SpecifiCancer: Dissecting the Tumor Specificity of Cancer Drivers


GRAND CHALLENGE AWARD, IN PARTNERSHIP WITH CANCER RESEARCH UK (2019-Present)

Recent research from the individual SPECIFICANCER laboratories suggests that different tissues/organs respond quite differently to the “stop” and “go” signals within cells that cause cancer. For example, a “go” signal in one tissue (e.g. a mutated gene) will cause cells to divide uncontrollably, while the same signal will have no effect in another tissue. Scientists on the SPECIFICANCER team hypothesize that tissues respond so differently to these signals because they are “programmed” differently. Understanding how the DNA from different tissues is programmed will be essential for understanding how specific genes cause cancer in different organs and, ultimately, how to prevent or treat cancers.

To accomplish this task, the SPECIFCANCER team is taking a multidisciplinary approach. First, the team will take normal cells from the tissue types that give rise to most human cancers and perform extensive genetic and biochemical analyses to determine how their DNA networks are programmed. Next, hundreds of cancer-causing genes will be introduced into each of these cell types to determine how they respond to each gene – Do they divide uncontrollably or not? Similar analyses will be performed in mice to understand better how these genes function in a living organism.

These differences in tissue programming may also affect how a cancer in that tissue responds to therapy, and so the team will perform extensive genetic studies to identify a unique “Achilles heel” for specific cancer tissue–gene combinations. They will also study the unique challenges caused by multiple cancer-causing genes occurring in the same tumor, particularly regarding the response to cancer therapeutics. Building on the knowledge gained from these experiments, the team aims to enable true “precision medicine,” a process by which physicians can match the right drug to the right patient.

This project has pulled together the expertise of scientists in different disciplines (i.e. geneticists, bioinformaticians, mouse modelers, biochemists, translational scientists) with expertise in many types of cancer (e.g. colon, skin, breast, lung, brain, etc.) to unlock the secret of how and why different genes cause cancers in different tissues. Their efforts will improve our understanding of cancer development and will also impact the development of new therapies.

PUBLISHED RESEARCH

Haigis KM, Cichowski K, Elledge SJ. Tissue-specificity in cancer: The rule, not the exception. Science. 2019.

Poulin EJ, Bera AK, Lu J, Lin YJ, Strasser SD, Paulo JA, Huang TQ, Morales C, Yan W, Cook J, Nowak JA, Brubaker DK, Joughin BA, Johnson CW, DeStefanis RA, Ghazi PC, Gondi S, Wales TE, Iacob RE, Bogdanova L, Gierut JJ, Li Y, Engen JR, Perez-Mancera PA, Braun BS, Gygi SP, Lauffenburger DA, Westover KD, Haigis KM. Tissue-Specific Oncogenic Activity of KRASA146T. Cancer Discov. 2019.

Brubaker DK, Paulo JA, Sheth S, Poulin EJ, Popow O, Joughin BA, Strasser SD, Starchenko A, Gygi SP, Lauffenburger DA, Haigis KM. Proteogenomic Network Analysis of Context-Specific KRAS Signaling in Mouse-to-Human Cross-Species Translation. Cell Syst. 2019.

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