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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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.
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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.
Shui B, La Rocca G, Ventura A, Haigis KM. Interplay between K-RAS and miRNAs. Trends Cancer. 2022.
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.
Johnson C, Burkhart DL, Haigis KM. Classification of KRAS-Activating Mutations and the Implications for Therapeutic Intervention. Cancer Discov. 2022.
Cheng P, Zhao X, Katsnelson L, Camacho-Hernandez EM, Mermerian A, Mays JC, Lippman SM, Rosales-Alvarez RE, Moya R, Shwetar J, Grun D, Fenyo D, Davoli T. Proteogenomic analysis of cancer aneuploidy and normal tissues reveals divergent modes of gene regulation across cellular pathways. Elife. 2022.
Zhao X, Cohen EEW, William WN Jr, Bianchi JJ, Abraham JP, Magee D, Spetzler DB, Gutkind JS, Alexandrov LB, Cavenee WK, Lippman SM, Davoli T. Somatic 9p24.1 alterations in HPV- head and neck squamous cancer dictate immune microenvironment and anti-PD-1 checkpoint inhibitor activity. Proc Natl Acad Sci U S A. 2022.
Hendriks D, Brouwers JF, Hamer K, Geurts MH, Luciana L, Massalini S, López-Iglesias C, Peters PJ, Rodríguez-Colman MJ, Chuva de Sousa Lopes S, Artegiani B, Clevers H. Engineered human hepatocyte organoids enable CRISPR-based target discovery and drug screening for steatosis. Nat Biotechnol. 2023.
Centeno PP, Pavet V, Marais R. The journey from melanocytes to melanoma. Nat Rev Cancer. 2023.
Bosco N, Goldberg A, Zhao X, Mays JC, Cheng P, Johnson AF, Bianchi JJ, Toscani C, Di Tommaso E, Katsnelson L, Annuar D, Mei S, Faitelson RE, Pesselev IY, Mohamed KS, Mermerian A, Camacho-Hernandez EM, Gionco CA, Manikas J, Tseng YS, Sun Z, Fani S, Keegan S, Lippman SM, Fenyö D, Giunta S, Santaguida S, Davoli T. KaryoCreate: A CRISPR-based technology to study chromosome-specific aneuploidy by targeting human centromeres. Cell. 2023.
Schade AE, Kuzmickas R, Rodriguez CL, Mattioli K, Enos M, Gardner A, Cichowski K. Combating castration-resistant prostate cancer by co-targeting the epigenetic regulators EZH2 and HDAC. PLoS Biol. 2023.
Millen R, De Kort WWB, Koomen M, van Son GJF, Gobits R, Penning de Vries B, Begthel H, Zandvliet M, Doornaert P, Raaijmakers CPJ, Geurts MH, Elias SG, van Es RJJ, de Bree R, Devriese LA, Willems SM, Kranenburg O, Driehuis E, Clevers H. Patient-derived head and neck cancer organoids allow treatment stratification and serve as a tool for biomarker validation and identification. Med. 2023.
Lee JJ, Jung YL, Cheong TC, Espejo Valle-Inclan J, Chu C, Gulhan DC, Ljungström V, Jin H, Viswanadham VV, Watson EV, Cortés-Ciriano I, Elledge SJ, Chiarle R, Pellman D, Park PJ. ERα-associated translocations underlie oncogene amplifications in breast cancer. Nature. 2023.
Shui B, Beyett TS, Chen Z, Li X, La Rocca G, Gazlay WM, Eck MJ, Lau KS, Ventura A, Haigis KM. Oncogenic K-Ras suppresses global miRNA function. Mol Cell. 2023.
Najumudeen AK, Fey SK, Millett LM, Ford CA, Gilroy K, Gunduz N, Ridgway RA, Anderson E, Strathdee D, Clark W, Nixon C, Morton JP, Campbell AD, Sansom OJ. KRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo. Nat Commun. 2024.
Jin H, Gulhan DC, Geiger B, Ben-Isvy D, Geng D, Ljungström V, Park PJ. Accurate and sensitive mutational signature analysis with MuSiCal. Nat Genet. 2024.
Watson EV, Lee JJ, Gulhan DC, Melloni GEM, Venev SV, Magesh RY, Frederick A, Chiba K, Wooten EC, Naxerova K, Dekker J, Park PJ, Elledge SJ. Chromosome evolution screens recapitulate tissue-specific tumor aneuploidy patterns. Nat Genet. 2024.