Jason Meyer Sheltzer

All Publications

• Protein buffering of aneuploidy is driven by coordinated factors identified through machine learning. Molecular systems biology Heller, E. M., Barthel, K., Räschle, M., Schukken, K. M., Sheltzer, J. M., Storchová, Z. 2026

  Abstract

  Aneuploidy, a hallmark of cancer, alters chromosome copy numbers and with that the abundance of hundreds of proteins. Evidence suggests that levels of proteins encoded on affected chromosomes are often buffered toward their abundances observed in diploids. Despite its prevalence, the molecular mechanisms driving this protein dosage compensation remain largely unknown. It is unclear whether all proteins are buffered similarly, what factors determine buffering, and whether dosage compensation varies across different cell lines or tumor types. Moreover, its potential adaptive advantage and therapeutic relevance remain unexplored. We established a novel approach to quantify protein dosage buffering in a gene copy number-dependent manner, showing that dosage compensation is widespread but variable in cancer samples. By developing multifactorial machine learning models, we identify gene dependency, protein complex participation, haploinsufficiency, and mRNA decay as key predictors of buffering. We show that dosage compensation affects oncogenic potential and that higher buffering correlates with reduced proteotoxic stress and increased drug resistance. These findings highlight protein dosage compensation as a crucial regulatory mechanism with therapeutic potential in aneuploid cancers.

  View details for DOI 10.1038/s44320-026-00187-9

  View details for PubMedID 41571838

  View details for PubMedCentralID 7771966

• An elevated rate of whole-genome duplications in cancers from Black patients. Nature communications Brown, L. M., Hagenson, R. A., Koklič, T., Urbančič, I., Qiao, L., Strancar, J., Sheltzer, J. M. 2024; 15 (1): 8218

  Abstract

  In the United States, Black individuals have higher rates of cancer mortality than any other racial group. Here, we examine chromosome copy number changes in cancers from more than 1800 self-reported Black patients. We find that tumors from self-reported Black patients are significantly more likely to exhibit whole-genome duplications (WGDs), a genomic event that enhances metastasis and aggressive disease, compared to tumors from self-reported white patients. This increase in WGD frequency is observed across multiple cancer types, including breast, endometrial, and lung cancer, and is associated with shorter patient survival. We further demonstrate that combustion byproducts are capable of inducing WGDs in cell culture, and cancers from self-reported Black patients exhibit mutational signatures consistent with exposure to these carcinogens. In total, these findings identify a type of genomic alteration that is associated with environmental exposures and that may influence racial disparities in cancer outcomes.

  View details for DOI 10.1038/s41467-024-52554-5

  View details for PubMedID 39300140

  View details for PubMedCentralID PMC11413164

• Oncogene-like addiction to aneuploidy in human cancers. Science (New York, N.Y.) Girish, V., Lakhani, A. A., Thompson, S. L., Scaduto, C. M., Brown, L. M., Hagenson, R. A., Sausville, E. L., Mendelson, B. E., Kandikuppa, P. K., Lukow, D. A., Yuan, M. L., Stevens, E. C., Lee, S. N., Schukken, K. M., Akalu, S. M., Vasudevan, A., Zou, C., Salovska, B., Li, W., Smith, J. C., Taylor, A. M., Martienssen, R. A., Liu, Y., Sun, R., Sheltzer, J. M. 2023; 381 (6660): eadg4521

  Abstract

  Most cancers exhibit aneuploidy, but its functional significance in tumor development is controversial. Here, we describe ReDACT (Restoring Disomy in Aneuploid cells using CRISPR Targeting), a set of chromosome engineering tools that allow us to eliminate specific aneuploidies from cancer genomes. Using ReDACT, we created a panel of isogenic cells that have or lack common aneuploidies, and we demonstrate that trisomy of chromosome 1q is required for malignant growth in cancers harboring this alteration. Mechanistically, gaining chromosome 1q increases the expression of MDM4 and suppresses p53 signaling, and we show that TP53 mutations are mutually exclusive with 1q aneuploidy in human cancers. Thus, tumor cells can be dependent on specific aneuploidies, raising the possibility that these "aneuploidy addictions" could be targeted as a therapeutic strategy.

  View details for DOI 10.1126/science.adg4521

  View details for PubMedID 37410869

  View details for PubMedCentralID PMC10753973

• Synthesis and Structure-Activity relationships of cyclin-dependent kinase 11 inhibitors based on a diaminothiazole scaffold. European journal of medicinal chemistry Li, Z., Ishida, R., Liu, Y., Wang, J., Li, Y., Gao, Y., Jiang, J., Che, J., Sheltzer, J. M., Robers, M. B., Zhang, T., Westover, K. D., Nabet, B., Gray, N. S. 2022; 238: 114433

  Abstract

  Cyclin-dependent kinases (CDK) are attractive targets for drug discovery due to their wide range of cellular functions. CDK11 is an understudied CDK with roles in transcription and splicing, cell cycle regulation, neuronal function, and apoptosis. In this study, we describe a medicinal chemistry campaign to identify a CDK11 inhibitor. Employing a promising but nonselective CDK11-targeting scaffold (JWD-047), extensive structure-guided medicinal chemistry modifications led to the identification of ZNL-05-044. A combination of biochemical evaluations and NanoBRET cellular assays for target engagement guided the SAR towards a 2,4-diaminothiazoles CDK11 probe with significantly improved kinome-wide selectivity over JWD-047. CDK11 inhibition with ZNL-05-044 leads to G2/M cell cycle arrest, consistent with prior work evaluating OTS964, and impacts CDK11-dependent mRNA splicing in cells. Together, ZNL-05-044 serves as a tool compound for further optimization and interrogation of the consequences of CDK11 inhibition.

  View details for DOI 10.1016/j.ejmech.2022.114433

  View details for PubMedID 35597007

• Discovering and validating cancer genetic dependencies: approaches and pitfalls. Nature reviews. Genetics Lin, A. n., Sheltzer, J. M. 2020

  Abstract

  Cancer 'genetic dependencies' - genes whose products are essential for cancer cell fitness - are promising targets for therapeutic development. However, recent evidence has cast doubt on the validity of several putative dependencies that are currently being targeted in cancer clinical trials, underscoring the challenges inherent in correctly identifying cancer-essential genes. Here we review several common techniques and platforms for discovering and characterizing cancer dependencies. We discuss the strengths and drawbacks of different gene-perturbation approaches, and we highlight the use of poorly validated genetic and pharmacological agents as a common cause of target misidentification. A careful consideration of the limitations of current technologies and cancer models will improve our ability to correctly uncover cancer genetic dependencies and will facilitate the development of improved therapeutic agents.

  View details for DOI 10.1038/s41576-020-0247-7

  View details for PubMedID 32561862

• Increasing gender diversity in the STEM research workforce SCIENCE Greider, C. W., Sheltzer, J. M., Cantalupo, N. C., Copeland, W. B., Dasgupta, N., Hopkins, N., Jansen, J. M., Joshua-Tor, L., McDowell, G. S., Metcalf, J. L., McLaughlin, B., Olivarius, A., O'Shea, E. K., Raymond, J. L., Ruebain, D., Steitz, J. A., Stillman, B., Tilghman, S. M., Valian, V., Villa-Komaroff, L., Wong, J. Y. 2019; 366 (6466): 692-+

  View details for DOI 10.1126/science.aaz0649

  View details for Web of Science ID 000496500400032

  View details for PubMedID 31699926

• Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Science translational medicine Lin, A., Giuliano, C. J., Palladino, A., John, K. M., Abramowicz, C., Yuan, M. L., Sausville, E. L., Lukow, D. A., Liu, L., Chait, A. R., Galluzzo, Z. C., Tucker, C., Sheltzer, J. M. 2019; 11 (509)

  Abstract

  Ninety-seven percent of drug-indication pairs that are tested in clinical trials in oncology never advance to receive U.S. Food and Drug Administration approval. While lack of efficacy and dose-limiting toxicities are the most common causes of trial failure, the reason(s) why so many new drugs encounter these problems is not well understood. Using CRISPR-Cas9 mutagenesis, we investigated a set of cancer drugs and drug targets in various stages of clinical testing. We show that-contrary to previous reports obtained predominantly with RNA interference and small-molecule inhibitors-the proteins ostensibly targeted by these drugs are nonessential for cancer cell proliferation. Moreover, the efficacy of each drug that we tested was unaffected by the loss of its putative target, indicating that these compounds kill cells via off-target effects. By applying a genetic target-deconvolution strategy, we found that the mischaracterized anticancer agent OTS964 is actually a potent inhibitor of the cyclin-dependent kinase CDK11 and that multiple cancer types are addicted to CDK11 expression. We suggest that stringent genetic validation of the mechanism of action of cancer drugs in the preclinical setting may decrease the number of therapies tested in human patients that fail to provide any clinical benefit.

  View details for DOI 10.1126/scitranslmed.aaw8412

  View details for PubMedID 31511426

  View details for PubMedCentralID PMC7717492

• Aneuploidy drives genomic instability in yeast. Science (New York, N.Y.) Sheltzer, J. M., Blank, H. M., Pfau, S. J., Tange, Y., George, B. M., Humpton, T. J., Brito, I. L., Hiraoka, Y., Niwa, O., Amon, A. 2011; 333 (6045): 1026-30

  Abstract

  Aneuploidy decreases cellular fitness, yet it is also associated with cancer, a disease of enhanced proliferative capacity. To investigate one mechanism by which aneuploidy could contribute to tumorigenesis, we examined the effects of aneuploidy on genomic stability. We analyzed 13 budding yeast strains that carry extra copies of single chromosomes and found that all aneuploid strains exhibited one or more forms of genomic instability. Most strains displayed increased chromosome loss and mitotic recombination, as well as defective DNA damage repair. Aneuploid fission yeast strains also exhibited defects in mitotic recombination. Aneuploidy-induced genomic instability could facilitate the development of genetic alterations that drive malignant growth in cancer.

  View details for DOI 10.1126/science.1206412

  View details for PubMedID 21852501

  View details for PubMedCentralID PMC3278960