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Article ; Online: Optimization of Cas12a for multiplexed genome-scale transcriptional activation.

Griffith, Audrey L / Zheng, Fengyi / McGee, Abby V / Miller, Nathan W / Szegletes, Zsofia M / Reint, Ganna / Gademann, Fabian / Nwolah, Ifunanya / Hegde, Mudra / Liu, Yanjing V / Goodale, Amy / Doench, John G

Cell genomics

2023 Volume 3, Issue 9, Page(s) 100387

Abstract: Cas12a CRISPR technology, unlike Cas9, allows for facile multiplexing of guide RNAs from a single transcript, simplifying combinatorial perturbations. While Cas12a has been implemented for multiplexed knockout genetic screens, it has yet to be optimized ... ...

Abstract	Cas12a CRISPR technology, unlike Cas9, allows for facile multiplexing of guide RNAs from a single transcript, simplifying combinatorial perturbations. While Cas12a has been implemented for multiplexed knockout genetic screens, it has yet to be optimized for CRISPR activation (CRISPRa) screens in human cells. Here, we develop a new Cas12a-based transactivation domain (TAD) recruitment system using the ALFA nanobody and demonstrate simultaneous activation of up to four genes. We screen a genome-wide library to identify modulators of growth and MEK inhibition, and we compare these results with those obtained with open reading frame (ORF) overexpression and Cas9-based CRISPRa. We find that the activity of multiplexed arrays is largely predictable from the best-performing guide and provide criteria for selecting active guides. We anticipate that these results will greatly accelerate the exploration of gene function and combinatorial phenotypes at scale.
Language	English
Publishing date	2023-09-01
Publishing country	United States
Document type	Journal Article
ISSN	2666-979X
ISSN (online)	2666-979X
DOI	10.1016/j.xgen.2023.100387
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Article ; Online: Genome-wide pooled CRISPR screening in neurospheres.

Abid, Tanaz / Goodale, Amy B / Kalani, Zohra / Wyatt, Meghan / Gonzalez, Elizabeth M / Zhou, Kevin Ning / Qian, Kenin / Novikov, Dana / Condurat, Alexandra-Larisa / Bandopadhayay, Pratiti / Piccioni, Federica / Persky, Nicole S / Root, David E

Nature protocols

2023 Volume 18, Issue 7, Page(s) 2014–2031

Abstract: Spheroid culture systems have allowed in vitro propagation of cells unable to grow in canonical cell culturing conditions, and may capture cellular contexts that model tumor growth better than current model systems. The insights gleaned from genome-wide ... ...

Abstract	Spheroid culture systems have allowed in vitro propagation of cells unable to grow in canonical cell culturing conditions, and may capture cellular contexts that model tumor growth better than current model systems. The insights gleaned from genome-wide clustered regularly interspaced short palindromic repeat (CRISPR) screening of thousands of cancer cell lines grown in conventional culture conditions illustrate the value of such CRISPR pooled screens. It is clear that similar genome-wide CRISPR screens of three-dimensional spheroid cultures will be important for future biological discovery. Here, we present a protocol for genome-wide CRISPR screening of three-dimensional neurospheres. While many in-depth protocols and discussions have been published for more typical cell lines, few detailed protocols are currently available in the literature for genome-wide screening in spheroidal cell lines. For those who want to screen such cell lines, and particularly neurospheres, we provide a step-by-step description of assay development tests to be performed before screening, as well as for the screen itself. We highlight considerations of variables that make these screens distinct from, or similar to, typical nonspheroid cell lines throughout. Finally, we illustrate typical outcomes of neurosphere genome-wide screens, and how neurosphere screens typically produce slightly more heterogeneous signal distributions than more canonical cancer cell lines. Completion of this entire protocol will take 8-12 weeks from the initial assay development tests to deconvolution of the sequencing data.
MeSH term(s)	Humans ; Clustered Regularly Interspaced Short Palindromic Repeats/genetics ; CRISPR-Cas Systems ; Genome ; Cell Line ; Neoplasms
Language	English
Publishing date	2023-06-07
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2244966-8
ISSN	1750-2799 ; 1754-2189
ISSN (online)	1750-2799
ISSN	1754-2189
DOI	10.1038/s41596-023-00835-6
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Article ; Online: Three million images and morphological profiles of cells treated with matched chemical and genetic perturbations.

Nature methods

2024

Abstract: The identification of genetic and chemical perturbations with similar impacts on cell morphology can elucidate compounds' mechanisms of action or novel regulators of genetic pathways. Research on methods for identifying such similarities has lagged due ... ...

Abstract	The identification of genetic and chemical perturbations with similar impacts on cell morphology can elucidate compounds' mechanisms of action or novel regulators of genetic pathways. Research on methods for identifying such similarities has lagged due to a lack of carefully designed and well-annotated image sets of cells treated with chemical and genetic perturbations. Here we create such a Resource dataset, CPJUMP1, in which each perturbed gene's product is a known target of at least two chemical compounds in the dataset. We systematically explore the directionality of correlations among perturbations that target the same protein encoded by a given gene, and we find that identifying matches between chemical and genetic perturbations is a challenging task. Our dataset and baseline analyses provide a benchmark for evaluating methods that measure perturbation similarities and impact, and more generally, learn effective representations of cellular state from microscopy images. Such advancements would accelerate the applications of image-based profiling of cellular states, such as uncovering drug mode of action or probing functional genomics.
Language	English
Publishing date	2024-04-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	2169522-2
ISSN	1548-7105 ; 1548-7091
ISSN (online)	1548-7105
ISSN	1548-7091
DOI	10.1038/s41592-024-02241-6
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Article ; Online: Modular vector assembly enables rapid assessment of emerging CRISPR technologies.

McGee, Abby V / Liu, Yanjing V / Griffith, Audrey L / Szegletes, Zsofia M / Wen, Bronte / Kraus, Carolyn / Miller, Nathan W / Steger, Ryan J / Escude Velasco, Berta / Bosch, Justin A / Zirin, Jonathan D / Viswanatha, Raghuvir / Sontheimer, Erik J / Goodale, Amy / Greene, Matthew A / Green, Thomas M / Doench, John G

Cell genomics

2024 Volume 4, Issue 3, Page(s) 100519

Abstract: The diversity of CRISPR systems, coupled with scientific ingenuity, has led to an explosion of applications; however, to test newly described innovations in their model systems, researchers typically embark on cumbersome, one-off cloning projects to ... ...

Abstract	The diversity of CRISPR systems, coupled with scientific ingenuity, has led to an explosion of applications; however, to test newly described innovations in their model systems, researchers typically embark on cumbersome, one-off cloning projects to generate custom reagents that are optimized for their biological questions. Here, we leverage Golden Gate cloning to create the Fragmid toolkit, a modular set of CRISPR cassettes and delivery technologies, along with a web portal, resulting in a combinatorial platform that enables scalable vector assembly within days. We further demonstrate that multiple CRISPR technologies can be assessed in parallel in a pooled screening format using this resource, enabling the rapid optimization of both novel technologies and cellular models. These results establish Fragmid as a robust system for the rapid design of CRISPR vectors, and we anticipate that this assembly approach will be broadly useful for systematic development, comparison, and dissemination of CRISPR technologies.
MeSH term(s)	CRISPR-Cas Systems/genetics ; Clustered Regularly Interspaced Short Palindromic Repeats/genetics ; Genetic Vectors/genetics
Language	English
Publishing date	2024-03-12
Publishing country	United States
Document type	Journal Article
ISSN	2666-979X
ISSN (online)	2666-979X
DOI	10.1016/j.xgen.2024.100519
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Article ; Online: Mapping the landscape of genetic dependencies in chordoma.

Sharifnia, Tanaz / Wawer, Mathias J / Goodale, Amy / Lee, Yenarae / Kazachkova, Mariya / Dempster, Joshua M / Muller, Sandrine / Levy, Joan / Freed, Daniel M / Sommer, Josh / Kalfon, Jérémie / Vazquez, Francisca / Hahn, William C / Root, David E / Clemons, Paul A / Schreiber, Stuart L

Nature communications

2023 Volume 14, Issue 1, Page(s) 1933

Abstract: Identifying the spectrum of genes required for cancer cell survival can reveal essential cancer circuitry and therapeutic targets, but such a map remains incomplete for many cancer types. We apply genome-scale CRISPR-Cas9 loss-of-function screens to map ... ...

Abstract	Identifying the spectrum of genes required for cancer cell survival can reveal essential cancer circuitry and therapeutic targets, but such a map remains incomplete for many cancer types. We apply genome-scale CRISPR-Cas9 loss-of-function screens to map the landscape of selectively essential genes in chordoma, a bone cancer with few validated targets. This approach confirms a known chordoma dependency, TBXT (T; brachyury), and identifies a range of additional dependencies, including PTPN11, ADAR, PRKRA, LUC7L2, SRRM2, SLC2A1, SLC7A5, FANCM, and THAP1. CDK6, SOX9, and EGFR, genes previously implicated in chordoma biology, are also recovered. We find genomic and transcriptomic features that predict specific dependencies, including interferon-stimulated gene expression, which correlates with ADAR dependence and is elevated in chordoma. Validating the therapeutic relevance of dependencies, small-molecule inhibitors of SHP2, encoded by PTPN11, have potent preclinical efficacy against chordoma. Our results generate an emerging map of chordoma dependencies to enable biological and therapeutic hypotheses.
MeSH term(s)	Humans ; Chordoma/genetics ; Bone Neoplasms/genetics ; Bone Neoplasms/metabolism ; Genes, Essential ; Gene Expression Profiling ; Transcriptome ; Cell Line, Tumor ; DNA-Binding Proteins/metabolism ; Apoptosis Regulatory Proteins/genetics ; DNA Helicases/metabolism
Chemical Substances	THAP1 protein, human ; DNA-Binding Proteins ; Apoptosis Regulatory Proteins ; FANCM protein, human (EC 3.6.1.-) ; DNA Helicases (EC 3.6.4.-)
Language	English
Publishing date	2023-04-06
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-37593-8
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Article: Modular vector assembly enables rapid assessment of emerging CRISPR technologies.

McGee, Abby V / Liu, Yanjing V / Griffith, Audrey L / Szegletes, Zsofia M / Wen, Bronte / Kraus, Carolyn / Miller, Nathan W / Steger, Ryan J / Velasco, Berta Escude / Bosch, Justin A / Zirin, Jonathan D / Viswanatha, Raghuvir / Sontheimer, Erik J / Goodale, Amy / Greene, Matthew A / Green, Thomas M / Doench, John G

bioRxiv : the preprint server for biology

2023

Abstract: The diversity of CRISPR systems, coupled with scientific ingenuity, has led to an explosion of applications; however, to test newly-described innovations in their model systems, researchers typically embark on cumbersome, one-off cloning projects to ... ...

Abstract	The diversity of CRISPR systems, coupled with scientific ingenuity, has led to an explosion of applications; however, to test newly-described innovations in their model systems, researchers typically embark on cumbersome, one-off cloning projects to generate custom reagents that are optimized for their biological questions. Here, we leverage Golden Gate cloning to create the Fragmid toolkit, a modular set of CRISPR cassettes and delivery technologies, along with a web portal, resulting in a combinatorial platform that enables scalable vector assembly within days. We further demonstrate that multiple CRISPR technologies can be assessed in parallel in a pooled screening format using this resource, enabling the rapid optimization of both novel technologies and cellular models. These results establish Fragmid as a robust system for the rapid design of CRISPR vectors, and we anticipate that this assembly approach will be broadly useful for systematic development, comparison, and dissemination of CRISPR technologies.
Language	English
Publishing date	2023-10-27
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.10.25.564061
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Article ; Online: Genotype-Fitness Maps of EGFR-Mutant Lung Adenocarcinoma Chart the Evolutionary Landscape of Resistance for Combination Therapy Optimization.

Bolan, Patrick O / Zviran, Asaf / Brenan, Lisa / Schiffman, Joshua S / Dusaj, Neville / Goodale, Amy / Piccioni, Federica / Johannessen, Cory M / Landau, Dan A

Cell systems

2019 Volume 10, Issue 1, Page(s) 52–65.e7

Abstract: Cancer evolution poses a central obstacle to cure, as resistant clones expand under therapeutic selection pressures. Genome sequencing of relapsed disease can nominate genomic alterations conferring resistance but sample collection lags behind, limiting ... ...

Abstract	Cancer evolution poses a central obstacle to cure, as resistant clones expand under therapeutic selection pressures. Genome sequencing of relapsed disease can nominate genomic alterations conferring resistance but sample collection lags behind, limiting therapeutic innovation. Genome-wide screens offer a complementary approach to chart the compendium of escape genotypes, anticipating clinical resistance. We report genome-wide open reading frame (ORF) resistance screens for first- and third-generation epidermal growth factor receptor (EGFR) inhibitors and a MEK inhibitor. Using serial sampling, dose gradients, and mathematical modeling, we generate genotype-fitness maps across therapeutic contexts and identify alterations that escape therapy. Our data expose varying dose-fitness relationship across genotypes, ranging from complete dose invariance to paradoxical dose dependency where fitness increases in higher doses. We predict fitness with combination therapy and compare these estimates to genome-wide fitness maps of drug combinations, identifying genotypes where combination therapy results in unexpected inferior effectiveness. These data are applied to nominate combination optimization strategies to forestall resistant disease.
MeSH term(s)	Acrylamides/administration & dosage ; Acrylamides/pharmacology ; Adenocarcinoma of Lung/drug therapy ; Adenocarcinoma of Lung/enzymology ; Adenocarcinoma of Lung/genetics ; Aniline Compounds/administration & dosage ; Aniline Compounds/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Benzimidazoles/administration & dosage ; Benzimidazoles/pharmacology ; Drug Resistance, Neoplasm/genetics ; ErbB Receptors/genetics ; ErbB Receptors/metabolism ; Erlotinib Hydrochloride/administration & dosage ; Erlotinib Hydrochloride/pharmacology ; Genetic Fitness ; Genotype ; Humans ; Lung Neoplasms/drug therapy ; Lung Neoplasms/enzymology ; Lung Neoplasms/genetics ; MAP Kinase Signaling System ; Mutation
Chemical Substances	Acrylamides ; Aniline Compounds ; Benzimidazoles ; binimetinib (181R97MR71) ; osimertinib (3C06JJ0Z2O) ; Erlotinib Hydrochloride (DA87705X9K) ; EGFR protein, human (EC 2.7.10.1) ; ErbB Receptors (EC 2.7.10.1)
Language	English
Publishing date	2019-10-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2854138-8
ISSN	2405-4720 ; 2405-4712
ISSN (online)	2405-4720
ISSN	2405-4712
DOI	10.1016/j.cels.2019.10.002
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Article ; Online: Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma.

Hofman, Damon A / Ruiz-Orera, Jorge / Yannuzzi, Ian / Murugesan, Rakesh / Brown, Adam / Clauser, Karl R / Condurat, Alexandra L / van Dinter, Jip T / Engels, Sem A G / Goodale, Amy / van der Lugt, Jasper / Abid, Tanaz / Wang, Li / Zhou, Kevin N / Vogelzang, Jayne / Ligon, Keith L / Phoenix, Timothy N / Roth, Jennifer A / Root, David E /

Hubner, Norbert / Golub, Todd R / Bandopadhayay, Pratiti / van Heesch, Sebastiaan / Prensner, John R

Molecular cell

2024 Volume 84, Issue 2, Page(s) 261–276.e18

Abstract: A hallmark of high-risk childhood medulloblastoma is the dysregulation of RNA translation. Currently, it is unknown whether medulloblastoma dysregulates the translation of putatively oncogenic non-canonical open reading frames (ORFs). To address this ... ...

Abstract	A hallmark of high-risk childhood medulloblastoma is the dysregulation of RNA translation. Currently, it is unknown whether medulloblastoma dysregulates the translation of putatively oncogenic non-canonical open reading frames (ORFs). To address this question, we performed ribosome profiling of 32 medulloblastoma tissues and cell lines and observed widespread non-canonical ORF translation. We then developed a stepwise approach using multiple CRISPR-Cas9 screens to elucidate non-canonical ORFs and putative microproteins implicated in medulloblastoma cell survival. We determined that multiple lncRNA-ORFs and upstream ORFs (uORFs) exhibited selective functionality independent of main coding sequences. A microprotein encoded by one of these ORFs, ASNSD1-uORF or ASDURF, was upregulated, associated with MYC-family oncogenes, and promoted medulloblastoma cell survival through engagement with the prefoldin-like chaperone complex. Our findings underscore the fundamental importance of non-canonical ORF translation in medulloblastoma and provide a rationale to include these ORFs in future studies seeking to define new cancer targets.
MeSH term(s)	Humans ; Protein Biosynthesis ; Medulloblastoma/genetics ; Open Reading Frames/genetics ; Cell Survival/genetics ; Cerebellar Neoplasms/genetics
Language	English
Publishing date	2024-01-03
Publishing country	United States
Document type	Journal Article
ZDB-ID	1415236-8
ISSN	1097-4164 ; 1097-2765
ISSN (online)	1097-4164
ISSN	1097-2765
DOI	10.1016/j.molcel.2023.12.003
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Article ; Online: Transcriptional Antagonism by CDK8 Inhibition Improves Therapeutic Efficacy of MEK Inhibitors.

Malone, Clare F / Kim, Minjee / Alexe, Gabriela / Engel, Kathleen / Forman, Alexandra B / Robichaud, Amanda / Conway, Amy Saur / Goodale, Amy / Meyer, Ashleigh / Khalid, Delan / Thayakumar, Allen / Hatcher, John M / Gray, Nathanael S / Piccioni, Federica / Stegmaier, Kimberly

Cancer research

2022 Volume 83, Issue 2, Page(s) 285–300

Abstract: Aberrant RAS/MAPK signaling is a common driver of oncogenesis that can be therapeutically targeted with clinically approved MEK inhibitors. Disease progression on single-agent MEK inhibitors is common, however, and combination therapies are typically ... ...

Abstract	Aberrant RAS/MAPK signaling is a common driver of oncogenesis that can be therapeutically targeted with clinically approved MEK inhibitors. Disease progression on single-agent MEK inhibitors is common, however, and combination therapies are typically required to achieve significant clinical benefit in advanced cancers. Here we focused on identifying MEK inhibitor-based combination therapies in neuroblastoma with mutations that activate the RAS/MAPK signaling pathway, which are rare at diagnosis but frequent in relapsed neuroblastoma. A genome-scale CRISPR-Cas9 functional genomic screen was deployed to identify genes that when knocked out sensitize RAS-mutant neuroblastoma to MEK inhibition. Loss of either CCNC or CDK8, two members of the mediator kinase module, sensitized neuroblastoma to MEK inhibition. Furthermore, small-molecule kinase inhibitors of CDK8 improved response to MEK inhibitors in vitro and in vivo in RAS-mutant neuroblastoma and other adult solid tumors. Transcriptional profiling revealed that loss of CDK8 or CCNC antagonized the transcriptional signature induced by MEK inhibition. When combined, loss of CDK8 or CCNC prevented the compensatory upregulation of progrowth gene expression induced by MEK inhibition. These findings propose a new therapeutic combination for RAS-mutant neuroblastoma and may have clinical relevance for other RAS-driven malignancies. Significance: Transcriptional adaptation to MEK inhibition is mediated by CDK8 and can be blocked by the addition of CDK8 inhibitors to improve response to MEK inhibitors in RAS-mutant neuroblastoma, a clinically challenging disease.
MeSH term(s)	Adult ; Humans ; Cell Line, Tumor ; Neoplasm Recurrence, Local/drug therapy ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Neuroblastoma/drug therapy ; Neuroblastoma/genetics ; Neuroblastoma/pathology ; Mutation ; Mitogen-Activated Protein Kinase Kinases ; Cyclin-Dependent Kinase 8/genetics
Chemical Substances	Protein Kinase Inhibitors ; Mitogen-Activated Protein Kinase Kinases (EC 2.7.12.2) ; CDK8 protein, human (EC 2.7.11.22) ; Cyclin-Dependent Kinase 8 (EC 2.7.11.22)
Language	English
Publishing date	2022-11-30
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1432-1
ISSN	1538-7445 ; 0008-5472
ISSN (online)	1538-7445
ISSN	0008-5472
DOI	10.1158/0008-5472.CAN-21-4309
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Article ; Online: Comprehensive mutational scanning of EGFR reveals TKI sensitivities of extracellular domain mutants.

Hayes, Tikvah K / Aquilanti, Elisa / Persky, Nicole S / Yang, Xiaoping / Kim, Erica E / Brenan, Lisa / Goodale, Amy B / Alan, Douglas / Sharpe, Ted / Shue, Robert E / Westlake, Lindsay / Golomb, Lior / Silverman, Brianna R / Morris, Myshal D / Fisher, Ty Running / Beyene, Eden / Li, Yvonne Y / Cherniack, Andrew D / Piccioni, Federica /

Hicks, J Kevin / Chi, Andrew S / Cahill, Daniel P / Dietrich, Jorg / Batchelor, Tracy T / Root, David E / Johannessen, Cory M / Meyerson, Matthew

Nature communications

2024 Volume 15, Issue 1, Page(s) 2742

Abstract: The epidermal growth factor receptor, EGFR, is frequently activated in lung cancer and glioblastoma by genomic alterations including missense mutations. The different mutation spectra in these diseases are reflected in divergent responses to EGFR ... ...

Abstract	The epidermal growth factor receptor, EGFR, is frequently activated in lung cancer and glioblastoma by genomic alterations including missense mutations. The different mutation spectra in these diseases are reflected in divergent responses to EGFR inhibition: significant patient benefit in lung cancer, but limited in glioblastoma. Here, we report a comprehensive mutational analysis of EGFR function. We perform saturation mutagenesis of EGFR and assess function of ~22,500 variants in a human EGFR-dependent lung cancer cell line. This approach reveals enrichment of erlotinib-insensitive variants of known and unknown significance in the dimerization, transmembrane, and kinase domains. Multiple EGFR extracellular domain variants, not associated with approved targeted therapies, are sensitive to afatinib and dacomitinib in vitro. Two glioblastoma patients with somatic EGFR G598V dimerization domain mutations show responses to dacomitinib treatment followed by within-pathway resistance mutation in one case. In summary, this comprehensive screen expands the landscape of functional EGFR variants and suggests broader clinical investigation of EGFR inhibition for cancers harboring extracellular domain mutations.
MeSH term(s)	Humans ; Glioblastoma/drug therapy ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; ErbB Receptors/metabolism ; Lung Neoplasms/drug therapy ; Lung Neoplasms/genetics ; Mutation
Chemical Substances	Protein Kinase Inhibitors ; ErbB Receptors (EC 2.7.10.1) ; EGFR protein, human (EC 2.7.10.1)
Language	English
Publishing date	2024-03-28
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-024-45594-4
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