival in 2D and 3D cellular models derived from different primary tissue sites. We will also explore whether cancer vulnerabilities are influenced by the epigenetic state including combinatorial changes due to multiple drivers. In parallel, we will use genetically engineered mouse models to explore the tissue-specific cancer promoting properties of mutations affecting RAS/MAPK, WNT, and PRC2. In these studies, global transcriptional, epigenetic, and proteomic measurements will be used to understand the molecular mechanisms that define tissue specificity and responsiveness to drivers. This work will generate a functional map of tissue specificity that will allow us to better interpret cancer genomics and to develop therapeutic paradigms based on the tissue-specific biology of cancer genes. We hope to improve the basic understanding of what drives cancer and to provide a rational foundation for therapeutic choices made by physicians and patients.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS