Bio


Livnat Jerby is an Assistant Professor of Genetics at Stanford University. Her research focuses on multicellular dynamics, as a disease driver and therapeutic avenue, particularly in the context of cancer immunology. In her work, she aims to identify the drivers, molecular underpinnings, and causal structure of multifactorial immune evasion mechanisms, and use this information to identify new and more effective ways to augment and unleash targeted immunity via combinatorial interventions. To address this challenge at scale, she develops integrative approaches, fusing single-cell sequencing and imaging with machine learning, genetic and environmental perturbations.  

Thus far, her research provided new perspectives to key facets of tumor biology, encompassing metabolism, genetics, and immunology. As a postdoctoral fellow at the Broad Institute of MIT and Harvard, she identified regulators of T cell exclusion and dysfunction with Levi Garraway and Aviv Regev. She holds a B.Sc. in Computer Science and Biology and obtained her PhD in 2016 from Tel Aviv University, where she worked with Eytan Ruppin and developed new ways to interrogate cancer metabolism and genetics.

This fall Livnat joined Stanford Genetics to establish a multidisciplinary lab that will harness machine learning in combination with clinical data and extensive functional testing to dissect and target immune dysregulation in cancer, aiming to leverage the versatile, interconnected, and non-linear function of genes, cells, and tissues for disease detection, prevention, and treatment.

Her research has been generously supported by the Schmidt Family Foundation, Rothschild Foundation, the Cancer Research Institute (CRI), the Burroughs Wellcome Fund (BWF), and Chan Zuckerberg Biohub initiative.

Academic Appointments


Honors & Awards


  • Investigator award, Chan Zuckerberg biohub (2020 - 2025)
  • Career Awards at the Scientific Interface (CASI), Burroughs Wellcome Fund (BWF) (2019 - 2024)
  • Postdoctoral training fellowship, Cancer Research Institute (CRI) (2016-2019)
  • Postdoctoral award, Eric and Wendy Schmidt Foundation (2016-2017)
  • Postdoctoral fellowship, Rothschild, Yad Hanadiv (2015-2016)

Patents


  • Aviv Regev, Pratiksha Thakore, John Doench, JT Neal, Jesse Boehm, Oana Ursu, Livnat Jerby-Arnon. "United States Patent 16/809,458 Methods and Compositions for Massively Parallel Variant and Small Molecule Phenotyping"
  • Aviv Regev, Livnat Jerby-Arnon, Ana Anderson, Katherine Tooley, Vijay K. Kuchroo. "United States Patent 17/083,235 Pan-Cancer T Cell Exhaustion Genes"
  • A. Regev, O. Rozenblatt-Rosen, B. Izar, and L. Jerby. "United States Patent PCT/US2018/054020 and PCT/US2018/025507 Methods and compositions for detecting and modulating an immunotherapy resistance gene signature in cancer"
  • Livnat Jerby, A. Regev, L. Jerby, M. Suva, N. Riggi. "United States Patent PCT/US2020/022466 Detection means, Compositions and Methods for Modulating Synovial Sarcoma Cells"

2021-22 Courses


Stanford Advisees


Graduate and Fellowship Programs


All Publications


  • Opposing immune and genetic mechanisms shape oncogenic programs in synovial sarcoma. Nature medicine Jerby-Arnon, L. n., Neftel, C. n., Shore, M. E., Weisman, H. R., Mathewson, N. D., McBride, M. J., Haas, B. n., Izar, B. n., Volorio, A. n., Boulay, G. n., Cironi, L. n., Richman, A. R., Broye, L. C., Gurski, J. M., Luo, C. C., Mylvaganam, R. n., Nguyen, L. n., Mei, S. n., Melms, J. C., Georgescu, C. n., Cohen, O. n., Buendia-Buendia, J. E., Segerstolpe, A. n., Sud, M. n., Cuoco, M. S., Labes, D. n., Gritsch, S. n., Zollinger, D. R., Ortogero, N. n., Beechem, J. M., Petur Nielsen, G. n., Chebib, I. n., Nguyen-Ngoc, T. n., Montemurro, M. n., Cote, G. M., Choy, E. n., Letovanec, I. n., Cherix, S. n., Wagle, N. n., Sorger, P. K., Haynes, A. B., Mullen, J. T., Stamenkovic, I. n., Rivera, M. N., Kadoch, C. n., Wucherpfennig, K. W., Rozenblatt-Rosen, O. n., Suvà, M. L., Riggi, N. n., Regev, A. n. 2021

    Abstract

    Synovial sarcoma (SyS) is an aggressive neoplasm driven by the SS18-SSX fusion, and is characterized by low T cell infiltration. Here, we studied the cancer-immune interplay in SyS using an integrative approach that combines single-cell RNA sequencing (scRNA-seq), spatial profiling and genetic and pharmacological perturbations. scRNA-seq of 16,872 cells from 12 human SyS tumors uncovered a malignant subpopulation that marks immune-deprived niches in situ and is predictive of poor clinical outcomes in two independent cohorts. Functional analyses revealed that this malignant cell state is controlled by the SS18-SSX fusion, is repressed by cytokines secreted by macrophages and T cells, and can be synergistically targeted with a combination of HDAC and CDK4/CDK6 inhibitors. This drug combination enhanced malignant-cell immunogenicity in SyS models, leading to induced T cell reactivity and T cell-mediated killing. Our study provides a blueprint for investigating heterogeneity in fusion-driven malignancies and demonstrates an interplay between immune evasion and oncogenic processes that can be co-targeted in SyS and potentially in other malignancies.

    View details for DOI 10.1038/s41591-020-01212-6

    View details for PubMedID 33495604

  • A Cancer Cell Program Promotes T Cell Exclusion and Resistance to Checkpoint Blockade. Cell Jerby-Arnon, L. n., Shah, P. n., Cuoco, M. S., Rodman, C. n., Su, M. J., Melms, J. C., Leeson, R. n., Kanodia, A. n., Mei, S. n., Lin, J. R., Wang, S. n., Rabasha, B. n., Liu, D. n., Zhang, G. n., Margolais, C. n., Ashenberg, O. n., Ott, P. A., Buchbinder, E. I., Haq, R. n., Hodi, F. S., Boland, G. M., Sullivan, R. J., Frederick, D. T., Miao, B. n., Moll, T. n., Flaherty, K. T., Herlyn, M. n., Jenkins, R. W., Thummalapalli, R. n., Kowalczyk, M. S., Cañadas, I. n., Schilling, B. n., Cartwright, A. N., Luoma, A. M., Malu, S. n., Hwu, P. n., Bernatchez, C. n., Forget, M. A., Barbie, D. A., Shalek, A. K., Tirosh, I. n., Sorger, P. K., Wucherpfennig, K. n., Van Allen, E. M., Schadendorf, D. n., Johnson, B. E., Rotem, A. n., Rozenblatt-Rosen, O. n., Garraway, L. A., Yoon, C. H., Izar, B. n., Regev, A. n. 2018; 175 (4): 984–97.e24

    Abstract

    Immune checkpoint inhibitors (ICIs) produce durable responses in some melanoma patients, but many patients derive no clinical benefit, and the molecular underpinnings of such resistance remain elusive. Here, we leveraged single-cell RNA sequencing (scRNA-seq) from 33 melanoma tumors and computational analyses to interrogate malignant cell states that promote immune evasion. We identified a resistance program expressed by malignant cells that is associated with T cell exclusion and immune evasion. The program is expressed prior to immunotherapy, characterizes cold niches in situ, and predicts clinical responses to anti-PD-1 therapy in an independent cohort of 112 melanoma patients. CDK4/6-inhibition represses this program in individual malignant cells, induces senescence, and reduces melanoma tumor outgrowth in mouse models in vivo when given in combination with immunotherapy. Our study provides a high-resolution landscape of ICI-resistant cell states, identifies clinically predictive signatures, and suggests new therapeutic strategies to overcome immunotherapy resistance.

    View details for DOI 10.1016/j.cell.2018.09.006

    View details for PubMedID 30388455

    View details for PubMedCentralID PMC6410377

  • Predicting Cancer-Specific Vulnerability via Data-Driven Detection of Synthetic Lethality CELL Jerby-Arnon, L., Pfetzer, N., Waldman, Y. Y., McGarry, L., James, D., Shanks, E., Seashore-Ludlow, B., Weinstock, A., Geiger, T., Clemons, P. A., Gottlieb, E., Ruppin, E. 2014; 158 (5): 1199–1209

    Abstract

    Synthetic lethality occurs when the inhibition of two genes is lethal while the inhibition of each single gene is not. It can be harnessed to selectively treat cancer by identifying inactive genes in a given cancer and targeting their synthetic lethal (SL) partners. We present a data-driven computational pipeline for the genome-wide identification of SL interactions in cancer by analyzing large volumes of cancer genomic data. First, we show that the approach successfully captures known SL partners of tumor suppressors and oncogenes. We then validate SL predictions obtained for the tumor suppressor VHL. Next, we construct a genome-wide network of SL interactions in cancer and demonstrate its value in predicting gene essentiality and clinical prognosis. Finally, we identify synthetic lethality arising from gene overactivation and use it to predict drug efficacy. These results form a computational basis for exploiting synthetic lethality to uncover cancer-specific susceptibilities.

    View details for DOI 10.1016/j.cell.2014.07.027

    View details for Web of Science ID 000340945000023

    View details for PubMedID 25171417

  • Inter-cellular CRISPR screens reveal regulators of cancer cell phagocytosis. Nature Kamber, R. A., Nishiga, Y., Morton, B., Banuelos, A. M., Barkal, A. A., Vences-Catalan, F., Gu, M., Fernandez, D., Seoane, J. A., Yao, D., Liu, K., Lin, S., Spees, K., Curtis, C., Jerby-Arnon, L., Weissman, I. L., Sage, J., Bassik, M. C. 2021

    Abstract

    Monoclonal antibody therapies targeting tumour antigens drive cancer cell elimination in large part by triggering macrophage phagocytosis of cancer cells1-7. However, cancer cells evade phagocytosis using mechanisms that are incompletely understood. Here we develop a platform for unbiased identification of factors that impede antibody-dependent cellular phagocytosis (ADCP) using complementary genome-wide CRISPR knockout and overexpression screens in both cancer cells and macrophages. In cancer cells, beyond known factors such as CD47, we identify many regulators of susceptibility to ADCP, including the poorly characterized enzyme adipocyte plasma membrane-associated protein (APMAP). We find that loss of APMAP synergizes with tumour antigen-targeting monoclonal antibodies and/or CD47-blocking monoclonal antibodies to drive markedly increased phagocytosis across a wide range of cancer cell types, including those that are otherwise resistant to ADCP. Additionally, we show that APMAP loss synergizes with several different tumour-targeting monoclonal antibodies to inhibit tumour growth in mice. Using genome-wide counterscreens in macrophages, we find that the G-protein-coupled receptor GPR84 mediates enhanced phagocytosis of APMAP-deficient cancer cells. This work reveals a cancer-intrinsic regulator of susceptibility to antibody-driven phagocytosis and, more broadly, expands our knowledge of the mechanisms governing cancer resistance to macrophage phagocytosis.

    View details for DOI 10.1038/s41586-021-03879-4

    View details for PubMedID 34497417

  • Multimodal pooled Perturb-CITE-seq screens in patient models define mechanisms of cancer immune evasion NATURE GENETICS Frangieh, C. J., Melms, J. C., Thakore, P. I., Geiger-Schuller, K. R., Ho, P., Luoma, A. M., Cleary, B., Jerby-Arnon, L., Malu, S., Cuoco, M. S., Zhao, M., Ager, C. R., Rogava, M., Hovey, L., Rotem, A., Bernatchez, C., Wucherpfennig, K. W., Johnson, B. E., Rozenblatt-Rosen, O., Schadendorf, D., Regev, A., Izar, B. 2021: 332–41

    Abstract

    Resistance to immune checkpoint inhibitors (ICIs) is a key challenge in cancer therapy. To elucidate underlying mechanisms, we developed Perturb-CITE-sequencing (Perturb-CITE-seq), enabling pooled clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 perturbations with single-cell transcriptome and protein readouts. In patient-derived melanoma cells and autologous tumor-infiltrating lymphocyte (TIL) co-cultures, we profiled transcriptomes and 20 proteins in ~218,000 cells under ~750 perturbations associated with cancer cell-intrinsic ICI resistance (ICR). We recover known mechanisms of resistance, including defects in the interferon-γ (IFN-γ)-JAK/STAT and antigen-presentation pathways in RNA, protein and perturbation space, and new ones, including loss/downregulation of CD58. Loss of CD58 conferred immune evasion in multiple co-culture models and was downregulated in tumors of melanoma patients with ICR. CD58 protein expression was not induced by IFN-γ signaling, and CD58 loss conferred immune evasion without compromising major histocompatibility complex (MHC) expression, suggesting that it acts orthogonally to known mechanisms of ICR. This work provides a framework for the deciphering of complex mechanisms by large-scale perturbation screens with multimodal, single-cell readouts, and discovers potentially clinically relevant mechanisms of immune evasion.

    View details for DOI 10.1038/s41588-021-00779-1

    View details for Web of Science ID 000623746200001

    View details for PubMedID 33649592

  • Serine biosynthesis is a metabolic vulnerability in IDH2-driven breast cancer progression. Cancer research Barnabas, G. D., Sang Lee, J. n., Shami, T. n., Harel, M. n., Beck, L. n., Selitrennik, M. n., Jerby-Arnon, L. n., Erez, N. n., Ruppin, E. n., Geiger, T. n. 2021

    Abstract

    Cancer-specific metabolic phenotypes and their vulnerabilities represent a viable area of cancer research. In this study, we explored the association of breast cancer subtypes with different metabolic phenotypes and identified isocitrate dehydrogenase 2 (IDH2) as a key player in triple-negative breast cancer (TNBC) and HER2. Functional assays combined with mass spectrometry-based analyses revealed the oncogenic role of IDH2 in cell proliferation, anchorage-independent growth, glycolysis, mitochondrial respiration, and antioxidant defense. Genome-scale metabolic modeling identified PHGDH and PSAT1 as the synthetic dosage lethal (SDL) partners of IDH2. In agreement, CRISPR-Cas9 knockout of PHGDH and PSAT1 showed the essentiality of serine biosynthesis proteins in IDH2-high cells. The clinical significance of the SDL interaction was supported by patients with IDH2-high/PHGDH-low tumors, who exhibited longer survival than patients with IDH2-high/PHGDH-high tumors. Furthermore, PHGDH inhibitors were effective in treating IDH2-high cells in vitro and in vivo. Altogether, our study creates a new link between two known cancer regulators and emphasizes PHGDH as a promising target for TNBC with IDH2 overexpression.

    View details for DOI 10.1158/0008-5472.CAN-19-3020

    View details for PubMedID 33500247

  • Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis. Cell Mathewson, N. D., Ashenberg, O. n., Tirosh, I. n., Gritsch, S. n., Perez, E. M., Marx, S. n., Jerby-Arnon, L. n., Chanoch-Myers, R. n., Hara, T. n., Richman, A. R., Ito, Y. n., Pyrdol, J. n., Friedrich, M. n., Schumann, K. n., Poitras, M. J., Gokhale, P. C., Gonzalez Castro, L. N., Shore, M. E., Hebert, C. M., Shaw, B. n., Cahill, H. L., Drummond, M. n., Zhang, W. n., Olawoyin, O. n., Wakimoto, H. n., Rozenblatt-Rosen, O. n., Brastianos, P. K., Liu, X. S., Jones, P. S., Cahill, D. P., Frosch, M. P., Louis, D. N., Freeman, G. J., Ligon, K. L., Marson, A. n., Chiocca, E. A., Reardon, D. A., Regev, A. n., Suvà, M. L., Wucherpfennig, K. W. 2021

    Abstract

    T cells are critical effectors of cancer immunotherapies, but little is known about their gene expression programs in diffuse gliomas. Here, we leverage single-cell RNA sequencing (RNA-seq) to chart the gene expression and clonal landscape of tumor-infiltrating T cells across 31 patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma and IDH mutant glioma. We identify potential effectors of anti-tumor immunity in subsets of T cells that co-express cytotoxic programs and several natural killer (NK) cell genes. Analysis of clonally expanded tumor-infiltrating T cells further identifies the NK gene KLRB1 (encoding CD161) as a candidate inhibitory receptor. Accordingly, genetic inactivation of KLRB1 or antibody-mediated CD161 blockade enhances T cell-mediated killing of glioma cells in vitro and their anti-tumor function in vivo. KLRB1 and its associated transcriptional program are also expressed by substantial T cell populations in other human cancers. Our work provides an atlas of T cells in gliomas and highlights CD161 and other NK cell receptors as immunotherapy targets.

    View details for DOI 10.1016/j.cell.2021.01.022

    View details for PubMedID 33592174

  • A single-cell landscape of high-grade serous ovarian cancer NATURE MEDICINE Izar, B., Tirosh, I., Stover, E. H., Wakiro, I., Cuoco, M. S., Alter, I., Rodman, C., Leeson, R., Su, M., Shah, P., Iwanicki, M., Walker, S. R., Kanodia, A., Melms, J. C., Mei, S., Lin, J., Porter, C. M., Slyper, M., Waldman, J., Jerby-Arnon, L., Ashenberg, O., Brinker, T. J., Mills, C., Rogava, M., Vigneau, S., Sorger, P. K., Garraway, L. A., Konstantinopoulos, P. A., Liu, J. F., Matulonis, U., Johnson, B. E., Rozenblatt-Rosen, O., Rotem, A., Regev, A. 2020; 26 (8): 1271-+

    Abstract

    Malignant abdominal fluid (ascites) frequently develops in women with advanced high-grade serous ovarian cancer (HGSOC) and is associated with drug resistance and a poor prognosis1. To comprehensively characterize the HGSOC ascites ecosystem, we used single-cell RNA sequencing to profile ~11,000 cells from 22 ascites specimens from 11 patients with HGSOC. We found significant inter-patient variability in the composition and functional programs of ascites cells, including immunomodulatory fibroblast sub-populations and dichotomous macrophage populations. We found that the previously described immunoreactive and mesenchymal subtypes of HGSOC, which have prognostic implications, reflect the abundance of immune infiltrates and fibroblasts rather than distinct subsets of malignant cells2. Malignant cell variability was partly explained by heterogeneous copy number alteration patterns or expression of a stemness program. Malignant cells shared expression of inflammatory programs that were largely recapitulated in single-cell RNA sequencing of ~35,000 cells from additionally collected samples, including three ascites, two primary HGSOC tumors and three patient ascites-derived xenograft models. Inhibition of the JAK/STAT pathway, which was expressed in both malignant cells and cancer-associated fibroblasts, had potent anti-tumor activity in primary short-term cultures and patient-derived xenograft models. Our work contributes to resolving the HSGOC landscape3-5 and provides a resource for the development of novel therapeutic approaches.

    View details for DOI 10.1038/s41591-020-0926-0

    View details for Web of Science ID 000542094400003

    View details for PubMedID 32572264

    View details for PubMedCentralID PMC7723336

  • A single-cell and single-nucleus RNA-Seq toolbox for fresh and frozen human tumors NATURE MEDICINE Slyper, M., Porter, C. M., Ashenberg, O., Waldman, J., Drokhlyansky, E., Wakiro, I., Smillie, C., Smith-Rosario, G., Wu, J., Dionne, D., Vigneau, S., Jane-Valbuena, J., Tickle, T. L., Napolitano, S., Su, M., Patel, A. G., Karlstrom, A., Gritsch, S., Nomura, M., Waghray, A., Gohil, S. H., Tsankov, A. M., Jerby-Arnon, L., Cohen, O., Klughammer, J., Rosen, Y., Gould, J., Lan Nguyen, Hofree, M., Tramontozzi, P. J., Li, B., Wu, C. J., Izar, B., Haq, R., Hodi, F., Yoon, C. H., Hata, A. N., Baker, S. J., Suva, M. L., Bueno, R., Stover, E. H., Clay, M. R., Dyer, M. A., Collins, N. B., Matulonis, U. A., Wagle, N., Johnson, B. E., Rotem, A., Rozenblatt-Rosen, O., Regev, A. 2020; 26 (5): 792-+

    Abstract

    Single-cell genomics is essential to chart tumor ecosystems. Although single-cell RNA-Seq (scRNA-Seq) profiles RNA from cells dissociated from fresh tumors, single-nucleus RNA-Seq (snRNA-Seq) is needed to profile frozen or hard-to-dissociate tumors. Each requires customization to different tissue and tumor types, posing a barrier to adoption. Here, we have developed a systematic toolbox for profiling fresh and frozen clinical tumor samples using scRNA-Seq and snRNA-Seq, respectively. We analyzed 216,490 cells and nuclei from 40 samples across 23 specimens spanning eight tumor types of varying tissue and sample characteristics. We evaluated protocols by cell and nucleus quality, recovery rate and cellular composition. scRNA-Seq and snRNA-Seq from matched samples recovered the same cell types, but at different proportions. Our work provides guidance for studies in a broad range of tumors, including criteria for testing and selecting methods from the toolbox for other tumors, thus paving the way for charting tumor atlases.

    View details for DOI 10.1038/s41591-020-0844-1

    View details for Web of Science ID 000549240200006

    View details for PubMedID 32405060

    View details for PubMedCentralID PMC7220853

  • A Distinct Transcriptional Program in Human CAR T Cells Bearing the 4-1BB Signaling Domain Revealed by scRNA-Seq. Molecular therapy : the journal of the American Society of Gene Therapy Boroughs, A. C., Larson, R. C., Marjanovic, N. D., Gosik, K. n., Castano, A. P., Porter, C. B., Lorrey, S. J., Ashenberg, O. n., Jerby, L. n., Hofree, M. n., Smith-Rosario, G. n., Morris, R. n., Gould, J. n., Riley, L. S., Berger, T. R., Riesenfeld, S. J., Rozenblatt-Rosen, O. n., Choi, B. D., Regev, A. n., Maus, M. V. 2020; 28 (12): 2577–92

    Abstract

    T cells engineered to express chimeric antigen receptors (CARs) targeting CD19 have produced impressive outcomes for the treatment of B cell malignancies, but different products vary in kinetics, persistence, and toxicity profiles based on the co-stimulatory domains included in the CAR. In this study, we performed transcriptional profiling of bulk CAR T cell populations and single cells to characterize the transcriptional states of human T cells transduced with CD3ζ, 4-1BB-CD3ζ (BBζ), or CD28-CD3ζ (28ζ) co-stimulatory domains at rest and after activation by triggering their CAR or their endogenous T cell receptor (TCR). We identified a transcriptional signature common across CARs with the CD3ζ signaling domain, as well as a distinct program associated with the 4-1BB co-stimulatory domain at rest and after activation. CAR T cells bearing BBζ had increased expression of human leukocyte antigen (HLA) class II genes, ENPP2, and interleukin (IL)-21 axis genes, and decreased PD1 compared to 28ζ CAR T cells. Similar to previous studies, we also found BBζ CAR CD8 T cells to be enriched in a central memory cell phenotype and fatty acid metabolism genes. Our data uncovered transcriptional signatures related to costimulatory domains and demonstrated that signaling domains included in CARs uniquely shape the transcriptional programs of T cells.

    View details for DOI 10.1016/j.ymthe.2020.07.023

    View details for PubMedID 32755564

    View details for PubMedCentralID PMC7704462

  • Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma NATURE MEDICINE Liu, D., Schilling, B., Liu, D., Sucker, A., Livingstone, E., Jerby-Amon, L., Zimmer, L., Gutzmer, R., Satzger, I., Loquai, C., Grabbe, S., Vokes, N., Margolis, C. A., Conway, J., He, M., Elmarakeby, H., Dietlein, F., Miao, D., Tracy, A., Gogas, H., Goldinger, S. M., Utikal, J., Blank, C. U., Rauschenberg, R., von Bubnoff, D., Krackhardt, A., Weide, B., Haferkamp, S., Kiecker, F., Izar, B., Garraway, L., Regev, A., Flaherty, K., Paschen, A., Van Allen, E. M., Schadendorf, D. 2019; 25 (12): 1916-+

    Abstract

    Immune-checkpoint blockade (ICB) has demonstrated efficacy in many tumor types, but predictors of responsiveness to anti-PD1 ICB are incompletely characterized. In this study, we analyzed a clinically annotated cohort of patients with melanoma (n = 144) treated with anti-PD1 ICB, with whole-exome and whole-transcriptome sequencing of pre-treatment tumors. We found that tumor mutational burden as a predictor of response was confounded by melanoma subtype, whereas multiple novel genomic and transcriptomic features predicted selective response, including features associated with MHC-I and MHC-II antigen presentation. Furthermore, previous anti-CTLA4 ICB exposure was associated with different predictors of response compared to tumors that were naive to ICB, suggesting selective immune effects of previous exposure to anti-CTLA4 ICB. Finally, we developed parsimonious models integrating clinical, genomic and transcriptomic features to predict intrinsic resistance to anti-PD1 ICB in individual tumors, with validation in smaller independent cohorts limited by the availability of comprehensive data. Broadly, we present a framework to discover predictive features and build models of ICB therapeutic response.

    View details for DOI 10.1038/s41591-019-0654-5

    View details for Web of Science ID 000500824900035

    View details for PubMedID 31792460

    View details for PubMedCentralID PMC6898788

  • Genome-wide prediction of synthetic rescue mediators of resistance to targeted and immunotherapy MOLECULAR SYSTEMS BIOLOGY Das Sahu, A., Lee, J. S., Wang, Z., Zhang, G., Iglesias-Bartolome, R., Tian, T., We, Z., Miao, B., Nair, N., Ponomarova, O., Friedman, A. A., Amzallag, A., Moll, T., Kasumova, G., Greninger, P., Egan, R. K., Damon, L. J., Frederick, D. T., Jerby-Arnon, L., Wagner, A., Cheng, K., Park, S., Robinson, W., Gardner, K., Boland, G., Hannenhalli, S., Herlyn, M., Benes, C., Flaherty, K., Luo, J., Gutkind, J., Ruppin, E. 2019; 15 (3): e8323

    Abstract

    Most patients with advanced cancer eventually acquire resistance to targeted therapies, spurring extensive efforts to identify molecular events mediating therapy resistance. Many of these events involve synthetic rescue (SR) interactions, where the reduction in cancer cell viability caused by targeted gene inactivation is rescued by an adaptive alteration of another gene (the rescuer). Here, we perform a genome-wide in silico prediction of SR rescuer genes by analyzing tumor transcriptomics and survival data of 10,000 TCGA cancer patients. Predicted SR interactions are validated in new experimental screens. We show that SR interactions can successfully predict cancer patients' response and emerging resistance. Inhibiting predicted rescuer genes sensitizes resistant cancer cells to therapies synergistically, providing initial leads for developing combinatorial approaches to overcome resistance proactively. Finally, we show that the SR analysis of melanoma patients successfully identifies known mediators of resistance to immunotherapy and predicts novel rescuers.

    View details for DOI 10.15252/msb.20188323

    View details for Web of Science ID 000463969600007

    View details for PubMedID 30858180

    View details for PubMedCentralID PMC6413886

  • IL-33 Signaling Alters Regulatory T Cell Diversity in Support of Tumor Development. Cell reports Li, A. n., Herbst, R. H., Canner, D. n., Schenkel, J. M., Smith, O. C., Kim, J. Y., Hillman, M. n., Bhutkar, A. n., Cuoco, M. S., Rappazzo, C. G., Rogers, P. n., Dang, C. n., Jerby-Arnon, L. n., Rozenblatt-Rosen, O. n., Cong, L. n., Birnbaum, M. n., Regev, A. n., Jacks, T. n. 2019; 29 (10): 2998–3008.e8

    Abstract

    Regulatory T cells (Tregs) can impair anti-tumor immune responses and are associated with poor prognosis in multiple cancer types. Tregs in human tumors span diverse transcriptional states distinct from those of peripheral Tregs, but their contribution to tumor development remains unknown. Here, we use single-cell RNA sequencing (RNA-seq) to longitudinally profile dynamic shifts in the distribution of Tregs in a genetically engineered mouse model of lung adenocarcinoma. In this model, interferon-responsive Tregs are more prevalent early in tumor development, whereas a specialized effector phenotype characterized by enhanced expression of the interleukin-33 receptor ST2 is predominant in advanced disease. Treg-specific deletion of ST2 alters the evolution of effector Treg diversity, increases infiltration of CD8+ T cells into tumors, and decreases tumor burden. Our study shows that ST2 plays a critical role in Treg-mediated immunosuppression in cancer, highlighting potential paths for therapeutic intervention.

    View details for DOI 10.1016/j.celrep.2019.10.120

    View details for PubMedID 31801068

  • Harnessing synthetic lethality to predict the response to cancer treatment NATURE COMMUNICATIONS Lee, J., Das, A., Jerby-Arnon, L., Arafeh, R., Auslander, N., Davidson, M., McGarry, L., James, D., Amzallag, A., Park, S., Cheng, K., Robinson, W., Atias, D., Stossel, C., Buzhor, E., Stein, G., Waterfall, J. J., Meltzer, P. S., Golan, T., Hannenhalli, S., Gottlieb, E., Benes, C. H., Samuels, Y., Shanks, E., Ruppin, E. 2018; 9: 2546

    Abstract

    While synthetic lethality (SL) holds promise in developing effective cancer therapies, SL candidates found via experimental screens often have limited translational value. Here we present a data-driven approach, ISLE (identification of clinically relevant synthetic lethality), that mines TCGA cohort to identify the most likely clinically relevant SL interactions (cSLi) from a given candidate set of lab-screened SLi. We first validate ISLE via a benchmark of large-scale drug response screens and by predicting drug efficacy in mouse xenograft models. We then experimentally test a select set of predicted cSLi via new screening experiments, validating their predicted context-specific sensitivity in hypoxic vs normoxic conditions and demonstrating cSLi's utility in predicting synergistic drug combinations. We show that cSLi can successfully predict patients' drug treatment response and provide patient stratification signatures. ISLE thus complements existing actionable mutation-based methods for precision cancer therapy, offering an opportunity to expand its scope to the whole genome.

    View details for DOI 10.1038/s41467-018-04647-1

    View details for Web of Science ID 000436791400007

    View details for PubMedID 29959327

    View details for PubMedCentralID PMC6026173

  • Perturb-Seq: Dissecting Molecular Circuits with Scalable Single-Cell RNA Profiling of Pooled Genetic Screens CELL Dixit, A., Pamas, O., Li, B., Chen, J., Fulco, C. P., Jerby-Amon, L., Marjanovic, N. D., Dionne, D., Burks, T., Raychowdhury, R., Adamson, B., Norman, T. M., Lander, E. S., Weissman, J. S., Friedman, N., Regev, A. 2016; 167 (7): 1853-+

    Abstract

    Genetic screens help infer gene function in mammalian cells, but it has remained difficult to assay complex phenotypes-such as transcriptional profiles-at scale. Here, we develop Perturb-seq, combining single-cell RNA sequencing (RNA-seq) and clustered regularly interspaced short palindromic repeats (CRISPR)-based perturbations to perform many such assays in a pool. We demonstrate Perturb-seq by analyzing 200,000 cells in immune cells and cell lines, focusing on transcription factors regulating the response of dendritic cells to lipopolysaccharide (LPS). Perturb-seq accurately identifies individual gene targets, gene signatures, and cell states affected by individual perturbations and their genetic interactions. We posit new functions for regulators of differentiation, the anti-viral response, and mitochondrial function during immune activation. By decomposing many high content measurements into the effects of perturbations, their interactions, and diverse cell metadata, Perturb-seq dramatically increases the scope of pooled genomic assays.

    View details for DOI 10.1016/j.cell.2016.11.038

    View details for Web of Science ID 000393114700022

    View details for PubMedID 27984732

    View details for PubMedCentralID PMC5181115

  • Genome-scale study reveals reduced metabolic adaptability in patients with non-alcoholic fatty liver disease NATURE COMMUNICATIONS Hyotylainen, T., Jerby, L., Petaja, E. M., Mattila, I., Jantti, S., Auvinen, P., Gastaldelli, A., Yki-Jarvinen, H., Ruppin, E., Oresic, M. 2016; 7: 8994

    Abstract

    Non-alcoholic fatty liver disease (NAFLD) is a major risk factor leading to chronic liver disease and type 2 diabetes. Here we chart liver metabolic activity and functionality in NAFLD by integrating global transcriptomic data, from human liver biopsies, and metabolic flux data, measured across the human splanchnic vascular bed, within a genome-scale model of human metabolism. We show that an increased amount of liver fat induces mitochondrial metabolism, lipolysis, glyceroneogenesis and a switch from lactate to glycerol as substrate for gluconeogenesis, indicating an intricate balance of exacerbated opposite metabolic processes in glycemic regulation. These changes were associated with reduced metabolic adaptability on a network level in the sense that liver fat accumulation puts increasing demands on the liver to adaptively regulate metabolic responses to maintain basic liver functions. We propose that failure to meet excessive metabolic challenges coupled with reduced metabolic adaptability may lead to a vicious pathogenic cycle leading to the co-morbidities of NAFLD.

    View details for DOI 10.1038/ncomms9994

    View details for Web of Science ID 000371140200001

    View details for PubMedID 26839171

    View details for PubMedCentralID PMC4742839

  • Fumarate induces redox-dependent senescence by modifying glutathione metabolism NATURE COMMUNICATIONS Zheng, L., Cardaci, S., Jerby, L., MacKenzie, E. D., Sciacovelli, M., Johnson, T., Gaude, E., King, A., Leach, J. G., Edrada-Ebel, R., Hedley, A., Morrice, N. A., Kalna, G., Blyth, K., Ruppin, E., Frezza, C., Gottlieb, E. 2015; 6: 6001

    Abstract

    Mutations in the tricarboxylic acid (TCA) cycle enzyme fumarate hydratase (FH) are associated with a highly malignant form of renal cancer. We combined analytical chemistry and metabolic computational modelling to investigate the metabolic implications of FH loss in immortalized and primary mouse kidney cells. Here, we show that the accumulation of fumarate caused by the inactivation of FH leads to oxidative stress that is mediated by the formation of succinicGSH, a covalent adduct between fumarate and glutathione. Chronic succination of GSH, caused by the loss of FH, or by exogenous fumarate, leads to persistent oxidative stress and cellular senescence in vitro and in vivo. Importantly, the ablation of p21, a key mediator of senescence, in Fh1-deficient mice resulted in the transformation of benign renal cysts into a hyperplastic lesion, suggesting that fumarate-induced senescence needs to be bypassed for the initiation of renal cancers.

    View details for DOI 10.1038/ncomms7001

    View details for Web of Science ID 000348812400002

    View details for PubMedID 25613188

    View details for PubMedCentralID PMC4340546

  • Moving ahead on harnessing synthetic lethality to fight cancer MOLECULAR & CELLULAR ONCOLOGY Jerby-Arnon, L., Ruppin, E. 2015; 2 (2): e977150

    Abstract

    We have recently developed a data-mining pipeline that comprehensively identifies cancer unique susceptibilities, following the concept of Synthetic Lethality (SL). The approach enables, for the first time, to identify and harness genome-scale SL-networks to accurately predict gene essentiality, drug response, and clinical prognosis in cancer.

    View details for DOI 10.4161/23723556.2014.977150

    View details for Web of Science ID 000218553800022

    View details for PubMedID 27308440

    View details for PubMedCentralID PMC4904895

  • Metabolic Associations of Reduced Proliferation and Oxidative Stress in Advanced Breast Cancer CANCER RESEARCH Jerby, L., Wolf, L., Denkert, C., Stein, G. Y., Hilvo, M., Oresic, M., Geiger, T., Ruppin, E. 2012; 72 (22): 5712–20

    Abstract

    Aberrant metabolism is a hallmark of cancer, but whole metabolomic flux measurements remain scarce. To bridge this gap, we developed a novel metabolic phenotypic analysis (MPA) method that infers metabolic phenotypes based on the integration of transcriptomics or proteomics data within a human genome-scale metabolic model. MPA was applied to conduct the first genome-scale study of breast cancer metabolism based on the gene expression of a large cohort of clinical samples. The modeling correctly predicted cell lines' growth rates, tumor lipid levels, and amino acid biomarkers, outperforming extant metabolic modeling methods. Experimental validation was obtained in vitro. The analysis revealed a subtype-independent "go or grow" dichotomy in breast cancer, where proliferation rates decrease as tumors evolve metastatic capability. MPA also identified a stoichiometric tradeoff that links the observed reduction in proliferation rates to the growing need to detoxify reactive oxygen species. Finally, a fundamental stoichiometric tradeoff between serine and glutamine metabolism was found, presenting a novel hallmark of estrogen receptor (ER)(+) versus ER(-) tumor metabolism. Together, our findings greatly extend insights into core metabolic aberrations and their impact in breast cancer.

    View details for DOI 10.1158/0008-5472.CAN-12-2215

    View details for Web of Science ID 000311141300009

    View details for PubMedID 22986741

  • Predicting Drug Targets and Biomarkers of Cancer via Genome-Scale Metabolic Modeling CLINICAL CANCER RESEARCH Jerby, L., Ruppin, E. 2012; 18 (20): 5572–84

    Abstract

    The metabolism of cancer cells is reprogrammed in various ways to support their growth and survival. Studying these phenomena to develop noninvasive diagnostic tools and selective treatments is a promising avenue. Metabolic modeling has recently emerged as a new way to study human metabolism in a systematic, genome-scale manner by using pertinent high-throughput omics data. This method has been shown in various studies to provide fairly accurate estimates of the metabolic phenotype and its modifications following genetic and environmental perturbations. Here, we provide an overview of genome-scale metabolic modeling and its current use to model human metabolism in health and disease. We then describe the initial steps made using it to study cancer metabolism and how it may be harnessed to enhance ongoing experimental efforts to identify drug targets and biomarkers for cancer in a rationale-based manner.

    View details for DOI 10.1158/1078-0432.CCR-12-1856

    View details for Web of Science ID 000311908500009

    View details for PubMedID 23071359

  • Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase NATURE Frezza, C., Zheng, L., Folger, O., Rajagopalan, K. N., MacKenzie, E. D., Jerby, L., Micaroni, M., Chaneton, B., Adam, J., Hedley, A., Kalna, G., Tomlinson, I. M., Pollard, P. J., Watson, D. G., Deberardinis, R. J., Shlomi, T., Ruppin, E., Gottlieb, E. 2011; 477 (7363): 225–U132

    Abstract

    Fumarate hydratase (FH) is an enzyme of the tricarboxylic acid cycle (TCA cycle) that catalyses the hydration of fumarate into malate. Germline mutations of FH are responsible for hereditary leiomyomatosis and renal-cell cancer (HLRCC). It has previously been demonstrated that the absence of FH leads to the accumulation of fumarate, which activates hypoxia-inducible factors (HIFs) at normal oxygen tensions. However, so far no mechanism that explains the ability of cells to survive without a functional TCA cycle has been provided. Here we use newly characterized genetically modified kidney mouse cells in which Fh1 has been deleted, and apply a newly developed computer model of the metabolism of these cells to predict and experimentally validate a linear metabolic pathway beginning with glutamine uptake and ending with bilirubin excretion from Fh1-deficient cells. This pathway, which involves the biosynthesis and degradation of haem, enables Fh1-deficient cells to use the accumulated TCA cycle metabolites and permits partial mitochondrial NADH production. We predicted and confirmed that targeting this pathway would render Fh1-deficient cells non-viable, while sparing wild-type Fh1-containing cells. This work goes beyond identifying a metabolic pathway that is induced in Fh1-deficient cells to demonstrate that inhibition of haem oxygenation is synthetically lethal when combined with Fh1 deficiency, providing a new potential target for treating HLRCC patients.

    View details for DOI 10.1038/nature10363

    View details for Web of Science ID 000294603900039

    View details for PubMedID 21849978

  • Predicting selective drug targets in cancer through metabolic networks MOLECULAR SYSTEMS BIOLOGY Folger, O., Jerby, L., Frezza, C., Gottlieb, E., Ruppin, E., Shlomi, T. 2011; 7: 501

    Abstract

    The interest in studying metabolic alterations in cancer and their potential role as novel targets for therapy has been rejuvenated in recent years. Here, we report the development of the first genome-scale network model of cancer metabolism, validated by correctly identifying genes essential for cellular proliferation in cancer cell lines. The model predicts 52 cytostatic drug targets, of which 40% are targeted by known, approved or experimental anticancer drugs, and the rest are new. It further predicts combinations of synthetic lethal drug targets, whose synergy is validated using available drug efficacy and gene expression measurements across the NCI-60 cancer cell line collection. Finally, potential selective treatments for specific cancers that depend on cancer type-specific downregulation of gene expression and somatic mutations are compiled.

    View details for DOI 10.1038/msb.2011.35

    View details for Web of Science ID 000292463300005

    View details for PubMedID 21694718

    View details for PubMedCentralID PMC3159974

  • Computational reconstruction of tissue-specific metabolic models: application to human liver metabolism MOLECULAR SYSTEMS BIOLOGY Jerby, L., Shlomi, T., Ruppin, E. 2010; 6: 401

    Abstract

    The computational study of human metabolism has been advanced with the advent of the first generic (non-tissue specific) stoichiometric model of human metabolism. In this study, we present a new algorithm for rapid reconstruction of tissue-specific genome-scale models of human metabolism. The algorithm generates a tissue-specific model from the generic human model by integrating a variety of tissue-specific molecular data sources, including literature-based knowledge, transcriptomic, proteomic, metabolomic and phenotypic data. Applying the algorithm, we constructed the first genome-scale stoichiometric model of hepatic metabolism. The model is verified using standard cross-validation procedures, and through its ability to carry out hepatic metabolic functions. The model's flux predictions correlate with flux measurements across a variety of hormonal and dietary conditions, and improve upon the predictive performance obtained using the original, generic human model (prediction accuracy of 0.67 versus 0.46). Finally, the model better predicts biomarker changes in genetic metabolic disorders than the generic human model (accuracy of 0.67 versus 0.59). The approach presented can be used to construct other human tissue-specific models, and be applied to other organisms.

    View details for DOI 10.1038/msb.2010.56

    View details for Web of Science ID 000282766200001

    View details for PubMedID 20823844

    View details for PubMedCentralID PMC2964116