Multimodal Analysis of Composition and Spatial Architecture in Human Squamous Cell Carcinoma
Andrew L Ji, Adam J Rubin, Kim Thrane, Sizun Jiang, David L Reynolds, Robin M Meyers, Margaret G Guo, Benson M George, Annelie Mollbrink, Joseph Bergenstråhle, Ludvig Larsson, Yunhao Bai, Bokai Zhu, Aparna Bhaduri, Jordan M Meyers, Xavier Rovira-Clavé, S Tyler Hollmig, Sumaira Z Aasi, Garry P Nolan, Joakim Lundeberg, Paul A Khavari, Andrew L Ji, Adam J Rubin, Kim Thrane, Sizun Jiang, David L Reynolds, Robin M Meyers, Margaret G Guo, Benson M George, Annelie Mollbrink, Joseph Bergenstråhle, Ludvig Larsson, Yunhao Bai, Bokai Zhu, Aparna Bhaduri, Jordan M Meyers, Xavier Rovira-Clavé, S Tyler Hollmig, Sumaira Z Aasi, Garry P Nolan, Joakim Lundeberg, Paul A Khavari
Abstract
To define the cellular composition and architecture of cutaneous squamous cell carcinoma (cSCC), we combined single-cell RNA sequencing with spatial transcriptomics and multiplexed ion beam imaging from a series of human cSCCs and matched normal skin. cSCC exhibited four tumor subpopulations, three recapitulating normal epidermal states, and a tumor-specific keratinocyte (TSK) population unique to cancer, which localized to a fibrovascular niche. Integration of single-cell and spatial data mapped ligand-receptor networks to specific cell types, revealing TSK cells as a hub for intercellular communication. Multiple features of potential immunosuppression were observed, including T regulatory cell (Treg) co-localization with CD8 T cells in compartmentalized tumor stroma. Finally, single-cell characterization of human tumor xenografts and in vivo CRISPR screens identified essential roles for specific tumor subpopulation-enriched gene networks in tumorigenesis. These data define cSCC tumor and stromal cell subpopulations, the spatial niches where they interact, and the communicating gene networks that they engage in cancer.
Keywords: CRISPR screen; MIBI; intra-tumoral heterogeneity; multi-omics; scRNA-seq; skin cancer; spatial transcriptomics; squamous cell carcinoma; tumor immunology; tumor microenvironment.
Conflict of interest statement
Declaration of Interests G.P.N. is a co-founder and stockholder of Ionpath and an inventor on patent US20150287578A1. J.L. is a scientific consultant for 10X Genomics.
Published by Elsevier Inc.
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References
- Aibar S., González-Blas C.B., Moerman T., Huynh-Thu V.A., Imrichova H., Hulselmans G., Rambow F., Marine J.-C., Geurts P., Aerts J. SCENIC: single-cell regulatory network inference and clustering. Nat. Methods. 2017;14:1083–1086.
- Angelo M., Bendall S.C., Finck R., Hale M.B., Hitzman C., Borowsky A.D., Levenson R.M., Lowe J.B., Liu S.D., Zhao S. Multiplexed ion beam imaging of human breast tumors. Nat. Med. 2014;20:436–442.
- Benci J.L., Johnson L.R., Choa R., Xu Y., Qiu J., Zhou Z., Xu B., Ye D., Nathanson K.L., June C.H. Opposing Functions of Interferon Coordinate Adaptive and Innate Immune Responses to Cancer Immune Checkpoint Blockade. Cell. 2019;178:933–948.
- Bronte V., Brandau S., Chen S.H., Colombo M.P., Frey A.B., Greten T.F., Mandruzzato S., Murray P.J., Ochoa A., Ostrand-Rosenberg S. Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nat. Commun. 2016;7:12150.
- Browaeys R., Saelens W., Saeys Y. NicheNet: Modeling intercellular communication by linking ligands to target genes. Nat. Methods. 2019;17:159–162.
- Butler A., Hoffman P., Smibert P., Papalexi E., Satija R. Integrating single-cell transcriptomic data across different conditions, technologies, and species. Nat. Biotechnol. 2018;36:411–420.
- Calderwood D.A., Campbell I.D., Critchley D.R. Talins and kindlins: partners in integrin-mediated adhesion. Nat. Rev. Mol. Cell Biol. 2013;14:503–517.
- Campbell D.J., Koch M.A. Phenotypical and functional specialization of FOXP3+ regulatory T cells. Nat. Rev. Immunol. 2011;11:119–130.
- Chen L., Flies D.B. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat. Rev. Immunol. 2013;13:227–242.
- Costa A., Kieffer Y., Scholer-Dahirel A., Pelon F., Bourachot B., Cardon M., Sirven P., Magagna I., Fuhrmann L., Bernard C. Fibroblast Heterogeneity and Immunosuppressive Environment in Human Breast Cancer. Cancer Cell. 2018;33:463–479.
- David C.J., Massagué J. Contextual determinants of TGFβ action in development, immunity and cancer. Nat. Rev. Mol. Cell Biol. 2018;19:419–435.
- Diggins K.E., Greenplate A.R., Leelatian N., Wogsland C.E., Irish J.M. Characterizing cell subsets using marker enrichment modeling. Nat. Methods. 2017;14:275–278.
- Doench J.G., Fusi N., Sullender M., Hegde M., Vaimberg E.W., Donovan K.F., Smith I., Tothova Z., Wilen C., Orchard R. Optimized sgRNA design to maximize activity and minimize off-target effects of CRISPR-Cas9. Nat. Biotechnol. 2016;34:184–191.
- Groom J.R., Luster A.D. CXCR3 in T cell function. Exp. Cell Res. 2011;317:620–631.
- Guo X., Zhang Y., Zheng L., Zheng C., Song J., Zhang Q., Kang B., Liu Z., Jin L., Xing R. Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing. Nat. Med. 2018;24:978–985.
- Han G., Spitzer M.H., Bendall S.C., Fantl W.J., Nolan G.P. Metal-isotope-tagged monoclonal antibodies for high-dimensional mass cytometry. Nat. Protoc. 2018;13:2121–2148.
- Hemler M.E. Tetraspanin functions and associated microdomains. Nat. Rev. Mol. Cell Biol. 2005;6:801–811.
- Ho W.J., Yarchoan M., Charmsaz S., Munday R.M., Danilova L., Sztein M.B., Fertig E.J., Jaffee E.M. Multi-panel mass cytometry reveals anti-PD1 therapy-mediated B and T cell compartment remodeling in tumor-draining lymph nodes. JCI Insight. 2019:e132286. Published online January 30, 2020.
- Hu B., Castillo E., Harewood L., Ostano P., Reymond A., Dummer R., Raffoul W., Hoetzenecker W., Hofbauer G.F.L., Dotto G.P. Multifocal epithelial tumors and field cancerization from loss of mesenchymal CSL signaling. Cell. 2012;149:1207–1220.
- Huang W., Sherman B.T., Lempicki R.A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc. 2009;4:44–57.
- Jemt A., Salmén F., Lundmark A., Mollbrink A., Fernández Navarro J., Ståhl P.L., Yucel-Lindberg T., Lundeberg J. An automated approach to prepare tissue-derived spatially barcoded RNA-sequencing libraries. Sci. Rep. 2016;6:1–10.
- Jenh C.H., Cox M.A., Hipkin W., Lu T., Pugliese-Sivo C., Gonsiorek W., Chou C.C., Narula S.K., Zavodny P.J. Human B cell-attracting chemokine 1 (BCA-1; CXCL13) is an agonist for the human CXCR3 receptor. Cytokine. 2001;15:113–121.
- Jones P.H., Simons B.D., Watt F.M. Sic transit gloria: farewell to the epidermal transit amplifying cell? Cell Stem Cell. 2007;1:371–381.
- Joost S., Zeisel A., Jacob T., Sun X., La Manno G., Lönnerberg P., Linnarsson S., Kasper M. Single-Cell Transcriptomics Reveals that Differentiation and Spatial Signatures Shape Epidermal and Hair Follicle Heterogeneity. Cell Syst. 2016;3:221–237.
- Kalluri R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer. 2016;16:582–598.
- Karia P.S., Han J., Schmults C.D. Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal metastasis, and deaths from disease in the United States, 2012. J. Am. Acad. Dermatol. 2013;68:957–966.
- Keenan T.E., Burke K.P., Van Allen E.M. Genomic correlates of response to immune checkpoint blockade. Nat. Med. 2019;25:389–402.
- Keren L., Bosse M., Marquez D., Angoshtari R., Jain S., Varma S., Yang S.R., Kurian A., Van Valen D., West R. A Structured Tumor-Immune Microenvironment in Triple Negative Breast Cancer Revealed by Multiplexed Ion Beam Imaging. Cell. 2018;174:1373–1387.
- Keren L., Bosse M., Thompson S., Risom T., Vijayaragavan K., McCaffrey E., Marquez D., Angoshtari R., Greenwald N., Fienberg H.G. MIBI-TOF: A multi-modal multiplexed imaging platform for tissue pathology. Sci. Adv. 2019;5:1–16.
- Keyes W.M., Pecoraro M., Aranda V., Vernersson-Lindahl E., Li W., Vogel H., Guo X., Garcia E.L., Michurina T.V., Enikolopov G. ΔNp63α is an oncogene that targets chromatin remodeler Lsh to drive skin stem cell proliferation and tumorigenesis. Cell Stem Cell. 2011;8:164–176.
- Kiss M., Van Gassen S., Movahedi K., Saeys Y., Laoui D. Myeloid cell heterogeneity in cancer: not a single cell alike. Cell. Immunol. 2018;330:188–201.
- Kloeker S., Major M.B., Calderwood D.A., Ginsberg M.H., Jones D.A., Beckerle M.C. The Kindler syndrome protein is regulated by transforming growth factor-β and involved in integrin-mediated adhesion. J. Biol. Chem. 2004;279:6824–6833.
- Lambert A.W., Pattabiraman D.R., Weinberg R.A. Emerging Biological Principles of Metastasis. Cell. 2017;168:670–691.
- Lambrechts D., Wauters E., Boeckx B., Aibar S., Nittner D., Burton O., Bassez A., Decaluwé H., Pircher A., Van den Eynde K. Phenotype molding of stromal cells in the lung tumor microenvironment. Nat. Med. 2018;24:1277–1289.
- Larjava H., Plow E.F., Wu C. Kindlins: essential regulators of integrin signalling and cell-matrix adhesion. EMBO Rep. 2008;9:1203–1208.
- Lee C.S., Bhaduri A., Mah A., Johnson W.L., Ungewickell A., Aros C.J., Nguyen C.B., Rios E.J., Siprashvili Z., Straight A. Recurrent point mutations in the kinetochore gene KNSTRN in cutaneous squamous cell carcinoma. Nat. Genet. 2014;46:1060–1062.
- Li Y.Y., Hanna G.J., Laga A.C., Haddad R.I., Lorch J.H., Hammerman P.S. Genomic analysis of metastatic cutaneous squamous cell carcinoma. Clin. Cancer Res. 2015;21:1447–1456.
- Li H., van der Leun A.M., Yofe I., Lubling Y., Gelbard-Solodkin D., van Akkooi A.C.J., van den Braber M., Rozeman E.A., Haanen J.B.A.G., Blank C.U. Dysfunctional CD8 T Cells Form a Proliferative, Dynamically Regulated Compartment within Human Melanoma. Cell. 2019;176:775–789.
- Liberzon A., Birger C., Thorvaldsdóttir H., Ghandi M., Mesirov J.P., Tamayo P. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 2015;1:417–425.
- Liu J., Zhang N., Li Q., Zhang W., Ke F., Leng Q., Wang H., Chen J., Wang H. Tumor-associated macrophages recruit CCR6+ regulatory T cells and promote the development of colorectal cancer via enhancing CCL20 production in mice. PLoS ONE. 2011;6:1–13.
- Liu Z., Gerner M.Y., Van Panhuys N., Levine A.G., Rudensky A.Y., Germain R.N. Immune homeostasis enforced by co-localized effector and regulatory T cells. Nature. 2015;528:225–230.
- Löhr M., Schmidt C., Ringel J., Kluth M., Müller P., Nizze H., Jesnowski R. Transforming growth factor-β1 induces desmoplasia in an experimental model of human pancreatic carcinoma. Cancer Res. 2001;61:550–555.
- Lopez-Pajares V., Qu K., Zhang J., Webster D.E., Barajas B.C., Siprashvili Z., Zarnegar B.J., Boxer L.D., Rios E.J., Tao S. A LncRNA-MAF:MAFB transcription factor network regulates epidermal differentiation. Dev. Cell. 2015;32:693–706.
- Maier B., Leader A.M., Chen S.T., Tung N., Chang C., LeBerichel J., Chudnovskiy A., Maskey S., Walker L., Finnigan J.P. A conserved dendritic-cell regulatory program limits antitumour immunity. Nature. 2020;580:257–262.
- Margadant C., Sonnenberg A. Integrin-TGF-beta crosstalk in fibrosis, cancer and wound healing. EMBO Rep. 2010;11:97–105.
- Martin M. Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet. J. 2011;17:10–12.
- Maubec E., Petrow P., Scheer-Senyarich I., Duvillard P., Lacroix L., Gelly J., Certain A., Duval X., Crickx B., Buffard V. Phase II study of cetuximab as first-line single-drug therapy in patients with unresectable squamous cell carcinoma of the skin. J. Clin. Oncol. 2011;29:3419–3426.
- McFaline-Figueroa J.L., Hill A.J., Qiu X., Jackson D., Shendure J., Trapnell C. A pooled single-cell genetic screen identifies regulatory checkpoints in the continuum of the epithelial-to-mesenchymal transition. Nat. Genet. 2019;51:1389–1398.
- McInnes L., Healy J., Melville J. UMAP: Uniform Manifold Approximation and Projection for Dimension Reduction. arXiv. 2018 arXiv:1802.03426.
- Meyers R.M., Bryan J.G., McFarland J.M., Weir B.A., Sizemore A.E., Xu H., Dharia N.V., Montgomery P.G., Cowley G.S., Pantel S. Computational correction of copy number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells. Nat. Genet. 2017;49:1779–1784.
- Miao Y., Yang H., Levorse J., Yuan S., Polak L., Sribour M., Singh B., Rosenblum M.D., Fuchs E. Adaptive Immune Resistance Emerges from Tumor-Initiating Stem Cells. Cell. 2019;177:1172–1186.
- Migden M.R., Rischin D., Schmults C.D., Guminski A., Hauschild A., Lewis K.D., Chung C.H., Hernandez-Aya L., Lim A.M., Chang A.L.S. PD-1 Blockade with Cemiplimab in Advanced Cutaneous Squamous-Cell Carcinoma. N. Engl. J. Med. 2018;379:341–351.
- Munn D.H., Mellor A.L. IDO in the Tumor Microenvironment: Inflammation, Counter-Regulation, and Tolerance. Trends Immunol. 2016;37:193–207.
- Navarro J.F., Sjöstrand J., Salmén F., Lundeberg J., Ståhl P.L. ST Pipeline: an automated pipeline for spatial mapping of unique transcripts. Bioinformatics. 2017;33:2591–2593.
- Neftel C., Laffy J., Filbin M.G., Hara T., Shore M.E., Rahme G.J., Richman A.R., Silverbush D., Shaw M.L., Hebert C.M. An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma. Cell. 2019;178:835–849.
- Nieto M.A., Huang R.Y.Y.J., Jackson R.A.A., Thiery J.P.P. Emt: 2016. Cell. 2016;166:21–45.
- Pan J., Meyers R.M., Michel B.C., Mashtalir N., Sizemore A.E., Wells J.N., Cassel S.H., Vazquez F., Weir B.A., Hahn W.C. Interrogation of Mammalian Protein Complex Structure, Function, and Membership Using Genome-Scale Fitness Screens. Cell Syst. 2018;6:555–568.
- Pastushenko I., Brisebarre A., Sifrim A., Fioramonti M., Revenco T., Boumahdi S., Van Keymeulen A., Brown D., Moers V., Lemaire S. Identification of the tumour transition states occurring during EMT. Nature. 2018;556:463–468.
- Pickering C.R., Zhou J.H., Lee J.J., Drummond J.A., Peng S.A., Saade R.E., Tsai K.Y., Curry J.L., Tetzlaff M.T., Lai S.Y. Mutational landscape of aggressive cutaneous squamous cell carcinoma. Clin. Cancer Res. 2014;20:6582–6592.
- Prasad D.V.R., Nguyen T., Li Z., Yang Y., Duong J., Wang Y., Dong C. Murine B7-H3 is a negative regulator of T cells. J. Immunol. 2004;173:2500–2506.
- Prat A., Navarro A., Paré L., Reguart N., Galván P., Pascual T., Martínez A., Nuciforo P., Comerma L., Alos L. Immune-related gene expression profiling after PD-1 blockade in non–small cell lung carcinoma, head and neck squamous cell carcinoma, and melanoma. Cancer Res. 2017;77:3540–3550.
- Puram S.V., Tirosh I., Parikh A.S., Patel A.P., Yizhak K., Gillespie S., Rodman C., Luo C.L., Mroz E.A., Emerick K.S. Single-Cell Transcriptomic Analysis of Primary and Metastatic Tumor Ecosystems in Head and Neck Cancer. Cell. 2017;171:1611–1624.
- Purba T.S., Haslam I.S., Shahmalak A., Bhogal R.K., Paus R. Mapping the expression of epithelial hair follicle stem cell-related transcription factors LHX2 and SOX9 in the human hair follicle. Exp. Dermatol. 2015;24:462–467.
- Ramilowski J.A., Goldberg T., Harshbarger J., Kloppmann E., Lizio M., Satagopam V.P., Itoh M., Kawaji H., Carninci P., Rost B. A draft network of ligand–receptor-mediated multicellular signalling in human. Nat. Commun. 2015;6:7866.
- Redjimi N., Raffin C., Raimbaud I., Pignon P., Matsuzaki J., Odunsi K., Valmori D., Ayyoub M. CXCR3+ T regulatory cells selectively accumulate in human ovarian carcinomas to limit type I immunity. Cancer Res. 2012;72:4351–4360.
- Reuter J.A., Ortiz-Urda S., Kretz M., Garcia J., Scholl F.A., Pasmooij A.M.G., Cassarino D., Chang H.Y., Khavari P.A. Modeling inducible human tissue neoplasia identifies an extracellular matrix interaction network involved in cancer progression. Cancer Cell. 2009;15:477–488.
- Rogers H.W., Weinstock M.A., Feldman S.R., Coldiron B.M. Incidence Estimate of Nonmelanoma Skin Cancer (Keratinocyte Carcinomas) in the U.S. Population, 2012. JAMA Dermatol. 2015;151:1081–1086.
- Rognoni E., Widmaier M., Jakobson M., Ruppert R., Ussar S., Katsougkri D., Böttcher R.T., Lai-Cheong J.E., Rifkin D.B., McGrath J.A., Fässler R. Kindlin-1 controls Wnt and TGF-β availability to regulate cutaneous stem cell proliferation. Nat. Med. 2014;20:350–359.
- Rubin A.J., Parker K.R., Satpathy A.T., Greenleaf W.J., Chang H.Y., Khavari P.A., Rubin A.J., Parker K.R., Satpathy A.T., Qi Y. Coupled Single-Cell CRISPR Screening and Epigenomic Profiling Reveals Causal Gene Resource Coupled Single-Cell CRISPR Screening and Epigenomic Profiling Reveals Causal Gene Regulatory Networks. Cell. 2019;176:361–376.
- Salmén F., Vickovic S., Larsson L., Stenbeck L., Vallon-Christersson J., Ehinger A., Häkkinen J., Borg Å., Frisén J., Ståhl P.L. Multidimensional transcriptomics provides detailed information about immune cell distribution and identity in HER2+ breast tumors. bioRxiv. 2018 doi: 10.1101/358937.
- Salmén F., Ståhl P.L., Mollbrink A., Navarro J.F., Vickovic S., Frisén J., Lundeberg J. Barcoded solid-phase RNA capture for Spatial Transcriptomics profiling in mammalian tissue sections. Nat. Protoc. 2018;13:2501–2534.
- Savas P., Virassamy B., Ye C., Salim A., Mintoff C.P., Caramia F., Salgado R., Byrne D.J., Teo Z.L., Dushyanthen S., Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab) Single-cell profiling of breast cancer T cells reveals a tissue-resident memory subset associated with improved prognosis. Nat. Med. 2018;24:986–993.
- Shibue T., Weinberg R.A. EMT, CSCs, and drug resistance: the mechanistic link and clinical implications. Nat. Rev. Clin. Oncol. 2017;14:611–629.
- South A.P., Purdie K.J., Watt S.A., Haldenby S., den Breems N., Dimon M., Arron S.T., Kluk M.J., Aster J.C., McHugh A. NOTCH1 mutations occur early during cutaneous squamous cell carcinogenesis. J. Invest. Dermatol. 2014;134:2630–2638.
- Spranger S., Spaapen R.M., Zha Y., Williams J., Meng Y., Ha T.T., Gajewski T.F. Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells. Sci. Transl. Med. 2013;5:200ra116.
- Spranger S., Bao R., Gajewski T.F. Melanoma-intrinsic b -catenin signalling prevents anti-tumour immunity. Nature. 2015;523:231–235.
- Ståhl P.L., Salmén F., Vickovic S., Lundmark A., Navarro J.F., Magnusson J., Giacomello S., Asp M., Westholm J.O., Huss M. Visualization and analysis of gene expression in tissue sections by spatial transcriptomics. Science. 2016;353:78–82.
- Suh W.K., Gajewska B.U., Okada H., Gronski M.A., Bertram E.M., Dawicki W., Duncan G.S., Bukczynski J., Plyte S., Elia A. The B7 family member B7-H3 preferentially down-regulates T helper type 1-mediated immune responses. Nat. Immunol. 2003;4:899–906.
- Thommen D.S., Koelzer V.H., Herzig P., Roller A., Trefny M., Dimeloe S., Kiialainen A., Hanhart J., Schill C., Hess C. A transcriptionally and functionally distinct PD-1+ CD8+ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade. Nat. Med. 2018;24:994–1004.
- Thrane K., Eriksson H., Maaskola J., Hansson J., Lundeberg J. Spatially resolved transcriptomics enables dissection of genetic heterogeneity in stage III cutaneous malignant melanoma. Cancer Res. 2018;78:5970–5979.
- Tirosh I., Izar B., Prakadan S.M., Wadsworth M.H., Treacy D., Trombetta J.J., Rotem A., Rodman C., Lian C., Murphy G. Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science. 2016;352:189–196.
- Tirosh I., Venteicher A.S., Hebert C., Escalante L.E., Patel A.P., Yizhak K., Fisher J.M., Rodman C., Mount C., Filbin M.G. Single-cell RNA-seq supports a developmental hierarchy in human oligodendroglioma. Nature. 2016;539:309–313.
- Tsherniak A., Vazquez F., Montgomery P.G., Weir B.A., Kryukov G., Cowley G.S., Gill S., Harrington W.F., Pantel S., Krill-Burger J.M. Defining a Cancer Dependency Map. Cell. 2017;170:564–576.
- Uhlén M., Fagerberg L., Hallström B.M., Lindskog C., Oksvold P., Mardinoglu A., Sivertsson Å., Kampf C., Sjöstedt E., Asplund A. Tissue-based map of the human proteome. Science. 2015;347:1260419.
- Van Gassen S., Callebaut B., Van Helden M.J., Lambrecht B.N., Demeester P., Dhaene T., Saeys Y. FlowSOM: Using self-organizing maps for visualization and interpretation of cytometry data. Cytometry A. 2015;87:636–645.
- Van Valen D.A., Kudo T., Lane K.M., Macklin D.N., Quach N.T., DeFelice M.M., Maayan I., Tanouchi Y., Ashley E.A., Covert M.W. Deep Learning Automates the Quantitative Analysis of Individual Cells in Live-Cell Imaging Experiments. PLoS Comput. Biol. 2016;12:e1005177.
- Vento-Tormo R., Efremova M., Botting R.A., Turco M.Y., Vento-Tormo M., Meyer K.B., Park J.-E., Stephenson E., Polański K., Goncalves A. Single-cell reconstruction of the early maternal-fetal interface in humans. Nature. 2018;563:347–353.
- Villani A.-C., Satija R., Reynolds G., Sarkizova S., Shekhar K., Fletcher J., Griesbeck M., Butler A., Zheng S., Lazo S. Single-cell RNA-seq reveals new types of human blood dendritic cells, monocytes, and progenitors. Science. 2017;356:eaah4573.
- Wagenblast E., Soto M., Gutiérrez-Ángel S., Hartl C.A., Gable A.L., Maceli A.R., Erard N., Williams A.M., Kim S.Y., Dickopf S. A model of breast cancer heterogeneity reveals vascular mimicry as a driver of metastasis. Nature. 2015;520:358–362.
- Wagner J., Rapsomaniki M.A., Chevrier S., Anzeneder T., Langwieder C., Dykgers A., Rees M., Ramaswamy A., Muenst S., Soysal S.D. A Single-Cell Atlas of the Tumor and Immune Ecosystem of Human Breast Cancer. Cell. 2019;177:1330–1345.
- Wainberg M., Kamber R.A., Balsubramani A., Meyers R.M., Sinnott-Armstrong N., Hornburg D., Jiang L., Chan J., Jian R., Gu M. A genome-wide almanac of co-essential modules assigns function to uncharacterized genes. bioRxiv. 2019 doi: 10.1101/827071.
- Wei S.C., Levine J.H., Cogdill A.P., Zhao Y., Anang N.A.S., Andrews M.C., Sharma P., Wang J., Wargo J.A., Pe’er D., Allison J.P. Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade. Cell. 2017;170:1120–1133.
- White D.E., Kurpios N.A., Zuo D., Hassell J.A., Blaess S., Mueller U., Muller W.J. Targeted disruption of β1-integrin in a transgenic mouse model of human breast cancer reveals an essential role in mammary tumor induction. Cancer Cell. 2004;6:159–170.
- Wong K., Navarro J.F., Bergenstråhle L., Ståhl P.L., Lundeberg J. ST Spot Detector: a web-based application for automatic spot and tissue detection for spatial Transcriptomics image datasets. Bioinformatics. 2018;34:1966–1968.
- Yang X.H., Richardson A.L., Torres-Arzayus M.I., Zhou P., Sharma C., Kazarov A.R., Andzelm M.M., Strominger J.L., Brown M., Hemler M.E. CD151 accelerates breast cancer by regulating α 6 integrin function, signaling, and molecular organization. Cancer Res. 2008;68:3204–3213.
- Yost K.E., Satpathy A.T., Wells D.K., Qi Y., Wang C., Kageyama R., McNamara K.L., Granja J.M., Sarin K.Y., Brown R.A. Clonal replacement of tumor-specific T cells following PD-1 blockade. Nat. Med. 2019;25:1251–1259.
- Yuen G.J., Demissie E., Pillai S. B lymphocytes and cancer: a love-hate relationship. Trends Cancer. 2016;2:747–757.
- Zhang L., Yu X., Zheng L., Zhang Y., Li Y., Fang Q., Gao R., Kang B., Zhang Q., Huang J.Y. Lineage tracking reveals dynamic relationships of T cells in colorectal cancer. Nature. 2018;564:268–272.
- Zheng C., Zheng L., Yoo J.K., Guo H., Zhang Y., Guo X., Kang B., Hu R., Huang J.Y., Zhang Q. Landscape of Infiltrating T Cells in Liver Cancer Revealed by Single-Cell Sequencing. Cell. 2017;169:1342–1356.
- Zijlstra A., Lewis J., Degryse B., Stuhlmann H., Quigley J.P. The inhibition of tumor cell intravasation and subsequent metastasis via regulation of in vivo tumor cell motility by the tetraspanin CD151. Cancer Cell. 2008;13:221–234.
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