Jason Sheltzer, PhD
Research & Publications
Biography
News
Research Summary
The Sheltzer Lab is broadly interested in understanding the genomic changes that drive cancer progression. We are particularly fascinated by aneuploidy – a common feature of cancers in which cells gain or lose whole chromosomes. Additionally, we are working to identify genomic alterations that create druggable therapeutic vulnerabilities in cancer. We have recently discovered the first-ever selective inhibitor of the kinase CDK11, and we are developing CDK11 inhibition as a new strategy to treat aggressive malignancies.
Extensive Research Description
Uncovering the role of aneuploidy in tumor development and progression
Aneuploidy is found in more than 90% of human tumors, but its effects on cellular physiology are poorly understood. While many methods exist to study genetic changes in individual oncogenes and tumor suppressors, our ability to model and interrogate chromosome-scale alterations is extremely limited. We are working to develop and apply a variety of technologies, including chromosome engineering, CRISPR mutagenesis, and single cell sequencing, in order to create new ways to study aneuploidy and better understand its consequences. Using these techniques, we have uncovered key roles for aneuploidy in metastatic dissemination, drug resistance, genomic instability, and several other cancer-related phenotypes.
Identifying cancer vulnerabilities and improving cancer therapies
The genetic alterations that occur during tumorigenesis re-wire the underlying architecture of cancer cells and create certain cancer “dependencies”: genes and pathways that are required for cancer cell growth but that are dispensable in normal tissue. Drugs that are designed to target these unique dependencies can serve as potent therapeutic agents. Using CRISPR, our lab has unexpectedly discovered that many targeted therapies that have advanced into clinical trials actually kill cancer cells independently of their reported targets. This pervasive mischaracterization of cancer drugs may partially explain why so many new oncology therapies fail during clinical testing. We are working to develop new techniques to identify cancer dependencies and characterize the activity of anti-cancer agents in order to improve clinical trial efficacy.
Characterizing CDK11 inhibition as a novel anti-cancer strategy
While studying mischaracterized cancer drugs, we recently discovered a small-molecule compound that exhibits potent and selective inhibition of the key cancer kinase CDK11. We subsequently demonstrated that CDK11 blockade has a unique molecular phenotype across a variety of cancer types. We are currently working to understand the function of CDK11 in normal and malignant cells, and to identify the cancer types most responsive to CDK11 inhibition.
Coauthors
Research Image
Selected Publications
- Oncogene-like addiction to aneuploidy in human cancersGirish V, Lakhani A, Thompson S, Scaduto C, Brown L, Hagenson R, Sausville E, Mendelson B, Kandikuppa P, Lukow D, Yuan M, Stevens E, Lee S, Schukken K, Akalu S, Vasudevan A, Zou C, Salovska B, Li W, Smith J, Taylor A, Martienssen R, Liu Y, Sun R, Sheltzer J. Oncogene-like addiction to aneuploidy in human cancers. Science 2023, 381: eadg4521. PMID: 37410869, PMCID: PMC10753973, DOI: 10.1126/science.adg4521.
- Inhibition of a lower potency target drives the anticancer activity of a clinical p38 inhibitorBhattacharjee D, Bakar J, Chitnis S, Sausville E, Ashtekar K, Mendelson B, Long K, Smith J, Heppner D, Sheltzer J. Inhibition of a lower potency target drives the anticancer activity of a clinical p38 inhibitor. Cell Chemical Biology 2023, 30: 1211-1222.e5. PMID: 37827156, PMCID: PMC10715717, DOI: 10.1016/j.chembiol.2023.09.013.
- Aneuploidy in human cancer: new tools and perspectivesLakhani A, Thompson S, Sheltzer J. Aneuploidy in human cancer: new tools and perspectives. Trends In Genetics 2023, 39: 968-980. PMID: 37778926, PMCID: PMC10715718, DOI: 10.1016/j.tig.2023.09.002.
- Ricolinostat is not a highly selective HDAC6 inhibitorMédard G, Sheltzer J. Ricolinostat is not a highly selective HDAC6 inhibitor. Nature Cancer 2023, 4: 807-808. PMID: 37322365, DOI: 10.1038/s43018-023-00582-3.
- Extensive protein dosage compensation in aneuploid human cancersSchukken KM, Sheltzer J. Extensive protein dosage compensation in aneuploid human cancers. Genome Research 2022, 32: 1254-1270. PMID: 35701073, PMCID: PMC9341510, DOI: 10.1101/gr.276378.121.
- Synthesis and Structure–Activity relationships of cyclin-dependent kinase 11 inhibitors based on a diaminothiazole scaffoldLi Z, Ishida R, Liu Y, Wang J, Li Y, Gao Y, Jiang J, Che J, Sheltzer JM, Robers MB, Zhang T, Westover KD, Nabet B, Gray NS. Synthesis and Structure–Activity relationships of cyclin-dependent kinase 11 inhibitors based on a diaminothiazole scaffold. European Journal Of Medicinal Chemistry 2022, 238: 114433. PMID: 35597007, PMCID: PMC9477540, DOI: 10.1016/j.ejmech.2022.114433.
- Genome-wide identification and analysis of prognostic features in human cancersSmith JC, Sheltzer JM. Genome-wide identification and analysis of prognostic features in human cancers. Cell Reports 2022, 38: 110569. PMID: 35354049, PMCID: PMC9042322, DOI: 10.1016/j.celrep.2022.110569.
- Chromosomal instability and aneuploidy as causes of cancer drug resistanceLukow DA, Sheltzer JM. Chromosomal instability and aneuploidy as causes of cancer drug resistance. Trends In Cancer 2021, 8: 43-53. PMID: 34593353, DOI: 10.1016/j.trecan.2021.09.002.
- Chromosomal instability accelerates the evolution of resistance to anti-cancer therapiesLukow DA, Sausville EL, Suri P, Chunduri NK, Wieland A, Leu J, Smith JC, Girish V, Kumar AA, Kendall J, Wang Z, Storchova Z, Sheltzer JM. Chromosomal instability accelerates the evolution of resistance to anti-cancer therapies. Developmental Cell 2021, 56: 2427-2439.e4. PMID: 34352222, PMCID: PMC8933054, DOI: 10.1016/j.devcel.2021.07.009.
- Aneuploidy as a promoter and suppressor of malignant growthVasudevan A, Schukken KM, Sausville EL, Girish V, Adebambo OA, Sheltzer JM. Aneuploidy as a promoter and suppressor of malignant growth. Nature Reviews Cancer 2021, 21: 89-103. PMID: 33432169, DOI: 10.1038/s41568-020-00321-1.
- Aneuploidy increases resistance to chemotherapeutics by antagonizing cell divisionReplogle JM, Zhou W, Amaro AE, McFarland JM, Villalobos-Ortiz M, Ryan J, Letai A, Yilmaz O, Sheltzer J, Lippard SJ, Ben-David U, Amon A. Aneuploidy increases resistance to chemotherapeutics by antagonizing cell division. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 30566-30576. PMID: 33203674, PMCID: PMC7720170, DOI: 10.1073/pnas.2009506117.
- A CRISPR Competition Assay to Identify Cancer Genetic Dependencies.Girish V, Sheltzer JM. A CRISPR Competition Assay to Identify Cancer Genetic Dependencies. Bio-protocol 2020, 10: e3682. PMID: 33659353, PMCID: PMC7842800, DOI: 10.21769/bioprotoc.3682.
- Discovering and validating cancer genetic dependencies: approaches and pitfallsLin A, Sheltzer JM. Discovering and validating cancer genetic dependencies: approaches and pitfalls. Nature Reviews Genetics 2020, 21: 671-682. PMID: 32561862, DOI: 10.1038/s41576-020-0247-7.
- Single-Chromosomal Gains Can Function as Metastasis Suppressors and Promoters in Colon CancerVasudevan A, Baruah PS, Smith JC, Wang Z, Sayles NM, Andrews P, Kendall J, Leu J, Chunduri NK, Levy D, Wigler M, Storchová Z, Sheltzer JM. Single-Chromosomal Gains Can Function as Metastasis Suppressors and Promoters in Colon Cancer. Developmental Cell 2020, 52: 413-428.e6. PMID: 32097652, PMCID: PMC7354079, DOI: 10.1016/j.devcel.2020.01.034.
- Micronuclei-based model system reveals functional consequences of chromothripsis in human cellsKneissig M, Keuper K, de Pagter MS, van Roosmalen MJ, Martin J, Otto H, Passerini V, Sparr A, Renkens I, Kropveld F, Vasudevan A, Sheltzer JM, Kloosterman WP, Storchova Z. Micronuclei-based model system reveals functional consequences of chromothripsis in human cells. ELife 2019, 8: e50292. PMID: 31778112, PMCID: PMC6910827, DOI: 10.7554/elife.50292.
- Increasing gender diversity in the STEM research workforceGreider CW, Sheltzer JM, Cantalupo NC, Copeland WB, Dasgupta N, Hopkins N, Jansen JM, Joshua-Tor L, McDowell GS, Metcalf JL, McLaughlin B, Olivarius A, O'Shea EK, Raymond JL, Ruebain D, Steitz JA, Stillman B, Tilghman SM, Valian V, Villa-Komaroff L, Wong JY. Increasing gender diversity in the STEM research workforce. Science 2019, 366: 692-695. PMID: 31699926, DOI: 10.1126/science.aaz0649.
- Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trialsLin A, Giuliano CJ, Palladino A, John KM, Abramowicz C, Yuan ML, Sausville EL, Lukow DA, Liu L, Chait AR, Galluzzo ZC, Tucker C, Sheltzer JM. Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Science Translational Medicine 2019, 11 PMID: 31511426, PMCID: PMC7717492, DOI: 10.1126/scitranslmed.aaw8412.
- Generating Single Cell–Derived Knockout Clones in Mammalian Cells with CRISPR/Cas9Giuliano CJ, Lin A, Girish V, Sheltzer JM. Generating Single Cell–Derived Knockout Clones in Mammalian Cells with CRISPR/Cas9. Current Protocols In Molecular Biology 2019, 128: e100. PMID: 31503414, PMCID: PMC6741428, DOI: 10.1002/cpmb.100.
- Systematic identification of mutations and copy number alterations associated with cancer patient prognosisSmith J, Sheltzer J. Systematic identification of mutations and copy number alterations associated with cancer patient prognosis. ELife 2018, 7: e39217. PMID: 30526857, PMCID: PMC6289580, DOI: 10.7554/elife.39217.
- Gender disparities among independent fellows in biomedical researchSheltzer J. Gender disparities among independent fellows in biomedical research. Nature Biotechnology 2018, 36: 1018-1021. PMID: 30307910, DOI: 10.1038/nbt.4274.
- MELK expression correlates with tumor mitotic activity but is not required for cancer growthGiuliano C, Lin A, Smith J, Palladino A, Sheltzer J. MELK expression correlates with tumor mitotic activity but is not required for cancer growth. ELife 2018, 7: e32838. PMID: 29417930, PMCID: PMC5805410, DOI: 10.7554/elife.32838.
- CRISPR/Cas9 mutagenesis invalidates a putative cancer dependency targeted in on-going clinical trialsLin A, Giuliano C, Sayles N, Sheltzer J. CRISPR/Cas9 mutagenesis invalidates a putative cancer dependency targeted in on-going clinical trials. ELife 2017, 6: e24179. PMID: 28337968, PMCID: PMC5365317, DOI: 10.7554/elife.24179.
- Single-chromosome Gains Commonly Function as Tumor SuppressorsSheltzer J, Ko J, Replogle J, Burgos N, Chung E, Meehl C, Sayles N, Passerini V, Storchova Z, Amon A. Single-chromosome Gains Commonly Function as Tumor Suppressors. Cancer Cell 2017, 31: 240-255. PMID: 28089890, PMCID: PMC5713901, DOI: 10.1016/j.ccell.2016.12.004.
- Elite male faculty in the life sciences employ fewer womenSheltzer J, Smith J. Elite male faculty in the life sciences employ fewer women. Proceedings Of The National Academy Of Sciences Of The United States Of America 2014, 111: 10107-10112. PMID: 24982167, PMCID: PMC4104900, DOI: 10.1073/pnas.1403334111.
- A Transcriptional and Metabolic Signature of Primary Aneuploidy Is Present in Chromosomally Unstable Cancer Cells and Informs Clinical PrognosisSheltzer J. A Transcriptional and Metabolic Signature of Primary Aneuploidy Is Present in Chromosomally Unstable Cancer Cells and Informs Clinical Prognosis. Cancer Research 2013, 73: 6401-6412. PMID: 24041940, PMCID: PMC3901577, DOI: 10.1158/0008-5472.can-13-0749.
- Transcriptional consequences of aneuploidySheltzer J, Torres E, Dunham M, Amon A. Transcriptional consequences of aneuploidy. Proceedings Of The National Academy Of Sciences Of The United States Of America 2012, 109: 12644-12649. PMID: 22802626, PMCID: PMC3411958, DOI: 10.1073/pnas.1209227109.
- The aneuploidy paradox: costs and benefits of an incorrect karyotypeSheltzer J, Amon A. The aneuploidy paradox: costs and benefits of an incorrect karyotype. Trends In Genetics 2011, 27: 446-453. PMID: 21872963, PMCID: PMC3197822, DOI: 10.1016/j.tig.2011.07.003.
- Aneuploidy Drives Genomic Instability in YeastSheltzer J, Blank H, Pfau S, Tange Y, George B, Humpton T, Brito I, Hiraoka Y, Niwa O, Amon A. Aneuploidy Drives Genomic Instability in Yeast. Science 2011, 333: 1026-1030. PMID: 21852501, PMCID: PMC3278960, DOI: 10.1126/science.1206412.