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Article ; Online: Not all cancers are created equal: Tissue specificity in cancer genes and pathways.

Bianchi, Joy J / Zhao, Xin / Mays, Joseph C / Davoli, Teresa

2020 Volume 63, Page(s) 135–143

Abstract: Tumors arise through waves of genetic alterations and clonal expansion that allow tumor cells to acquire cancer hallmarks, such as genome instability and immune evasion. Recent genomic analyses showed that the vast majority of cancer driver genes are ... ...

Abstract	Tumors arise through waves of genetic alterations and clonal expansion that allow tumor cells to acquire cancer hallmarks, such as genome instability and immune evasion. Recent genomic analyses showed that the vast majority of cancer driver genes are mutated in a tissue-dependent manner, that is, are altered in some cancers but not others. Often the tumor type also affects the likelihood of therapy response. What is the origin of tissue specificity in cancer? Recent studies suggest that both cell-intrinsic and cell-extrinsic factors play a role. On one hand, cell type-specific wiring of the cell signaling network determines the outcome of cancer driver gene mutations. On the other hand, the tumor cells' exposure to tissue-specific microenvironments (e.g. immune cells) also contributes to shape the tissue specificity of driver genes and of therapy response. In the future, a more complete understanding of tissue specificity in cancer may inform methods to better predict and improve therapeutic outcomes.
MeSH term(s)	Animals ; Gene Expression Regulation, Neoplastic ; Genomic Instability/physiology ; Humans ; Mutation/physiology ; Neoplasms/classification ; Neoplasms/genetics ; Neoplasms/metabolism ; Neoplasms/pathology ; Oncogenes/physiology ; Organ Specificity/genetics ; Signal Transduction/genetics ; Tumor Microenvironment/genetics
Language	English
Publishing date	2020-02-21
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1026381-0
ISSN	1879-0410 ; 0955-0674
ISSN (online)	1879-0410
ISSN	0955-0674
DOI	10.1016/j.ceb.2020.01.005
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Article ; Online: Telomere-driven tetraploidization occurs in human cells undergoing crisis and promotes transformation of mouse cells.

Davoli, Teresa / de Lange, Titia

Cancer cell

2012 Volume 21, Issue 6, Page(s) 765–776

Abstract: Human cancers with a subtetraploid karyotype are thought to originate from tetraploid precursors, but the cause of tetraploidization is unknown. We previously documented endoreduplication in mouse cells with persistent telomere dysfunction or genome-wide ...

Abstract	Human cancers with a subtetraploid karyotype are thought to originate from tetraploid precursors, but the cause of tetraploidization is unknown. We previously documented endoreduplication in mouse cells with persistent telomere dysfunction or genome-wide DNA damage. We now report that endoreduplication and mitotic failure occur during telomere crisis in human fibroblasts and mammary epithelial cells and document the role of p53 and Rb in repressing tetraploidization. Using an inducible system to generate transient telomere damage, we show that telomere-driven tetraploidization enhances the tumorigenic transformation of mouse cells. Similar to human solid cancers, the resulting tumors evolved subtetraploid karyotypes. These data establish that telomere-driven tetraploidization is induced by critically short telomeres and has the potential to promote tumorigenesis in early cancerous lesions.
MeSH term(s)	Animals ; Cell Cycle Checkpoints/genetics ; Cell Line ; Cell Transformation, Neoplastic/genetics ; Cells, Cultured ; DNA Damage ; Epithelial Cells/metabolism ; Fibroblasts/cytology ; Fibroblasts/metabolism ; Flow Cytometry ; Humans ; Immunoblotting ; In Situ Hybridization, Fluorescence ; Karyotype ; Mammary Glands, Human/cytology ; Mice ; Mitosis/genetics ; RNA Interference ; Retinoblastoma Protein/genetics ; Retinoblastoma Protein/metabolism ; Telomere/genetics ; Tetraploidy ; Time Factors ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Retinoblastoma Protein ; Tumor Suppressor Protein p53
Language	English
Publishing date	2012-06-14
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2078448-X
ISSN	1878-3686 ; 1535-6108
ISSN (online)	1878-3686
ISSN	1535-6108
DOI	10.1016/j.ccr.2012.03.044
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Article ; Online: Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy.

Davoli, Teresa / Uno, Hajime / Wooten, Eric C / Elledge, Stephen J

Science (New York, N.Y.)

2017 Volume 355, Issue 6322

Abstract: Immunotherapies based on immune checkpoint blockade are highly effective in a subset of patients. An ongoing challenge is the identification of biomarkers that predict which patients will benefit from these therapies. Aneuploidy, also known as somatic ... ...

Abstract	Immunotherapies based on immune checkpoint blockade are highly effective in a subset of patients. An ongoing challenge is the identification of biomarkers that predict which patients will benefit from these therapies. Aneuploidy, also known as somatic copy number alterations (SCNAs), is widespread in cancer and is posited to drive tumorigenesis. Analyzing 12 human cancer types, we find that, for most, highly aneuploid tumors show reduced expression of markers of cytotoxic infiltrating immune cells, especially CD8
MeSH term(s)	Biomarkers, Tumor/immunology ; CTLA-4 Antigen/antagonists & inhibitors ; Cell Cycle/immunology ; Cell Proliferation ; Cytotoxicity, Immunologic ; DNA Copy Number Variations ; Humans ; Immunotherapy ; Lymphocytes, Tumor-Infiltrating/immunology ; Models, Biological ; Neoplasms/genetics ; Neoplasms/immunology ; Neoplasms/mortality ; Neoplasms/therapy ; Point Mutation ; Prognosis ; T-Lymphocytes, Cytotoxic/immunology ; Transcriptome ; Tumor Escape/genetics
Chemical Substances	Biomarkers, Tumor ; CTLA-4 Antigen ; CTLA4 protein, human
Language	English
Publishing date	2017--20
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.aaf8399
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Zs.A 27: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Proteogenomic analysis of cancer aneuploidy and normal tissues reveals divergent modes of gene regulation across cellular pathways.

Cheng, Pan / Zhao, Xin / Katsnelson, Lizabeth / Camacho-Hernandez, Elaine M / Mermerian, Angela / Mays, Joseph C / Lippman, Scott M / Rosales-Alvarez, Reyna Edith / Moya, Raquel / Shwetar, Jasmine / Grun, Dominic / Fenyo, David / Davoli, Teresa

eLife

2022 Volume 11

Abstract: How cells control gene expression is a fundamental question. The relative contribution of protein-level and RNA-level regulation to this process remains unclear. Here, we perform a proteogenomic analysis of tumors and untransformed cells containing ... ...

Abstract	How cells control gene expression is a fundamental question. The relative contribution of protein-level and RNA-level regulation to this process remains unclear. Here, we perform a proteogenomic analysis of tumors and untransformed cells containing somatic copy number alterations (SCNAs). By revealing how cells regulate RNA and protein abundances of genes with SCNAs, we provide insights into the rules of gene regulation. Protein complex genes have a strong protein-level regulation while non-complex genes have a strong RNA-level regulation. Notable exceptions are plasma membrane protein complex genes, which show a weak protein-level regulation and a stronger RNA-level regulation. Strikingly, we find a strong negative association between the degree of RNA-level and protein-level regulation across genes and cellular pathways. Moreover, genes participating in the same pathway show a similar degree of RNA- and protein-level regulation. Pathways including translation, splicing, RNA processing, and mitochondrial function show a stronger protein-level regulation while cell adhesion and migration pathways show a stronger RNA-level regulation. These results suggest that the evolution of gene regulation is shaped by functional constraints and that many cellular pathways tend to evolve one predominant mechanism of gene regulation at the protein level or at the RNA level.
MeSH term(s)	Aneuploidy ; Humans ; Membrane Proteins ; Neoplasms/genetics ; Proteogenomics ; RNA
Chemical Substances	Membrane Proteins ; RNA (63231-63-0)
Language	English
Publishing date	2022-09-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.75227
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Article ; Online: Somatic 9p24.1 alterations in HPV

Zhao, Xin / Cohen, Ezra E W / William, William N / Bianchi, Joy J / Abraham, Jim P / Magee, Daniel / Spetzler, David B / Gutkind, J Silvio / Alexandrov, Ludmil B / Cavenee, Webster K / Lippman, Scott M / Davoli, Teresa

Proceedings of the National Academy of Sciences of the United States of America

2022 Volume 119, Issue 47, Page(s) e2213835119

Abstract: Somatic copy number alterations (SCNAs), generally (1) losses containing interferons and interferon-pathway genes, many on chromosome 9p, predict immune-cold, immune checkpoint therapy (ICT)-resistant tumors (2); however, genomic regions mediating these ... ...

Abstract	Somatic copy number alterations (SCNAs), generally (1) losses containing interferons and interferon-pathway genes, many on chromosome 9p, predict immune-cold, immune checkpoint therapy (ICT)-resistant tumors (2); however, genomic regions mediating these effects are unclear and probably tissue specific. Previously, 9p21.3 loss was found to be an early genetic driver of human papillomavirus-negative (HPV
MeSH term(s)	Humans ; Tumor Microenvironment/genetics ; Immune Checkpoint Inhibitors ; Papillomavirus Infections/genetics ; Squamous Cell Carcinoma of Head and Neck/drug therapy ; Squamous Cell Carcinoma of Head and Neck/genetics ; Carcinoma, Squamous Cell ; Head and Neck Neoplasms/drug therapy ; Head and Neck Neoplasms/genetics
Chemical Substances	Immune Checkpoint Inhibitors
Language	English
Publishing date	2022-11-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2213835119
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Article ; Online: A genome-scale screen for synthetic drivers of T cell proliferation.

Legut, Mateusz / Gajic, Zoran / Guarino, Maria / Daniloski, Zharko / Rahman, Jahan A / Xue, Xinhe / Lu, Congyi / Lu, Lu / Mimitou, Eleni P / Hao, Stephanie / Davoli, Teresa / Diefenbach, Catherine / Smibert, Peter / Sanjana, Neville E

Nature

2022 Volume 603, Issue 7902, Page(s) 728–735

Abstract: The engineering of autologous patient T cells for adoptive cell therapies has revolutionized the treatment of several types of ... ...

Abstract	The engineering of autologous patient T cells for adoptive cell therapies has revolutionized the treatment of several types of cancer
MeSH term(s)	CD4-Positive T-Lymphocytes ; CD8-Positive T-Lymphocytes ; Cell Proliferation ; Humans ; Immunotherapy, Adoptive ; Lymphocyte Activation/genetics ; Neoplasms
Language	English
Publishing date	2022-03-16
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/s41586-022-04494-7
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Zs.A 26: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: The causes and consequences of polyploidy in normal development and cancer.

Davoli, Teresa / de Lange, Titia

Annual review of cell and developmental biology

2011 Volume 27, Page(s) 585–610

Abstract: Although nearly all mammalian species are diploid, whole-genome duplications occur in select mammalian tissues as part of normal development. Such programmed polyploidization involves changes in the regulatory pathways that normally maintain the diploid ... ...

Abstract	Although nearly all mammalian species are diploid, whole-genome duplications occur in select mammalian tissues as part of normal development. Such programmed polyploidization involves changes in the regulatory pathways that normally maintain the diploid state of the mammalian genome. Unscheduled whole-genome duplications, which lead primarily to tetraploid cells, also take place in a substantial fraction of human tumors and have been proposed to constitute an important step in the development of cancer aneuploidy. The origins of these polyploidization events and their consequences for tumor progression are explored in this review.
MeSH term(s)	Aging/genetics ; Aneuploidy ; Animals ; Cell Cycle/physiology ; Cell Transformation, Neoplastic/genetics ; DNA Damage ; Diploidy ; Genome ; Humans ; Karyotyping ; Morphogenesis/genetics ; Neoplasms/genetics ; Polyploidy ; Stress, Physiological/genetics ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism
Chemical Substances	Tumor Suppressor Protein p53
Language	English
Publishing date	2011-07-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1293750-2
ISSN	1530-8995 ; 1081-0706
ISSN (online)	1530-8995
ISSN	1081-0706
DOI	10.1146/annurev-cellbio-092910-154234
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Article ; Online: A genetic interaction analysis identifies cancer drivers that modify EGFR dependency.

Liao, Sida / Davoli, Teresa / Leng, Yumei / Li, Mamie Z / Xu, Qikai / Elledge, Stephen J

Genes & development

2017 Volume 31, Issue 2, Page(s) 184–196

Abstract: A large number of cancer drivers have been identified through tumor sequencing efforts, but how they interact and the degree to which they can substitute for each other have not been systematically explored. To comprehensively investigate how cancer ... ...

Abstract	A large number of cancer drivers have been identified through tumor sequencing efforts, but how they interact and the degree to which they can substitute for each other have not been systematically explored. To comprehensively investigate how cancer drivers genetically interact, we searched for modifiers of epidermal growth factor receptor (EGFR) dependency by performing CRISPR, shRNA, and expression screens in a non-small cell lung cancer (NSCLC) model. We elucidated a broad spectrum of tumor suppressor genes (TSGs) and oncogenes (OGs) that can genetically modify proliferation and survival of cancer cells when EGFR signaling is altered. These include genes already known to mediate EGFR inhibitor resistance as well as many TSGs not previously connected to EGFR and whose biological functions in tumorigenesis are not well understood. We show that mutation of
MeSH term(s)	Adenocarcinoma/genetics ; Adenocarcinoma/physiopathology ; Adenocarcinoma of Lung ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Drug Resistance, Neoplasm/genetics ; Enzyme Activation/drug effects ; ErbB Receptors/genetics ; ErbB Receptors/metabolism ; Gefitinib ; Gene Expression Regulation, Neoplastic/drug effects ; HEK293 Cells ; Humans ; Lung Neoplasms/genetics ; Lung Neoplasms/physiopathology ; Nuclear Proteins/genetics ; Oncogene Protein v-akt/metabolism ; Quinazolines/pharmacology ; Repressor Proteins/genetics ; Sequence Deletion ; Signal Transduction/genetics ; Transcription Factors/genetics ; Transcriptome
Chemical Substances	Antineoplastic Agents ; Nuclear Proteins ; PBRM1 protein, human ; Quinazolines ; Repressor Proteins ; Transcription Factors ; ErbB Receptors (EC 2.7.10.1) ; Oncogene Protein v-akt (EC 2.7.11.1) ; Gefitinib (S65743JHBS)
Language	English
Publishing date	2017-02-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	806684-x
ISSN	1549-5477 ; 0890-9369
ISSN (online)	1549-5477
ISSN	0890-9369
DOI	10.1101/gad.291948.116
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Zs.A 2292: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Spatial PD-L1, immune-cell microenvironment, and genomic copy-number alteration patterns and drivers of invasive-disease transition in prospective oral precancer cohort.

Cancer

2023 Volume 129, Issue 5, Page(s) 714–727

Abstract: Background: Studies of the immune landscape led to breakthrough trials of programmed death-1 (PD-1) inhibitors for recurrent/metastatic head and neck squamous cell carcinoma therapy. This study investigated the timing, influence of somatic copy-number ... ...

Abstract	Background: Studies of the immune landscape led to breakthrough trials of programmed death-1 (PD-1) inhibitors for recurrent/metastatic head and neck squamous cell carcinoma therapy. This study investigated the timing, influence of somatic copy-number alterations (SCNAs), and clinical implications of PD-L1 and immune-cell patterns in oral precancer (OPC). Methods: The authors evaluated spatial CD3, CD3/8, and CD68 density (cells/mm Results: Epithelial, but not CD68 immune-cell, PD-L1 expression was detected in 28% of OPCs, correlated with immune-cell infiltration, 9p21.3 loss of heterozygosity (LOH), and inferior oral cancer-free survival (OCFS), notably in OPCs with low CD3/8 cell density, dysplasia, and/or 9p21.3 LOH. High CD3/8 cell density in dysplastic lesions predicted better OCFS and eliminated the excess risk associated with prior oral cancer and dysplasia. PD-L1 and CD3/8 patterns revealed inferior OCFS in PD-L1 high intrinsic induction and dysplastic immune-cold subgroups. Conclusion: This report provides spatial insight into the immune landscape and drivers of OPCs, and a publicly available immunogenomic data set for future precancer interrogation. The data suggest that 9p21.3 LOH triggers an immune-hot inflammatory phenotype; whereas increased 9p deletion size encompassing CD274 at 9p24.1 may contribute to CD3/8 and PD-L1 depletion during invasive transition. The inferior OCFS in PD-L1-high, immune-cold OPCs support the development of T-cell recruitment strategies.
MeSH term(s)	Humans ; B7-H1 Antigen ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Genomics ; Head and Neck Neoplasms/metabolism ; Lymphocytes, Tumor-Infiltrating ; Mouth Neoplasms/genetics ; Mouth Neoplasms/metabolism ; Neoplasm Recurrence, Local/metabolism ; Prospective Studies ; Squamous Cell Carcinoma of Head and Neck/metabolism ; Tumor Microenvironment/genetics
Chemical Substances	B7-H1 Antigen ; Biomarkers, Tumor ; CD274 protein, human
Language	English
Publishing date	2023-01-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	1429-1
ISSN	1097-0142 ; 0008-543X ; 1934-662X
ISSN (online)	1097-0142
ISSN	0008-543X ; 1934-662X
DOI	10.1002/cncr.34607
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Article ; Online: KaryoCreate: A CRISPR-based technology to study chromosome-specific aneuploidy by targeting human centromeres

Bosco, Nazario / Goldberg, Aleah / Zhao, Xin / Mays, Joseph C. / Cheng, Pan / Johnson, Adam F. / Bianchi, Joy J. / Toscani, Cecilia / Di Tommaso, Elena / Katsnelson, Lizabeth / Annuar, Dania / Mei, Sally / Faitelson, Roni E. / Pesselev, Ilan Y. / Mohamed, Kareem S. / Mermerian, Angela / Camacho-Hernandez, Elaine M. / Gionco, Courtney A. / Manikas, Julie /

Tseng, Yi-Shuan / Sun, Zhengxi / Fani, Somayeh / Keegan, Sarah / Lippman, Scott M. / Fenyo, David / Giunta, Simona / Santaguida, Stefano / Davoli, Teresa

Cell. 2023 Apr. 18,

2023

Abstract: Aneuploidy, the presence of chromosome gains or losses, is a hallmark of cancer. Here, we describe KaryoCreate (karyotype CRISPR-engineered aneuploidy technology), a system that enables the generation of chromosome-specific aneuploidies by co-expression ... ...

Abstract	Aneuploidy, the presence of chromosome gains or losses, is a hallmark of cancer. Here, we describe KaryoCreate (karyotype CRISPR-engineered aneuploidy technology), a system that enables the generation of chromosome-specific aneuploidies by co-expression of an sgRNA targeting chromosome-specific CENPA-binding ɑ-satellite repeats together with dCas9 fused to mutant KNL1. We design unique and highly specific sgRNAs for 19 of the 24 chromosomes. Expression of these constructs leads to missegregation and induction of gains or losses of the targeted chromosome in cellular progeny, with an average efficiency of 8% for gains and 12% for losses (up to 20%) validated across 10 chromosomes. Using KaryoCreate in colon epithelial cells, we show that chromosome 18q loss, frequent in gastrointestinal cancers, promotes resistance to TGF-β, likely due to synergistic hemizygous deletion of multiple genes. Altogether, we describe an innovative technology to create and study chromosome missegregation and aneuploidy in the context of cancer and beyond.
Keywords	aneuploidy ; centromeres ; colon ; epithelium ; humans ; karyotyping ; mutants ; progeny ; technology ; centromere ; chromosome gains and losses ; kinetochore ; DNA damage ; mitosis ; chromosome missegregation ; CRISPR ; cancer
Language	English
Dates of publication	2023-0418
Publishing place	Elsevier Inc.
Document type	Article ; Online
Note	Pre-press version
ZDB-ID	187009-9
ISSN	1097-4172 ; 0092-8674
ISSN (online)	1097-4172
ISSN	0092-8674
DOI	10.1016/j.cell.2023.03.029
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