SpecifiCancer: Dissecting the Tumor Specificity of Cancer Drivers


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

Stephen Elledge, PhD, Harvard University, Principal Investigator

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

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Elman JS, Ni TK, Mengwasser KE, Jin D, Wronski A, Elledge SJ, Kuperwasser C. Identification of FUBP1 as a Long Tail Cancer Driver and Widespread Regulator of Tumor Suppressor and Oncogene Alternative Splicing. Cell Rep. 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.

Gay DM, Ridgway RA, Müller M, Hodder MC, Hedley A, Clark W, Leach JD, Jackstadt R, Nixon C, Huels DJ, Campbell AD, Bird TG, Sansom OJ. Loss of BCL9/9l suppresses Wnt driven tumourigenesis in models that recapitulate human cancer. Nat Commun. 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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Arnal-Estapé A, Cai WL, Albert AE, Zhao M, Stevens LE, López-Giráldez F, Patel KD, Tyagi S, Schmitt EM, Westbrook TF, Nguyen DX. Tumor progression and chromatin landscape of lung cancer are regulated by the lineage factor GATA6. Oncogene. 2020.

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William WN Jr, Zhao X, Bianchi JJ, Lin HY, Cheng P, Lee JJ, Carter H, Alexandrov LB, Abraham JP, Spetzler DB, Dubinett SM, Cleveland DW, Cavenee W, Davoli T, Lippman SM. Immune evasion in HPV- head and neck precancer-cancer transition is driven by an aneuploid switch involving chromosome 9p loss. Proc Natl Acad Sci U S A. 2021.

Cook JH, Melloni GEM, Gulhan DC, Park PJ, Haigis KM. The origins and genetic interactions of KRAS mutations are allele- and tissue-specific. Nat Commun. 2021.

Flanagan DJ, Pentinmikko N, Luopajärvi K, Willis NJ, Gilroy K, Raven AP, Mcgarry L, Englund JI, Webb AT, Scharaw S, Nasreddin N, Hodder MC, Ridgway RA, Minnee E, Sphyris N, Gilchrist E, Najumudeen AK, Romagnolo B, Perret C, Williams AC, Clevers H, Nummela P, Lähde M, Alitalo K, Hietakangas V, Hedley A, Clark W, Nixon C, Kirschner K, Jones EY, Ristimäki A, Leedham SJ, Fish PV, Vincent JP, Katajisto P, Sansom OJ. NOTUM from Apc-mutant cells biases clonal competition to initiate cancer. Nature. 2021.

Bowling EA, Wang JH, Gong F, Wu W, Neill NJ, Kim IS, Tyagi S, Orellana M, Kurley SJ, Dominguez-Vidaña R, Chung HC, Hsu TY, Dubrulle J, Saltzman AB, Li H, Meena JK, Canlas GM, Chamakuri S, Singh S, Simon LM, Olson CM, Dobrolecki LE, Lewis MT, Zhang B, Golding I, Rosen JM, Young DW, Malovannaya A, Stossi F, Miles G, Ellis MJ, Yu L, Buonamici S, Lin CY, Karlin KL, Zhang XH, Westbrook TF. Spliceosome-targeted therapies trigger an antiviral immune response in triple-negative breast cancer. Cell. 2021.

Einstein JM, Perelis M, Chaim IA, Meena JK, Nussbacher JK, Tankka AT, Yee BA, Li H, Madrigal AA, Neill NJ, Shankar A, Tyagi S, Westbrook TF, Yeo GW. Inhibition of YTHDF2 triggers proteotoxic cell death in MYC-driven breast cancer. Mol Cell. 2021.

Beumer J, Geurts MH, Lamers MM, Puschhof J, Zhang J, van der Vaart J, Mykytyn AZ, Breugem TI, Riesebosch S, Schipper D, van den Doel PB, de Lau W, Pleguezuelos-Manzano C, Busslinger G, Haagmans BL, Clevers H. A CRISPR/Cas9 genetically engineered organoid biobank reveals essential host factors for coronaviruses. Nat Commun. 2021.

Cortés-Ciriano I, Gulhan DC, Lee JJ, Melloni GEM, Park PJ. Computational analysis of cancer genome sequencing data. Nat Rev Genet. 2021.

Leach JDG, Vlahov N, Tsantoulis P, Ridgway RA, Flanagan DJ, Gilroy K, Sphyris N, Vázquez EG, Vincent DF, Faller WJ, Hodder MC, Raven A, Fey S, Najumudeen AK, Strathdee D, Nixon C, Hughes M, Clark W, Shaw R, van Hooff SR, Huels DJ, Medema JP, Barry ST, Frame MC, Unciti-Broceta A, Leedham SJ, Inman GJ, Jackstadt R, Thompson BJ, Campbell AD, Tejpar S, Sansom OJ. Oncogenic BRAF, unrestrained by TGFβ-receptor signalling, drives right-sided colonic tumorigenesis. Nat Commun. 2021.

Geurts MH, de Poel E, Pleguezuelos-Manzano C, Oka R, Carrillo L, Andersson-Rolf A, Boretto M, Brunsveld JE, van Boxtel R, Beekman JM, Clevers H. Evaluating CRISPR-based prime editing for cancer modeling and CFTR repair in organoids. Life Sci Alliance. 2021.

Martin TM, Patel RS, Cook DR, Choi MY, Patil A, Liang AC, Li MZ, Haigis KM, Elledge SJ. The adaptive immune system is a major driver of selection for tumor suppressor gene inactivation. Science. 2021.

Johnson CW, Seo HS, Terrell EM, Yang MH, KleinJan F, Gebregiworgis T, Gasmi-Seabrook GMC, Geffken EA, Lakhani J, Song K, Bashyal P, Popow O, Paulo JA, Liu A, Mattos C, Marshall CB, Ikura M, Morrison DK, Dhe-Paganon S, Haigis KM. Regulation of GTPase function by autophosphorylation. Mol Cell. 2022.

 

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