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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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.

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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 KMClassification 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.

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Centeno PP, Pavet V, Marais R. The journey from melanocytes to melanoma. Nat Rev Cancer. 2023.

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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.

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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.

Celotti M, Derks LLM, van Es J, van Boxtel R, Clevers H, Geurts MH. Protocol to create isogenic disease models from adult stem cell-derived organoids using next-generation CRISPR tools. STAR Protoc. 2024.

Loi P, Schade AE, Rodriguez CL, Krishnan A, Perurena N, Nguyen VTM, Xu Y, Watanabe M, Davis RA, Gardner A, Pilla NF, Mattioli K, Popow O, Gunduz N, Lannagan TRM, Fitzgerald S, Sicinska ET, Lin JR, Tan W, Brais LK, Haigis KM, Giannakis M, Ng K, Santagata S, Helin K, Sansom OJ, Cichowski K. Epigenetic and oncogenic inhibitors cooperatively drive differentiation and kill KRAS-mutant colorectal cancers. Cancer Discov. 2024.

Meena JK, Wang JH, Neill NJ, Keough D, Putluri N, Katsonis P, Koire AM, Lee H, Bowling EA, Tyagi S, Orellana M, Dominguez-Vidaña R, Li H, Eagle K, Danan C, Chung HC, Yang AD, Wu W, Kurley SJ, Ho BM, Zoeller JR, Olson CM, Meerbrey KL, Lichtarge O, Sreekumar A, Dacso CC, Guddat LW, Rejman D, Hocková D, Janeba Z, Simon LM, Lin CY, Pillon MC, Westbrook TF. MYC Induces Oncogenic Stress through RNA Decay and Ribonucleotide Catabolism in Breast Cancer. Cancer Discov. 2024.

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