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Cell Systems
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Archetype tasks link intratumoral heterogeneity to plasticity and cancer hallmarks in small cell lung cancer

Published:August 17, 2022DOI:https://doi.org/10.1016/j.cels.2022.07.006

      Highlights

      • SCLC intra-tumor heterogeneity is explained by functional tasks of normal PNECs
      • Archetypes matching cancer hallmarks constrain SCLC phenotypic heterogeneity
      • Task trade-offs along the Pareto front in archetype space drive single-cell plasticity
      • MYC reshapes TF network dynamics to drive formation of new SCLC archetypes

      Summary

      Small cell lung cancer (SCLC) tumors comprise heterogeneous mixtures of cell states, categorized into neuroendocrine (NE) and non-neuroendocrine (non-NE) transcriptional subtypes. NE to non-NE state transitions, fueled by plasticity, likely underlie adaptability to treatment and dismal survival rates. Here, we apply an archetypal analysis to model plasticity by recasting SCLC phenotypic heterogeneity through multi-task evolutionary theory. Cell line and tumor transcriptomics data fit well in a five-dimensional convex polytope whose vertices optimize tasks reminiscent of pulmonary NE cells, the SCLC normal counterparts. These tasks, supported by knowledge and experimental data, include proliferation, slithering, metabolism, secretion, and injury repair, reflecting cancer hallmarks. SCLC subtypes, either at the population or single-cell level, can be positioned in archetypal space by bulk or single-cell transcriptomics, respectively, and characterized as task specialists or multi-task generalists by the distance from archetype vertex signatures. In the archetype space, modeling single-cell plasticity as a Markovian process along an underlying state manifold indicates that task trade-offs, in response to microenvironmental perturbations or treatment, may drive cell plasticity. Stifling phenotypic transitions and plasticity may provide new targets for much-needed translational advances in SCLC. A record of this paper’s Transparent Peer Review process is included in the supplemental information.

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      References

        • Agaimy A.
        • Erlenbach-Wünsch K.
        • Konukiewitz B.
        • Schmitt A.M.
        • Rieker R.J.
        • Vieth M.
        • Kiesewetter F.
        • Hartmann A.
        • Zamboni G.
        • Perren A.
        • Klöppel G.
        ISL1 expression is not restricted to pancreatic well-differentiated neuroendocrine neoplasms, but is also commonly found in well and poorly differentiated neuroendocrine neoplasms of extrapancreatic origin.
        Mod. Pathol. 2013; 26: 995-1003
        • Alam Sk.K.
        • Wang L.
        • Ren Y.
        • Hernandez C.E.
        • Kosari F.
        • Roden A.C.
        • Yang R.
        • Hoeppner L.H.
        ASCL1-regulated DARPP-32 and t-DARPP stimulate small cell lung cancer growth and neuroendocrine tumour cell proliferation.
        Br. J. Cancer. 2020; 123: 819-832
        • Altschuler S.J.
        • Wu L.F.
        Cellular heterogeneity: do differences make a difference?.
        Cell. 2010; 141: 559-563
        • Baine M.K.
        • Hsieh M.-S.
        • Lai W.V.
        • Egger J.V.
        • Jungbluth A.A.
        • Daneshbod Y.
        • Beras A.
        • Spencer R.
        • Lopardo J.
        • Bodd F.
        • et al.
        SCLC subtypes defined by ASCL1, NEUROD1, POU2F3, and YAP1: a comprehensive immunohistochemical and histopathologic characterization.
        J. Thorac. Oncol. 2020; 15: 1823-1835
        • Banerjee A.
        • Herring C.A.
        • Chen B.
        • Kim H.
        • Simmons A.J.
        • Southard-Smith A.N.
        • Allaman M.M.
        • White J.R.
        • Macedonia M.C.
        • Mckinley E.T.
        • et al.
        Succinate produced by intestinal microbes promotes specification of tuft cells to suppress ileal inflammation.
        Gastroenterology. 2020; 159: 2101-2115.e5
        • Barretina J.
        • Caponigro G.
        • Stransky N.
        • Venkatesan K.
        • Margolin A.A.
        • Kim S.
        • Wilson C.J.
        • Lehár J.
        • Kryukov G.V.
        • Sonkin D.
        • et al.
        The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity.
        Nature. 2012; 483: 603-607
        • Bepler G.
        • Rotsch M.
        • Jaques G.
        • Haeder M.
        • Heymanns J.
        • Hartogh G.
        • Kiefer P.
        • Havemann K.
        Peptides and growth factors in small cell lung cancer: production, binding sites, and growth effects.
        J. Cancer Res. Clin. Oncol. 1988; 114: 235-244
        • Bergen V.
        • Lange M.
        • Peidli S.
        • Wolf F.A.
        • Theis F.J.
        Generalizing RNA velocity to transient cell states through dynamical modeling.
        Nat. Biotechnol. 2020; 38: 1408-1414
        • Borromeo M.D.
        • Savage T.K.
        • Kollipara R.K.
        • He M.
        • Augustyn A.
        • Osborne J.K.
        • Girard L.
        • Minna J.D.
        • Gazdar A.F.
        • Cobb M.H.
        • Johnson J.E.
        ASCL1 and NEUROD1 reveal heterogeneity in pulmonary neuroendocrine tumors and regulate distinct genetic programs.
        Cell Rep. 2016; 16: 1259-1272
        • Bostwick D.G.
        • Bensch K.G.
        Gastrin releasing peptide in human neuroendocrine tumours.
        J. Pathol. 1985; 147: 237-244
        • Branchfield K.
        • Nantie L.
        • Verheyden J.M.
        • Sui P.
        • Wienhold M.D.
        • Sun X.
        Pulmonary neuroendocrine cells function as airway sensors to control lung immune response.
        Science. 2016; 351: 707-710
        • Cai L.
        • Liu H.
        • Huang F.
        • Fujimoto J.
        • Girard L.
        • Chen J.
        • Li Y.
        • Zhang Y.-A.
        • Deb D.
        • Stastny V.
        • et al.
        Cell-autonomous immune gene expression is repressed in pulmonary neuroendocrine cells and small cell lung cancer.
        Commun. Biol. 2021; 4: 314
        • Calbo J.
        • van Montfort E.
        • Proost N.
        • van Drunen E.
        • Beverloo H.B.
        • Meuwissen R.
        • Berns A.
        A functional role for tumor cell heterogeneity in a mouse model of small cell lung cancer.
        Cancer Cell. 2011; 19: 244-256
        • Carney D.N.
        • Gazdar A.F.
        • Bepler G.
        • Guccion J.G.
        • Marangos P.J.
        • Moody T.W.
        • Zweig M.H.
        • Minna J.D.
        Establishment and identification of small cell lung cancer cell lines having classic and variant features.
        Cancer Res. 1985; 45: 2913-2923
        • Cerami E.
        • Gao J.
        • Dogrusoz U.
        • Gross B.E.
        • Sumer S.O.
        • Aksoy B.A.
        • Jacobsen A.
        • Byrne C.J.
        • Heuer M.L.
        • Larsson E.
        • et al.
        The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data.
        Cancer Discov. 2012; 2: 401-404
        • Chan J.M.
        • Quintanal-Villalonga Á.
        • Gao V.R.
        • Xie Y.
        • Allaj V.
        • Chaudhary O.
        • Masilionis I.
        • Egger J.
        • Chow A.
        • Walle T.
        • et al.
        Signatures of plasticity, metastasis, and immunosuppression in an atlas of human small cell lung cancer.
        Cancer Cell. 2021; 39: 1479-1496.e18https://doi.org/10.1016/j.ccell.2021.09.008
        • Chen E.Y.
        • Tan C.M.
        • Kou Y.
        • Duan Q.
        • Wang Z.
        • Meirelles G.V.
        • Clark N.R.
        • Ma’ayan A.
        Enrichr: interactive and collaborative HTML5 gene list enrichment analysis tool.
        BMC Bioinformatics. 2013; 14: 128
        • Chi J.-Y.
        • Hsiao Y.-W.
        • Liu H.-L.
        • Fan X.-J.
        • Wan X.-B.
        • Liu T.-L.
        • Hung S.-J.
        • Chen Y.-T.
        • Liang H.-Y.
        • Wang J.-M.
        Fibroblast CEBPD/SDF4 axis in response to chemotherapy-induced angiogenesis through CXCR4.
        Cell Death Discov. 2021; 7: 94
        • Cingolani P.
        • Platts A.
        • Wang L.L.
        • Coon M.
        • Nguyen T.
        • Wang L.
        • Land S.J.
        • Lu X.
        • Ruden D.M.
        A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3.
        Fly. 2012; 6: 80-92
        • Cutler A.
        • Breiman L.
        Archetypal Analysis.
        Technometrics. 1994; 36: 338-347
        • Dobin A.
        • Davis C.A.
        • Schlesinger F.
        • Drenkow J.
        • Zaleski C.
        • Jha S.
        • Batut P.
        • Chaisson M.
        • Gingeras T.R.
        STAR: ultrafast universal RNA-seq aligner.
        Bioinformatics. 2013; 29: 15-21
        • Gallaher J.A.
        • Brown J.S.
        • Anderson A.R.A.
        The impact of proliferation-migration tradeoffs on phenotypic evolution in cancer.
        Sci. Rep. 2019; 9: 2425
        • Gao J.
        • Aksoy B.A.
        • Dogrusoz U.
        • Dresdner G.
        • Gross B.
        • Sumer S.O.
        • Sun Y.
        • Jacobsen A.
        • Sinha R.
        • Larsson E.
        • et al.
        Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal.
        Sci. Signal. 2013; 6: pl1
        • Gao Y.
        • Geng J.
        • Hong X.
        • Qi J.
        • Teng Y.
        • Yang Y.
        • Qu D.
        • Chen G.
        Expression of p300 and CBP is associated with poor prognosis in small cell lung cancer.
        Int J Clin Exp Patho. 2014; 7: 760-767
        • Garg A.
        • Sui P.
        • Verheyden J.M.
        • Young L.R.
        • Sun X.
        Consider the lung as a sensory organ: A tip from pulmonary neuroendocrine cells.
        Curr. Top. Dev. Biol. 2019; 132: 67-89https://doi.org/10.1016/bs.ctdb.2018.12.002
        • Gay C.M.
        • Stewart C.A.
        • Park E.M.
        • Diao L.
        • Groves S.M.
        • Heeke S.
        • Nabet B.Y.
        • Fujimoto J.
        • Solis L.M.
        • Lu W.
        • et al.
        Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities.
        Cancer Cell. 2021; 39: 346-360.e7https://doi.org/10.1016/j.ccell.2020.12.014
        • Gazdar A.F.
        • Carney D.N.
        • Nau M.M.
        • Minna J.D.
        Characterization of variant subclasses of cell lines derived from small cell lung cancer having distinctive biochemical, morphological, and growth properties.
        Cancer Res. 1985; 45: 2924-2930
        • George J.
        • Lim J.S.
        • Jang S.J.
        • Cun Y.
        • Ozretić L.
        • Kong G.
        • Leenders F.
        • Lu X.
        • Fernández-Cuesta L.
        • Bosco G.
        • et al.
        Comprehensive genomic profiles of small cell lung cancer.
        Nature. 2015; 524: 47-53
        • Gola M.
        • Doga M.
        • Bonadonna S.
        • Mazziotti G.
        • Vescovi P.P.
        • Giustina A.
        Neuroendocrine tumors secreting growth hormone-releasing hormone: pathophysiological and clinical aspects.
        Pituitary. 2006; 9: 221-229
        • Goldfarbmuren K.C.
        • Jackson N.D.
        • Sajuthi S.P.
        • Dyjack N.
        • Li K.S.
        • Rios C.L.
        • Plender E.G.
        • Montgomery M.T.
        • Everman J.L.
        • Bratcher P.E.
        • Seibold M.A.
        Dissecting the cellular specificity of smoking effects and reconstructing lineages in the human airway epithelium.
        Nat. Commun. 2020; 11: 2485
        • Gu X.
        • Karp P.H.
        • Brody S.L.
        • Pierce R.A.
        • Welsh M.J.
        • Holtzman M.J.
        • Ben-Shahar Y.
        Chemosensory functions for pulmonary neuroendocrine cells.
        Am. J. Respir. Cell Mol. Biol. 2014; 50: 637-646
        • Gupta P.B.
        • Fillmore C.M.
        • Jiang G.
        • Shapira S.D.
        • Tao K.
        • Kuperwasser C.
        • Lander E.S.
        Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells.
        Cell. 2011; 146: 633-644
        • Hagberg A.A.
        • Schult D.A.
        • Swart P.J.
        Exploring network structure, dynamics, and function using NetworkX.
        in: Proceedings of the 7th python in science conference (SciPy 2008). SCIPY, Pasadena2008
        • Hart Y.
        • Sheftel H.
        • Hausser J.
        • Szekely P.
        • Ben-Moshe N.B.
        • Korem Y.
        • Tendler A.
        • Mayo A.E.
        • Alon U.
        Inferring biological tasks using Pareto analysis of high-dimensional data.
        Nat. Methods. 2015; 12: 233-235
        • Hatzikirou H.
        • Basanta D.
        • Simon M.
        • Schaller K.
        • Deutsch A.
        Go or Grow”: the key to the emergence of invasion in tumor progression?.
        Math. Med. Biol. 2012; 29: 49-65
        • Hausser J.
        • Alon U.
        Tumour heterogeneity and the evolutionary trade-offs of cancer.
        Nat Rev Cancer. 2020; 20: 247-257
        • Hausser J.
        • Szekely P.
        • Bar N.
        • Zimmer A.
        • Sheftel H.
        • Caldas C.
        • Alon U.
        Tumor diversity and the trade-off between universal cancer tasks.
        Nat. Commun. 2019; 10: 5423https://doi.org/10.1038/s41467-019-13195-1
        • Hayford C.E.
        • Tyson D.R.
        • Robbins C.J.
        • Frick P.L.
        • Quaranta V.
        • Harris L.A.
        An in vitro model of tumor heterogeneity resolves genetic, epigenetic, and stochastic sources of cell state variability.
        PLoS Biol. 2021; 19: e3000797
        • Hie B.
        • Bryson B.
        • Berger B.
        Efficient integration of heterogeneous single-cell transcriptomes using Scanorama.
        Nat. Biotechnol. 2019; 37: 685-691
        • Hou X.
        • Gong R.
        • Zhan J.
        • Zhou T.
        • Ma Y.
        • Zhao Y.
        • Zhang Y.
        • Chen G.
        • Zhang Z.
        • Ma S.
        • et al.
        p300 promotes proliferation, migration, and invasion via inducing epithelial-mesenchymal transition in non-small cell lung cancer cells.
        BMC Cancer. 2018; 18: 641
        • Howard G.R.
        • Johnson K.E.
        • Ayala A.R.
        • Yankeelov T.E.
        • Brock A.
        A multi-state model of chemoresistance to characterize phenotypic dynamics in breast cancer.
        Sci. Rep. 2018; 8: 12058
        • Huang Y.-H.
        • Klingbeil O.
        • He X.-Y.
        • Wu X.S.
        • Arun G.
        • Lu B.
        • Somerville T.D.D.
        • Milazzo J.P.
        • Wilkinson J.E.
        • Demerdash O.E.
        • et al.
        POU2F3 is a master regulator of a tuft cell-like variant of small cell lung cancer.
        Genes Dev. 2018; 32: 915-928
        • Huch M.
        • Rawlins E.L.
        Cancer: tumours build their niche.
        Nature. 2017; 545: 292-293
        • Hunter J.D.
        Matplotlib: A 2D Graphics Environment.
        Comput Sci Eng. 2007; 9: 90-95
        • Ireland A.S.
        • Micinski A.M.
        • Kastner D.W.
        • Guo B.
        • Wait S.J.
        • Spainhower K.B.
        • Conley C.C.
        • Chen O.S.
        • Guthrie M.R.
        • Soltero D.
        • et al.
        MYC drives temporal evolution of small cell lung cancer subtypes by reprogramming neuroendocrine fate.
        Cancer Cell. 2020; 38: 60-78.e12https://doi.org/10.1016/j.ccell.2020.05.001
        • Jahchan N.S.
        • Lim J.S.
        • Bola B.
        • Morris K.
        • Seitz G.
        • Tran K.Q.
        • Xu L.
        • Trapani F.
        • Morrow C.J.
        • Cristea S.
        • et al.
        Identification and targeting of long-term tumor- propagating cells in small cell lung cancer.
        Cell Rep. 2016; 16: 644-656
        • Jaitin D.A.
        • Kenigsberg E.
        • Keren-Shaul H.
        • Elefant N.
        • Paul F.
        • Zaretsky I.
        • Mildner A.
        • Cohen N.
        • Jung S.
        • Tanay A.
        • Amit I.
        Massively parallel single-cell RNA-seq for marker-free decomposition of tissues into cell types.
        Science. 2014; 343: 776-779
        • Jia D.
        • Augert A.
        • Kim D.-W.
        • Eastwood E.
        • Wu N.
        • Ibrahim A.H.
        • Kim K.-B.
        • Dunn C.T.
        • Pillai S.P.S.
        • Gazdar A.F.
        • et al.
        Crebbp loss drives small cell lung cancer and increases sensitivity to HDAC inhibition.
        Cancer Discov. 2018; 8: 1422-1437
        • Jia D.
        • Jolly M.K.
        • Kulkarni P.
        • Levine H.
        Phenotypic plasticity and cell fate decisions in cancer: insights from dynamical systems theory.
        Cancers. 2017; 9: 70
        • Johnson W.E.
        • Li C.
        • Rabinovic A.
        Adjusting batch effects in microarray expression data using empirical Bayes methods.
        Biostatistics. 2007; 8: 118-127
        • Kamburov A.
        • Stelzl U.
        • Lehrach H.
        • Herwig R.
        The ConsensusPathDB interaction database: 2013 update.
        Nucleic Acids Res. 2013; 41: D793-D800
        • Klein A.M.
        • Mazutis L.
        • Akartuna I.
        • Tallapragada N.
        • Veres A.
        • Li V.
        • Peshkin L.
        • Weitz D.A.
        • Kirschner M.W.
        Droplet barcoding for single-cell transcriptomics applied to embryonic stem cells.
        Cell. 2015; 161: 1187-1201
        • Kleshchevnikov V.
        vitkl/ParetoTI: Beta release 2 (v0.1.10-beta.2).
        Zenodo, 2019https://doi.org/10.5281/zenodo.3269891
        • Korem Y.
        • Szekely P.
        • Hart Y.
        • Sheftel H.
        • Hausser J.
        • Mayo A.
        • Rothenberg M.E.
        • Kalisky T.
        • Alon U.
        Geometry of the gene expression space of individual cells.
        PLoS Comput. Biol. 2015; 11: e1004224
        • Krohn A.
        • Ahrens T.
        • Yalcin A.
        • Plönes T.
        • Wehrle J.
        • Taromi S.
        • Wollner S.
        • Follo M.
        • Brabletz T.
        • Mani S.A.
        • et al.
        Tumor cell heterogeneity in small cell lung cancer (SCLC): phenotypical and functional differences associated with epithelial-mesenchymal transition (EMT) and DNA methylation changes.
        PLoS ONE. 2014; 9: e100249
        • Kuleshov M.V.
        • Jones M.R.
        • Rouillard A.D.
        • Fernandez N.F.
        • Duan Q.
        • Wang Z.
        • Koplev S.
        • Jenkins S.L.
        • Jagodnik K.M.
        • Lachmann A.
        • et al.
        Enrichr: a comprehensive gene set enrichment analysis web server 2016 update.
        Nucleic Acids Res. 2016; 44: W90-W97
        • Kuo C.S.
        • Krasnow M.A.
        Formation of a neurosensory organ by epithelial cell slithering.
        Cell. 2015; 163: 394-405
        • Kwon M.
        • Proost N.
        • Song J.-Y.
        • Sutherland K.D.
        • Zevenhoven J.
        • Berns A.
        Paracrine signaling between tumor subclones of mouse SCLC: a critical role of ETS transcription factor Pea3 in facilitating metastasis.
        Genes Dev. 2015; 29: 1587-1592
        • La Manno G.
        • Soldatov R.
        • Zeisel A.
        • Braun E.
        • Hochgerner H.
        • Petukhov V.
        • Lidschreiber K.
        • Kastriti M.E.
        • Lönnerberg P.
        • Furlan A.
        • et al.
        RNA velocity of single cells.
        Nature. 2018; 560: 494-498
        • Lange M.
        • Bergen V.
        • Klein M.
        • Setty M.
        • Reuter B.
        • Bakhti M.
        • Lickert H.
        • Ansari M.
        • Schniering J.
        • Schiller H.B.
        • et al.
        CellRank for directed single-cell fate mapping.
        Nat. Methods. 2022; 19: 159-170https://doi.org/10.1038/s41592-021-01346-6
        • Langfelder P.
        • Horvath S.
        WGCNA: an R package for weighted correlation network analysis.
        BMC Bioinformatics. 2008; 9: 559
        • Leek J.T.
        • Storey J.D.
        Capturing heterogeneity in gene expression studies by surrogate variable analysis.
        PLoS Genet. 2007; 3: 1724-1735
        • Li H.
        • Durbin R.
        Fast and accurate short read alignment with Burrows–Wheeler transform.
        Bioinformatics. 2009; 25: 1754-1760
        • Li L.
        • Song W.
        • Yan X.
        • Li A.
        • Zhang X.
        • Li W.
        • Wen X.
        • Zhou L.
        • Yu D.
        • Hu J.-F.
        • Cui J.
        Friend leukemia virus integration 1 promotes tumorigenesis of small cell lung cancer cells by activating the miR-17-92 pathway.
        Oncotarget. 2017; 8: 41975-41987
        • Liberzon A.
        • Subramanian A.
        • Pinchback R.
        • Thorvaldsdóttir H.
        • Tamayo P.
        • Mesirov J.P.
        Molecular signatures database (MSigDB) 3.0.
        Bioinformatics. 2011; 27: 1739-1740
        • Lim J.S.
        • Ibaseta A.
        • Fischer M.M.
        • Cancilla B.
        • O’Young G.
        • Cristea S.
        • Luca V.C.
        • Yang D.
        • Jahchan N.S.
        • Hamard C.
        • et al.
        Intratumoural heterogeneity generated by Notch signalling promotes small-cell lung cancer.
        Nature. 2017; 545: 360-364
        • Lin C.Y.
        • Lovén J.
        • Rahl P.B.
        • Paranal R.M.
        • Burge C.B.
        • Bradner J.E.
        • Lee T.I.
        • Young R.A.
        Transcriptional amplification in tumor cells with elevated c-Myc.
        Cell. 2012; 151: 56-67
        • Lubbock A.L.R.
        • Harris L.A.
        • Quaranta V.
        • Tyson D.R.
        • Lopez C.F.
        Thunor: visualization and analysis of high-throughput dose–response datasets.
        Nucleic Acids Res. 2021; 49: W633-W640
        • Luecken M.D.
        • Theis F.J.
        Current best practices in single-cell RNA-seq analysis: a tutorial.
        Mol. Syst. Biol. 2019; 15: e8746
        • McGovern S.
        • Pan J.
        • Oliver G.
        • Cutz E.
        • Yeger H.
        The role of hypoxia and neurogenic genes (Mash-1 and Prox-1) in the developmental programming and maturation of pulmonary neuroendocrine cells in fetal mouse lung.
        Lab. Invest. 2010; 90: 180-195
        • McInnes L.
        • Healy J.
        • Saul N.
        • Großberger L.
        UMAP: uniform manifold approximation and projection.
        J. Open Source Softw. 2018; 3: 861
        • McMillan E.A.
        • Ryu M.-J.
        • Diep C.H.
        • Mendiratta S.
        • Clemenceau J.R.
        • Vaden R.M.
        • Kim J.-H.
        • Motoyaji T.
        • Covington K.R.
        • Peyton M.
        • et al.
        Chemistry-First Approach for Nomination of Personalized Treatment in Lung Cancer.
        Cell. 2018; 173: 864-878.e29
        • Mollaoglu G.
        • Guthrie M.R.
        • Böhm S.
        • Brägelmann J.
        • Can I.
        • Ballieu P.M.
        • Marx A.
        • George J.
        • Heinen C.
        • Chalishazar M.D.
        • et al.
        MYC drives progression of small cell lung cancer to a variant neuroendocrine subtype with vulnerability to Aurora kinase inhibition.
        Cancer Cell. 2017; 31: 270-285
        • Montoro D.T.
        • Haber A.L.
        • Biton M.
        • Vinarsky V.
        • Lin B.
        • Birket S.E.
        • Yuan F.
        • Chen S.
        • Leung H.M.
        • Villoria J.
        • et al.
        A revised airway epithelial hierarchy includes CFTR-expressing ionocytes.
        Nature. 2018; 560: 319-324
        • Mørup M.
        • Hansen L.K.
        Archetypal analysis for machine learning and data mining.
        Neurocomputing. 2012; 80: 54-63
        • Nadjsombati M.S.
        • McGinty J.W.
        • Lyons-Cohen M.R.
        • Jaffe J.B.
        • DiPeso L.
        • Schneider C.
        • Miller C.N.
        • Pollack J.L.
        • Nagana Gowda G.A.N.
        • Fontana M.F.
        • et al.
        Detection of succinate by intestinal tuft cells triggers a Type 2 innate immune circuit.
        Immunity. 2018; 49: 33-41.e7
        • Newman A.M.
        • Liu C.L.
        • Green M.R.
        • Gentles A.J.
        • Feng W.
        • Xu Y.
        • Hoang C.D.
        • Diehn M.
        • Alizadeh A.A.
        Robust enumeration of cell subsets from tissue expression profiles.
        Nat. Methods. 2015; 12: 453-457
        • Noguchi M.
        • Furukawa K.T.
        • Morimoto M.
        Pulmonary neuroendocrine cells: physiology, tissue homeostasis and disease.
        Dis. Model. Mech. 2020; 13: dmm046920
        • Oliphant T.E.
        Guide to NumPy. 2nd. CreateSpace Independent Publishing Platform, 2006
        • Olsen R.R.
        • Ireland A.S.
        • Kastner D.W.
        • Groves S.M.
        • Spainhower K.B.
        • Pozo K.
        • Kelenis D.P.
        • Whitney C.P.
        • Guthrie M.R.
        • Wait S.J.
        • et al.
        ASCL1 represses a SOX9+ neural crest stem-like state in small cell lung cancer.
        Genes Dev. 2021; 35: 847-869https://doi.org/10.1101/gad.348295.121
        • Osborne J.K.
        • Larsen J.E.
        • Shields M.D.
        • Gonzales J.X.
        • Shames D.S.
        • Sato M.
        • Kulkarni A.
        • Wistuba I.I.
        • Girard L.
        • Minna J.D.
        • Cobb M.H.
        NeuroD1 regulates survival and migration of neuroendocrine lung carcinomas via signaling molecules TrkB and NCAM.
        Proc. Natl. Acad. Sci. USA. 2013; 110: 6524-6529
        • Ouadah Y.
        • Rojas E.R.
        • Riordan D.P.
        • Capostagno S.
        • Kuo C.S.
        • Krasnow M.A.
        Rare pulmonary neuroendocrine cells are stem cells regulated by Rb, p53, and Notch.
        Cell. 2019; 179: 403-416.e23
        • Patel A.S.
        • Yoo S.
        • Kong R.
        • Sato T.
        • Sinha A.
        • Karam S.
        • Bao L.
        • Fridrikh M.
        • Emoto K.
        • Nudelman G.
        • et al.
        Prototypical oncogene family Myc defines unappreciated distinct lineage states of small cell lung cancer.
        Sci. Adv. 2021; 7: eabc2578
        • Petukhov V.
        • Guo J.
        • Baryawno N.
        • Severe N.
        • Scadden D.T.
        • Samsonova M.G.
        • Kharchenko P.V.
        dropEst: pipeline for accurate estimation of molecular counts in droplet-based single-cell RNA-seq experiments.
        Genome Biol. 2018; 19: 78
        • Pisco A.O.
        • Huang S.
        Non-genetic cancer cell plasticity and therapy-induced stemness in tumour relapse: ‘What does not kill me strengthens me.
        Br. J. Cancer. 2015; 112: 1725-1732
        • Polley E.
        • Kunkel M.
        • Evans D.
        • Silvers T.
        • Delosh R.
        • Laudeman J.
        • Ogle C.
        • Reinhart R.
        • Selby M.
        • Connelly J.
        • et al.
        Small cell lung cancer screen of oncology drugs, investigational agents, and gene and microRNA expression.
        J. Natl. Cancer Inst. 2016; 108: djw122
        • Ratié L.
        • Ware M.
        • Jagline H.
        • David V.
        • Dupé V.
        Dynamic expression of Notch-dependent neurogenic markers in the chick embryonic nervous system.
        Front. Neuroanat. 2014; 8: 158
        • Risse-Hackl G.
        • Adamkiewicz J.
        • Wimmel A.
        • Schuermann M.
        Transition from SCLC to NSCLC phenotype is accompanied by an increased TRE-binding activity and recruitment of specific AP-1 proteins.
        Oncogene. 1998; 16: 3057-3068
        • Rudin C.M.
        • Poirier J.T.
        • Byers L.A.
        • Dive C.
        • Dowlati A.
        • George J.
        • Heymach J.V.
        • Johnson J.E.
        • Lehman J.M.
        • MacPherson D.
        • et al.
        Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data.
        Nat. Rev. Cancer. 2019; 19: 289-297
        • Sáez-Ayala M.
        • Montenegro M.F.
        • Sánchez-del-Campo L.
        • Fernández-Pérez M.P.
        • Chazarra S.
        • Freter R.
        • Middleton M.
        • Piñero-Madrona A.
        • Cabezas-Herrera J.
        • Goding C.R.
        • Rodríguez-López J.N.
        Directed phenotype switching as an effective antimelanoma strategy.
        Cancer Cell. 2013; 24: 105-119
        • Semenova E.A.
        • Nagel R.
        • Berns A.
        Origins, genetic landscape, and emerging therapies of small cell lung cancer.
        Genes Dev. 2015; 29: 1447-1462
        • Sen T.
        • Gay C.M.
        • Byers L.A.
        Targeting DNA damage repair in small cell lung cancer and the biomarker landscape.
        Transl. Lung Cancer Res. 2018; 7: 50-68
        • Shen-Orr S.S.
        • Tibshirani R.
        • Khatri P.
        • Bodian D.L.
        • Staedtler F.
        • Perry N.M.
        • Hastie T.
        • Sarwal M.M.
        • Davis M.M.
        • Butte A.J.
        Cell type–specific gene expression differences in complex tissues.
        Nat. Methods. 2010; 7: 287-289
        • Shi Y.
        • Shu B.
        • Yang R.
        • Xu Y.
        • Xing B.
        • Liu J.
        • Chen L.
        • Qi S.
        • Liu X.
        • Wang P.
        • et al.
        Wnt and Notch signaling pathway involved in wound healing by targeting c-Myc and Hes1 separately.
        Stem Cell Res. Ther. 2015; 6: 120
        • Shimizu Y.
        • Kinoshita I.
        • Kikuchi J.
        • Yamazaki K.
        • Nishimura M.
        • Birrer M.J.
        • Dosaka-Akita H.
        Growth inhibition of non-small cell lung cancer cells by AP-1 blockade using a cJun dominant-negative mutant.
        Br. J. Cancer. 2008; 98: 915-922
        • Shoval O.
        • Sheftel H.
        • Shinar G.
        • Hart Y.
        • Ramote O.
        • Mayo A.
        • Dekel E.
        • Kavanagh K.
        • Alon U.
        Evolutionary trade-offs, Pareto optimality, and the geometry of phenotype space.
        Science. 2012; 336: 1157-1160
        • Simpson K.L.
        • Stoney R.
        • Frese K.K.
        • Simms N.
        • Rowe W.
        • Pearce S.P.
        • Humphrey S.
        • Booth L.
        • Morgan D.
        • Dynowski M.
        • et al.
        A biobank of small cell lung cancer CDX models elucidates inter- and intratumoral phenotypic heterogeneity.
        Nat. Cancer. 2020; 1: 437-451https://doi.org/10.1038/s43018-020-0046-2
        • Snel B.
        • Lehmann G.
        • Bork P.
        • Huynen M.A.
        String: a web-server to retrieve and display the repeatedly occurring neighbourhood of a gene.
        Nucleic Acids Res. 2000; 28: 3442-3444
        • Song H.
        • Yao E.
        • Lin C.
        • Gacayan R.
        • Chen M.-H.
        • Chuang P.-T.
        Functional characterization of pulmonary neuroendocrine cells in lung development, injury, and tumorigenesis.
        Proc. Natl. Acad. Sci. USA. 2012; 109: 17531-17536
        • Southard-Smith A.N.
        • Simmons A.J.
        • Chen B.
        • Jones A.L.
        • Ramirez Solano M.A.R.
        • Vega P.N.
        • Scurrah C.R.
        • Zhao Y.
        • Brenan M.J.
        • Xuan J.
        • et al.
        Dual indexed library design enables compatibility of in-Drop single-cell RNA-sequencing with exAMP chemistry sequencing platforms.
        BMC Genomics. 2020; 21: 456
        • Stewart C.A.
        • Gay C.M.
        • Xi Y.
        • Sivajothi S.
        • Sivakamasundari V.
        • Fujimoto J.
        • Bolisetty M.
        • Hartsfield P.M.
        • Balasubramaniyan V.
        • Chalishazar M.D.
        • et al.
        Single-cell analyses reveal increased intratumoral heterogeneity after the onset of therapy resistance in small-cell lung cancer.
        Nat. Cancer. 2020; 1: 423-436https://doi.org/10.1038/s43018-019-0020-z
        • Su Y.
        • Bintz M.
        • Yang Y.
        • Robert L.
        • Ng A.H.C.
        • Liu V.
        • Ribas A.
        • Heath J.R.
        • Wei W.
        Phenotypic heterogeneity and evolution of melanoma cells associated with targeted therapy resistance.
        PLoS Comput. Biol. 2019; 15: e1007034
        • Szklarczyk D.
        • Gable A.L.
        • Nastou K.C.
        • Lyon D.
        • Kirsch R.
        • Pyysalo S.
        • Doncheva N.T.
        • Legeay M.
        • Fang T.
        • Bork P.
        • et al.
        The STRING database in 2021: customizable protein–protein networks, and functional characterization of user-uploaded gene/measurement sets.
        Nucleic Acids Res. 2021; 49: D605-D612
        • Teschendorff A.E.
        • Feinberg A.P.
        Statistical mechanics meets single-cell biology.
        Nat. Rev. Genet. 2021; 22: 459-476
        • Tirosh I.
        • Izar B.
        • Prakadan S.M.
        • Wadsworth M.H.
        • Treacy D.
        • Trombetta J.J.
        • Rotem A.
        • Rodman C.
        • Lian C.
        • Murphy G.
        • et al.
        Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq.
        Science. 2016; 352: 189-196
        • Tripathi S.C.
        • Fahrmann J.F.
        • Celiktas M.
        • Aguilar M.
        • Marini K.D.
        • Jolly M.K.
        • Katayama H.
        • Wang H.
        • Murage E.N.
        • Dennison J.B.
        • et al.
        MCAM mediates chemoresistance in small-cell lung cancer via the PI3K/AKT/SOX2 signaling pathway.
        Cancer Res. 2017; 77: 4414-4425
        • Udyavar A.R.
        • Wooten D.J.
        • Hoeksema M.
        • Bansal M.
        • Califano A.
        • Estrada L.
        • Schnell S.
        • Irish J.M.
        • Massion P.P.
        • Quaranta V.
        Novel hybrid phenotype revealed in small cell lung cancer by a transcription factor network model that can explain tumor heterogeneity.
        Cancer Res. 2017; 77: 1063-1074
        • Van Dijk D.
        • Sharma R.
        • Nainys J.
        • Yim K.
        • Kathail P.
        • Carr A.J.
        • Burdziak C.
        • Moon K.R.
        • Chaffer C.L.
        • Pattabiraman D.
        • et al.
        Recovering gene interactions from single-cell data using data diffusion.
        Cell. 2018; 174: 716-729.e27
        • Van Lommel A.V.
        Pulmonary neuroendocrine cells (PNEC) and neuroepithelial bodies (NEB): chemoreceptors and regulators of lung development.
        Paediatr. Respir. Rev. 2001; 2: 171-176
        • Velten L.
        • Haas S.F.
        • Raffel S.
        • Blaszkiewicz S.
        • Islam S.
        • Hennig B.P.
        • Hirche C.
        • Lutz C.
        • Buss E.C.
        • Nowak D.
        • et al.
        Human haematopoietic stem cell lineage commitment is a continuous process.
        Nat. Cell Biol. 2017; 19: 271-281
        • Virtanen P.
        • Gommers R.
        • Oliphant T.E.
        • Haberland M.
        • Reddy T.
        • Cournapeau D.
        • Burovski E.
        • Peterson P.
        • Weckesser W.
        • Bright J.
        • et al.
        SciPy 1.0: fundamental algorithms for scientific computing in Python.
        Nat. Methods. 2020; 17: 261-272
        • Wagner A.H.
        • Devarakonda S.
        • Skidmore Z.L.
        • Krysiak K.
        • Ramu A.
        • Trani L.
        • Kunisaki J.
        • Masood A.
        • Waqar S.N.
        • Spies N.C.
        • et al.
        Recurrent WNT pathway alterations are frequent in relapsed small cell lung cancer.
        Nat. Commun. 2018; 9: 3787
        • Wang T.
        • Chen X.
        • Qiao W.
        • Kong L.
        • Sun D.
        • Li Z.
        Transcription factor E2F1 promotes EMT by regulating ZEB2 in small cell lung cancer.
        BMC Cancer. 2017; 17: 719
        • Wang Y.
        • Conlon J.M.
        Neuroendocrine peptides (NPY, GRP, VIP, somatostatin) from the brain and stomach of the alligator.
        Peptides. 1993; 14: 573-579
        • Waskom M.
        Seaborn: statistical data visualization.
        J. Open Source Software. 2021; 6
        • Weinreb C.
        • Wolock S.
        • Tusi B.K.
        • Socolovsky M.
        • Klein A.M.
        Fundamental limits on dynamic inference from single-cell snapshots.
        Proc. Natl. Acad. Sci. USA. 2018; 115: E2467-E2476
        • Wolf F.A.
        • Angerer P.
        • Theis F.J.
        SCANPY: large-scale single-cell gene expression data analysis.
        Genome Biol. 2018; 19: 15
        • Wolock S.L.
        • Lopez R.
        • Klein A.M.
        Scrublet: computational identification of cell doublets in single-cell transcriptomic data.
        Cell Syst. 2019; 8: 281-291.e9
        • Wooten D.J.
        • Groves S.M.
        • Tyson D.R.
        • Liu Q.
        • Lim J.S.
        • Albert R.
        • Lopez C.F.
        • Sage J.
        • Quaranta V.
        Systems-level network modeling of small cell lung Cancer subtypes identifies master regulators and destabilizers.
        PLoS Comput. Biol. 2019; 15: e1007343
        • Yang D.
        • Qu F.
        • Cai H.
        • Chuang C.-H.
        • Lim J.S.
        • Jahchan N.
        • Grüner B.M.
        • Kuo C.S.
        • Kong C.
        • Oudin M.J.
        • et al.
        Axon-like protrusions promote small cell lung cancer migration and metastasis.
        eLife. 2019; 8: e50616
        • Yu G.
        • Li F.
        • Qin Y.
        • Bo X.
        • Wu Y.
        • Wang S.
        GOSemSim: an R package for measuring semantic similarity among GO terms and gene products.
        Bioinformatics. 2010; 26: 976-978
        • Zhang D.
        • Huo D.
        • Xie H.
        • Wu L.
        • Zhang J.
        • Liu L.
        • Jin Q.
        • Chen X.
        CHG: A systematically integrated database of cancer hallmark genes.
        Front. Genet. 2020; 11: 29
        • Zhang W.
        • Girard L.
        • Zhang Y.-A.
        • Haruki T.
        • Papari-Zareei M.
        • Stastny V.
        • Ghayee H.K.
        • Pacak K.
        • Oliver T.G.
        • Minna J.D.
        • Gazdar A.F.
        Small cell lung cancer tumors and preclinical models display heterogeneity of neuroendocrine phenotypes.
        Transl. Lung Cancer Res. 2018; 7: 32-49