Abstract
Notch is a key evolutionary conserved pathway, which has fascinated and engaged the work of investigators in an uncountable number of biological fields, from development of metazoans to immunotherapy for cancer. The study of Notch has greatly contributed to the understanding of cancer biology and a substantial effort has been spent in designing Notch-targeting therapies. Due to its broad involvement in cancer, targeting Notch would allow to virtually modulate any aspect of the disease. However, this means that Notch-based therapies must be highly specific to avoid off-target effects. This review will present the newest mechanistic and therapeutic advances in the Notch field and discuss the promises and challenges of this constantly evolving field.
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References
Agrawal N, Frederick MJ, Pickering CR, Bettegowda C, Chang K, Li RJ et al (2011) Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science 333:1154–1157
Alfred V, Vaccari T (2018) Mechanisms of non-canonical signaling in health and disease: diversity to take therapy up a Notch? Springer, Cham, pp 187–204
American Association of Immunologists. AN, Thounaojam MC, Thomas PL, Shanker A. The journal of immunology: official journal of the American Association of Immunologists. Williams & Wilkins, 2018. https://www.jimmunol.org/content/200/1_Supplement/57.2.abstract. Accessed 9 Oct 2019.
American Association of Immunologists. AN, Thounaojam M, Chaudhuri E, Dash C, Shanker A. The journal of immunology: official journal of the American Association of Immunologists. Williams & Wilkins, 2019. https://www.jimmunol.org/content/202/1_Supplement/136.18.abstract. Accessed 9 Oct 2019.
Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284:770–776
Aster JC, Pear WS, Blacklow SC (2017) The varied roles of Notch in cancer. Annu Rev Pathol Mech Dis 12:245–275
Bayin NS, Frenster JD, Sen R, Si S, Modrek AS, Galifianakis N et al (2017) Notch signaling regulates metabolic heterogeneity in glioblastoma stem cells. Oncotarget 8:64932–64953
Beavis PA, Milenkovski N, Stagg J, Smyth MJ, Darcy PK (2013a) A 2A blockade enhances anti-metastatic immune responses. Onco Targets Ther 2:e26705
Beavis PA, Divisekera U, Paget C, Chow MT, John LB, Devaud C et al (2013b) Blockade of A2A receptors potently suppresses the metastasis of CD73+ tumors. Proc Natl Acad Sci U S A 110:14711–14716
Beavis PA, Milenkovski N, Henderson MA, John LB, Allard B, Loi S et al (2015) Adenosine receptor 2A blockade increases the efficacy of anti–PD-1 through enhanced antitumor T-cell responses. Cancer Immunol Res 3:506–517
Beavis PA, Henderson MA, Giuffrida L, Mills JK, Sek K, Cross RS et al (2017) Targeting the adenosine 2A receptor enhances chimeric antigen receptor T cell efficacy. J Clin Invest 127:929–941
Bender MH, Gao H, Capen AR, Clay JM, Hipskind PA, Reel JK et al (2013) Novel inhibitor of Notch signaling for the treatment of cancer. In: Experimental and molecular therapeutics. American Association for Cancer Research, pp 1131–1131
Berges C, Haberstock H, Fuchs D, Miltz M, Sadeghi M, Opelz G et al (2008) Proteasome inhibition suppresses essential immune functions of human CD4+ T cells. Immunology 124:234–246
Besser MJ, Shapira-Frommer R, Treves AJ, Zippel D, Itzhaki O, Hershkovitz L et al (2010) Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients. Clin Cancer Res 16:2646–2655
Bhola NE, Jansen VM, Koch JP, Li H, Formisano L, Williams JA et al (2016) Treatment of triple-negative breast cancer with TORC1/2 inhibitors sustains a drug-resistant and Notch-dependent cancer stem cell population. Cancer Res 76:440–452
Biktasova AK, Dudimah DF, Uzhachenko RV, Park K, Akhter A, Arasada RR et al (2015) Multivalent forms of the Notch ligand DLL-1 enhance antitumor T-cell immunity in lung cancer and improve efficacy of EGFR-targeted therapy. Cancer Res 75:4728–4741
Borgegård T, Gustavsson S, Nilsson C, Parpal S, Klintenberg R, Berg A-L et al (2012) Alzheimer’s disease: presenilin 2-sparing γ-secretase inhibition is a tolerable Aβ peptide-lowering strategy. J Neurosci 32:17297–17305
Bray SJ (2016) Notch signalling in context. Nat Rev Mol Cell Biol 17:722
Bray SJ, Gomez-Lamarca M (2018) Notch after cleavage. Curr Opin Cell Biol 51:103–109
Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG et al (2013) CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 5:177ra38
Carrieri FA, Murray PJ, Ditsova D, Ferris MA, Davies P, Dale JK (2019) CDK 1 and CDK 2 regulate NICD 1 turnover and the periodicity of the segmentation clock. EMBO Rep 20. https://doi.org/10.15252/embr.201846436
Chastagner P, Israël A, Brou C (2008) AIP4/itch regulates Notch receptor degradation in the absence of ligand. PLoS One 3:e2735
Chastagner P, Rubinstein E, Brou C (2017) Ligand-activated Notch undergoes DTX4-mediated ubiquitylation and bilateral endocytosis before ADAM10 processing. Sci Signal 10:eaag2989
Chiorean EG, LoRusso P, Strother RM, Diamond JR, Younger A, Messersmith WA et al (2015) A phase I first-in-human study of enoticumab (REGN421), a fully human delta-like ligand 4 (Dll4) monoclonal antibody in patients with advanced solid tumors. In: Clinical cancer research. American Association for Cancer Research Inc, pp 2695–2703
Cho J-H, Patel B, Bonala S, Manne S, Zhou Y, Vadrevu SK et al (2017) Notch transactivates Rheb to maintain the multipotency of TSC-null cells. Nat Commun 8:1848
Cho JH, Okuma A, Al-Rubaye D, Intisar E, Junghans RP, Wong WW (2018) Engineering Axl specific CAR and SynNotch receptor for cancer therapy. Sci Rep 8:3846
Ciofani M, Zúñiga-Pflücker JC (2005) Notch promotes survival of pre–T cells at the β-selection checkpoint by regulating cellular metabolism. Nat Immunol 6:881–888
Collu GM, Hidalgo-Sastre A, Brennan K (2014) Wnt–Notch signalling crosstalk in development and disease. Cell Mol Life Sci 71:3553–3567
Couch JA, Zhang G, Beyer JC, de Zafra CLZ, Gupta P, Kamath AV et al (2016) Balancing efficacy and safety of an anti-DLL4 antibody through pharmacokinetic modulation. Clin Cancer Res 22:1469–1479
Das S, Knust E (2018) A dual role of the extracellular domain of Drosophila Crumbs for morphogenesis of the embryonic neuroectoderm. Biol Open 7:bio031435
del Álamo D, Rouault H, Schweisguth F (2011) Mechanism and significance of cis-inhibition in Notch signalling. Curr Biol 21:R40–R47
Dexter JS (1914) The analysis of a case of continuous variation in Drosophila by a study of its linkage relations. Am Nat 48:712–758
Dudley ME, Yang JC, Sherry R, Hughes MS, Royal R, Kammula U et al (2008) Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol 26:5233–5239
Ellisen LW, Bird J, West DC, Soreng AL, Reynolds TC, Smith SD et al (1991) TAN-1, the human homolog of the Drosophila Notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66:649–661
Falo-Sanjuan J, Lammers NC, Garcia HG, Bray SJ (2019) Enhancer priming enables fast and sustained transcriptional responses to Notch signaling. Dev Cell 50:411–425.e8
Faronato M, Nguyen VTM, Patten DK, Lombardo Y, Steel JH, Patel N et al (2015) DMXL2 drives epithelial to mesenchymal transition in hormonal therapy resistant breast cancer through Notch hyper-activation. Oncotarget 6:22467–22479
Fleming RJ (1998) Structural conservation of Notch receptors and ligands. Semin Cell Dev Biol 9:599–607
Fryer CJ, White JB, Jones KA (2004) Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover. Mol Cell 16:509–520
Fu W, Lei C, Yu Y, Liu S, Li T, Lin F et al (2019) EGFR/Notch antagonists enhance the response to inhibitors of the PI3K-Akt pathway by decreasing tumor-initiating cell frequency. Clin Cancer Res 25:2835–2847
Gallahan D, Callahan R (1997) The mouse mammary tumor associated gene INT3 is a unique member of the NOTCH gene family (NOTCH4). Oncogene 14:1883–1890
Garber K (2018) Driving T-cell immunotherapy to solid tumors. Nat Biotechnol 36:215–219
Gavai AV, Quesnelle C, Norris D, Han W-C, Gill P, Shan W et al (2015) Discovery of clinical candidate BMS-906024: a potent pan-notch inhibitor for the treatment of leukemia and solid tumors. ACS Med Chem Lett 6:523–527
Gentle ME, Rose A, Bugeon L, Dallman MJ (2012) Noncanonical Notch signaling modulates cytokine responses of dendritic cells to inflammatory stimuli. J Immunol 189:1274–1284
George J, Lim JS, Jang SJ, Cun Y, Ozretić L, Kong G et al (2015) Comprehensive genomic profiles of small cell lung cancer. Nature 524:47–53
Gomez-Lamarca MJ, Snowdon LA, Seib E, Klein T, Bray SJ (2015) Rme-8 depletion perturbs Notch recycling and predisposes to pathogenic signaling. J Cell Biol 210:303–318
Gomez-Lamarca MJ, Falo-Sanjuan J, Stojnic R, Abdul Rehman S, Muresan L, Jones ML et al (2018) Activation of the Notch signaling pathway in vivo elicits changes in CSL nuclear dynamics. Dev Cell 44:611–623.e7
Gordon WR, Arnett KL, Blacklow SC (2008) The molecular logic of Notch signaling--a structural and biochemical perspective. J Cell Sci 121:3109–3119
Grazioli P, Felli MP, Screpanti I, Campese AF (2017) The mazy case of Notch and immunoregulatory cells. J Leukoc Biol 102:361–368
Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR et al (2013) Chimeric antigen receptor–modified T cells for acute lymphoid leukemia. N Engl J Med 368:1509–1518
Gupta-Rossi N, Six E, LeBail O, Logeat F, Chastagner P, Olry A et al (2004) Monoubiquitination and endocytosis direct gamma-secretase cleavage of activated Notch receptor. J Cell Biol 166:73–83
Gutierrez A, Look AT (2007) NOTCH and PI3K-AKT pathways intertwined. Cancer Cell 12:411–413
Haapasalo A, Kovacs DM (2011) The many substrates of presenilin/γ-secretase. J Alzheimers Dis 25:3–28
Habets RA, de Bock CE, Serneels L, Lodewijckx I, Verbeke D, Nittner D et al (2019) Safe targeting of T cell acute lymphoblastic leukemia by pathology-specific NOTCH inhibition. Sci Transl Med 11:eaau6246
Harvey BM, Rana NA, Moss H, Leonardi J, Jafar-Nejad H, Haltiwanger RS (2016) Mapping sites of O-glycosylation and fringe elongation on Drosophila Notch. J Biol Chem 291:16348–16360
Hayward AN, Aird EJ, Gordon WR (2019) A toolkit for studying cell surface shedding of diverse transmembrane receptors. elife 8. https://doi.org/10.7554/eLife.46983
He L, Huang J, Perrimon N (2017) Development of an optimized synthetic Notch receptor as an in vivo cell-cell contact sensor. Proc Natl Acad Sci U S A 114:5467–5472
Herranz D, Ambesi-Impiombato A, Sudderth J, Sánchez-Martín M, Belver L, Tosello V et al (2015) Metabolic reprogramming induces resistance to anti-NOTCH1 therapies in T cell acute lymphoblastic leukemia. Nat Med 21:1182–1189
Hori K, Sen A, Kirchhausen T, Artavanis-Tsakonas S (2011) Synergy between the ESCRT-III complex and Deltex defines a ligand-independent Notch signal. J Cell Biol 195:1005–1015
Hossain F, Majumder S, Ucar DA, Rodriguez PC, Golde TE, Minter LM et al (2018) Notch signaling in myeloid cells as a regulator of tumor immune responses. Front Immunol 9. https://doi.org/10.3389/FIMMU.2018.01288
Huang Y, Lin L, Shanker A, Malhotra A, Yang L, Dikov MM et al (2011) Resuscitating cancer immunosurveillance: selective stimulation of DLL1-Notch signaling in T cells rescues T-cell function and inhibits tumor growth. Cancer Res 71:6122–6131
Iannone R, Miele L, Maiolino P, Pinto A, Morello S (2014) Adenosine limits the therapeutic effectiveness of anti-CTLA4 mAb in a mouse melanoma model. Am J Cancer Res 4:172–181
Izon DJ, Aster JC, He Y, Weng A, Karnell FG, Patriub V et al (2002) Deltex1 redirects lymphoid progenitors to the B cell lineage by antagonizing Notch1. Immunity 16:231–243
Izumchenko E, Sun K, Jones S, Brait M, Agrawal N, Koch WM et al (2014) Notch1 mutations are drivers of oral tumorigenesis. Cancer Prev Res 8:277–286
Jehn BM, Dittert I, Beyer S, Von Der Mark K, Bielke W. c-Cbl binding and ubiquitin dependent lysosomal degradation of membrane associated Notch1 downloaded from. JBC Papers in Press, 2002. http://www.jbc.org/. Accessed 13 Sept 2018.
Jimeno A, Moore KN, Gordon M, Chugh R, Diamond JR, Aljumaily R et al (2019) A first-in-human phase 1a study of the bispecific anti-DLL4/anti-VEGF antibody navicixizumab (OMP-305B83) in patients with previously treated solid tumors. Investig New Drugs 37:461–472
Jitschin R, Braun M, Qorraj M, Saul D, Le Blanc K, Zenz T et al (2015) Stromal cell–mediated glycolytic switch in CLL cells involves Notch-c-Myc signaling. Blood 125:3432–3436
Kakuda S, Haltiwanger RS (2017) Deciphering the fringe-mediated Notch code: identification of activating and inhibiting sites allowing discrimination between ligands. Dev Cell 40:193–201
Karbowniczek M, Zitserman D, Khabibullin D, Hartman T, Yu J, Morrison T et al (2010) The evolutionarily conserved TSC/Rheb pathway activates Notch in tuberous sclerosis complex and Drosophila external sensory organ development. J Clin Invest 120:93–102
Kassner N, Krueger M, Yagita H, Dzionek A, Hutloff A, Kroczek R et al (2010) Cutting edge: plasmacytoid dendritic cells induce IL-10 production in T cells via the Delta-like-4/Notch axis. J Immunol 184:550–554
Kershaw NJ, Church NL, Griffin MDW, Luo CS, Adams TE, Burgess AW (2015) Notch ligand delta-like1: X-ray crystal structure and binding affinity. Biochem J 468:159–166
Kidd S, Kelley MR, Young MW (1986) Sequence of the notch locus of Drosophila melanogaster: relationship of the encoded protein to mammalian clotting and growth factors. Mol Cell Biol 6:3094–3108
Kishton RJ, Barnes CE, Nichols AG, Cohen S, Gerriets VA, Siska PJ et al (2016) AMPK is essential to balance glycolysis and mitochondrial metabolism to control T-ALL cell stress and survival. Cell Metab 23:649–662
Kobia F, Duchi S, Deflorian G, Vaccari T (2014) Pharmacologic inhibition of vacuolar H+ ATPase reduces physiologic and oncogenic Notch signaling. Mol Oncol 8:207–220
Kondo T, Morita R, Okuzono Y, Nakatsukasa H, Sekiya T, Chikuma S et al (2017) Notch-mediated conversion of activated T cells into stem cell memory-like T cells for adoptive immunotherapy. Nat Commun 8:15338
Kondo T, Imura Y, Chikuma S, Hibino S, Omata-Mise S, Ando M et al (2018) Generation and application of human induced-stem cell memory T cells for adoptive immunotherapy. Cancer Sci 109:2130–2140
Kong G, You X, Wen Z, Chang Y-I, Qian S, Ranheim EA et al (2019) Downregulating Notch counteracts KrasG12D-induced ERK activation and oxidative phosphorylation in myeloproliferative neoplasm. Leukemia 33:671–685
Kopan R, Ilagan MXG (2009) The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137:216–233
Kumar A, Lee JH, Suknuntha K, D’Souza SS, Thakur AS, Slukvin II (2019) NOTCH activation at the hematovascular mesoderm stage facilitates efficient generation of T cells with high proliferation potential from human pluripotent stem cells. J Immunol 202:770–776
Kummar S, O’Sullivan Coyne G, Do KT, Turkbey B, Meltzer PS, Polley E et al (2017) Clinical activity of the γ-secretase inhibitor PF-03084014 in adults with Desmoid tumors (aggressive fibromatosis). J Clin Oncol 35:1561–1569
Lee D, Kim D, Bin CY, Kang K, Sung E-S, Ahn J-H et al (2016) Simultaneous blockade of VEGF and Dll4 by HD105, a bispecific antibody, inhibits tumor progression and angiogenesis. MAbs 8:892–904
Lei F, Zhao B, Haque R, Xiong X, Budgeon L, Christensen ND et al (2011) In vivo programming of tumor antigen-specific T lymphocytes from pluripotent stem cells to promote cancer immunosurveillance. Cancer Res 71:4742–4747
Leitch CC, Lodh S, Prieto-Echagüe V, Badano JL, Zaghloul NA (2014) Basal body proteins regulate Notch signaling through endosomal trafficking. J Cell Sci 127:2407–2419
Leone RD, Emens LA (2018) Targeting adenosine for cancer immunotherapy. J Immunother Cancer 6:57
Leone RD, Lo Y-C, Powell JD (2015) A2aR antagonists: next generation checkpoint blockade for cancer immunotherapy. Comput Struct Biotechnol J 13:265–272
Lim JS, Ibaseta A, Fischer MM, Cancilla B, O’Young G, Cristea S et al (2017) Intratumoural heterogeneity generated by Notch signalling promotes small-cell lung cancer. Nature 545:360–364
Luca VC, Jude KM, Pierce NW, Nachury MV, Fischer S, Garcia KC (2015) Structural biology. Structural basis for Notch1 engagement of Delta-like 4. Science 347:847–853
Luca VC, Kim BC, Ge C, Kakuda S, Wu D, Roein-Peikar M et al (2017) Notch-jagged complex structure implicates a catch bond in tuning ligand sensitivity. Science 355:1320–1324
Ma J, Meng Y, Kwiatkowski DJ, Chen X, Peng H, Sun Q et al (2010) Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade. J Clin Invest 120:103–114
Maekawa Y, Ishifune C, Tsukumo S, Hozumi K, Yagita H, Yasutomo K (2015) Notch controls the survival of memory CD4+ T cells by regulating glucose uptake. Nat Med 21:55–61
Man J, Yu X, Huang H, Zhou W, Xiang C, Huang H et al (2018) Hypoxic induction of vasorin regulates Notch1 turnover to maintain glioma stem-like cells. Cell Stem Cell 22:104–118.e6
Marambaud P, Shioi J, Serban G, Georgakopoulos A, Sarner S, Nagy V et al (2002) A presenilin-1/gamma-secretase cleavage releases the E-cadherin intracellular domain and regulates disassembly of adherens junctions. EMBO J 21:1948–1956
Massard C, Michiels S, Ferté C, Le Deley M-C, Lacroix L, Hollebecque A et al (2017) High-throughput genomics and clinical outcome in hard-to-treat advanced cancers: results of the MOSCATO 01 trial. Cancer Discov 7:586. https://doi.org/10.1158/2159-8290.CD-16-1396
Massard C, Azaro A, Soria J-C, Lassen U, Le Tourneau C, Sarker D et al (2018) First-in-human study of LY3039478, an oral Notch signaling inhibitor in advanced or metastatic cancer. Ann Oncol 29:1911–1917
Matsuno K, Eastman D, Mitsiades T, Quinn AM, Carcanciu ML, Ordentlich P et al (1998) Human deltex is a conserved regulator of Notch signalling. Nat Genet 19:74–78
McAuliffe SM, Morgan SL, Wyant GA, Tran LT, Muto KW, Chen YS et al (2012) Targeting Notch, a key pathway for ovarian cancer stem cells, sensitizes tumors to platinum therapy. Proc Natl Acad Sci 109:E2939–E2948
McGill MA, Dho SE, Weinmaster G, McGlade CJ (2009) Numb regulates post-endocytic trafficking and degradation of Notch1. J Biol Chem 284:26427–26438
McMillan BJ, Zimmerman B, Egan ED, Lofgren M, Xu X, Hesser A et al (2017) Structure of human POFUT1, its requirement in ligand-independent oncogenic Notch signaling, and functional effects of Dowling-Degos mutations. Glycobiology 27:777–786
Meng L, Bai Z, He S, Mochizuki K, Liu Y, Purushe J et al (2016) The Notch ligand DLL4 defines a capability of human dendritic cells in regulating Th1 and Th17 differentiation. J Immunol 196:1070–1080
Mittal D, Young A, Stannard K, Yong M, Teng MWL, Allard B et al (2014) Antimetastatic effects of blocking PD-1 and the adenosine A2A receptor. Cancer Res 74:3652–3658
Molon B, Calì B, Viola A (2016) T cells and cancer: how metabolism shapes immunity. Front Immunol 7:20
Morgan TH (1917) The theory of the gene. Am Nat 51:513–544
Morgan KM, Fischer BS, Lee FY, Shah JJ, Bertino JR, Rosenfeld J et al (2017) Gamma secretase inhibition by BMS-906024 enhances efficacy of paclitaxel in lung adenocarcinoma. Mol Cancer Ther 16:2759–2769
Morsut L, Roybal KT, Xiong X, Gordley RM, Coyle SM, Thomson M et al (2016) Engineering customized cell sensing and response behaviors using synthetic Notch receptors. Cell 164:780–791
Mukherjee A, Veraksa A, Bauer A, Rosse C, Camonis J, Artavanis-Tsakonas S (2005) Regulation of Notch signalling by non-visual β-arrestin. Nat Cell Biol 7:1191–1201
Nandagopal N., Santat L. A. & Elowitz M. B. (2019) Cis-activation in the Notch signaling pathway. Elife 8:e37880
Nemetschke L, Knust E (2016) Drosophila Crumbs prevents ectopic Notch activation in developing wings by inhibiting ligand-independent endocytosis. Development 143:4543–4553
Ntziachristos P, Lim JS, Sage J, Aifantis I (2014) From fly wings to targeted cancer therapies: a centennial for notch signaling. Cancer Cell 25:318–334
O’Rourke CJ, Matter MS, Nepal C, Caetano-Oliveira R, Ton PT, Factor VM et al (2020) Identification of a pan-gamma-secretase inhibitor response signature for Notch-driven cholangiocarcinoma. Hepatology 71(1):196–213
Ohta A, Gorelik E, Prasad SJ, Ronchese F, Lukashev D, Wong MKK et al (2006) A2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci U S A 103:13132–13137
Palmer WH, Jia D, Deng W-M (2014) Cis-interactions between Notch and its ligands block ligand-independent Notch activity. elife 3. https://doi.org/10.7554/eLife.04415
Palomero T, Sulis ML, Cortina M, Real PJ, Barnes K, Ciofani M et al (2007) Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med 13:1203–1210
Patel B, Patel J, Cho J-H, Manne S, Bonala S, Henske E et al (2016) Exosomes mediate the acquisition of the disease phenotypes by cells with normal genome in tuberous sclerosis complex. Oncogene 35:3027–3036
Pece S, Serresi M, Santolini E, Capra M, Hulleman E, Galimberti V et al (2004) Loss of negative regulation by Numb over Notch is relevant to human breast carcinogenesis. J Cell Biol 167:215–221
Pellom ST, Dudimah DF, Thounaojam MC, Uzhachenko RV, Singhal A, Richmond A et al (2017) Bortezomib augments lymphocyte stimulatory cytokine signaling in the tumor microenvironment to sustain CD8+T cell antitumor function. Oncotarget 8:8604–8621
Pikman Y, Alexe G, Roti G, Conway AS, Furman A, Lee ES et al (2017) Synergistic drug combinations with a CDK4/6 inhibitor in T-cell acute lymphoblastic leukemia. Clin Cancer Res 23:1012–1024
Platonova N, Manzo T, Mirandola L, Colombo M, Calzavara E, Vigolo E et al (2015) PI3K/AKT signaling inhibits NOTCH1 lysosome-mediated degradation. Genes Chromosom Cancer 54:516–526
Qiu M, Peng Q, Jiang I, Carroll C, Han G, Rymer I et al (2013) Specific inhibition of Notch1 signaling enhances the antitumor efficacy of chemotherapy in triple negative breast cancer through reduction of cancer stem cells. Cancer Lett 328:261–270
Ran Y, Hossain F, Pannuti A, Lessard CB, Ladd GZ, Jung JI et al (2017) γ-Secretase inhibitors in cancer clinical trials are pharmacologically and functionally distinct. EMBO Mol Med 9:950–966
Ridgway J, Zhang G, Wu Y, Stawicki S, Liang W-C, Chanthery Y et al (2006) Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 444:1083–1087
Roti G, Carlton A, Ross KN, Markstein M, Pajcini K, Su AH et al (2013) Complementary genomic screens identify SERCA as a therapeutic target in NOTCH1 mutated cancer. Cancer Cell 23:390–405
Roybal KT, Rupp LJ, Morsut L, Walker WJ, McNally KA, Park JS et al (2016) Precision tumor recognition by T cells with combinatorial antigen-sensing circuits. Cell 164:770–779
Schneider M, Troost T, Grawe F, Martinez-Arias A, Klein T, Akbar MA et al (2013) Activation of Notch in lgd mutant cells requires the fusion of late endosomes with the lysosome. J Cell Sci 126:645–656
Schneider M, Kumar V, Nordstrøm LU, Feng L, Takeuchi H, Hao H et al (2018) Inhibition of Delta-induced Notch signaling using fucose analogs. Nat Chem Biol 14:65–71
Schott AF, Landis MD, Dontu G, Griffith KA, Layman RM, Krop I et al (2013) Preclinical and clinical studies of gamma secretase inhibitors with docetaxel on human breast tumors. Clin Cancer Res 19:1512–1524
Sestan N, Artavanis-Tsakonas S, Rakic P (1999) Contact-dependent inhibition of cortical neurite growth mediated by notch signaling. Science 286:741–746
Shanker A, Pellom ST, Dudimah DF, Thounaojam MC, de Kluyver RL, Brooks AD et al (2015) Bortezomib improves adoptive T-cell therapy by sensitizing cancer cells to FasL cytotoxicity. Cancer Res 75:5260–5272
Sheldon H, Heikamp E, Turley H, Dragovic R, Thomas P, Oon CE et al (2010) New mechanism for Notch signaling to endothelium at a distance by Delta-like 4 incorporation into exosomes. Blood 116:2385–2394
Shilo B, Sprinzak D (2017) The lipid-binding side of Notch ligands. EMBO J 36:2182–2183
Shimizu H, Woodcock SA, Wilkin MB, Trubenová B, NAM M, Baron M (2014) Compensatory flux changes within an endocytic trafficking network maintain thermal robustness of Notch signaling. Cell 157:1160–1174
Sierra RA, Thevenot P, Raber PL, Cui Y, Parsons C, Ochoa AC et al (2014) Rescue of Notch-1 signaling in antigen-specific CD8+ T cells overcomes tumor-induced T-cell suppression and enhances immunotherapy in cancer. Cancer Immunol Res 2:800–811
Sierra RA, Trillo-Tinoco J, Mohamed E, Yu L, Achyut BR, Arbab A et al (2017) Anti-jagged immunotherapy inhibits MDSCs and overcomes tumor-induced tolerance. Cancer Res 77:5628–5638
Song Y, Li L, Ou Y, Gao Z, Li E, Li X et al (2014) Identification of genomic alterations in oesophageal squamous cell cancer. Nature 509:91–95
Sorrentino C, Hossain F, Rodriguez PC, Sierra RA, Pannuti A, Osborne BA et al (2019) Adenosine A2A receptor stimulation inhibits TCR-induced Notch1 activation in CD8+T-cells. Front Immunol 10:1–12
Sprinzak D, Lakhanpal A, Lebon L, Santat LA, Fontes ME, Anderson GA et al (2010) Cis-interactions between Notch and Delta generate mutually exclusive signalling states. Nature 465:86–90
Srivastava S, Salter AI, Liggitt D, Yechan-Gunja S, Sarvothama M, Cooper K et al (2019) Logic-gated ROR1 chimeric antigen receptor expression rescues T cell-mediated toxicity to normal tissues and enables selective tumor targeting. Cancer Cell 35:489–503.e8
Steinbuck MP, Winandy S (2018) A review of Notch processing with new insights into ligand-independent Notch signaling in T-cells. Front Immunol 9:1230
Steinbuck MP, Arakcheeva K, Winandy S (2018) Novel TCR-mediated mechanisms of Notch activation and signaling. J Immunol 200:997–1007
Stransky N, Egloff AM, Tward AD, Kostic AD, Cibulskis K, Sivachenko A et al (2011) The mutational landscape of head and neck squamous cell carcinoma. Science 333:1157–1160
Stylianou S, Clarke RB, Brennan K (2006) Aberrant activation of Notch signaling in human breast cancer. Cancer Res 66:1517–1525
Suckling RJ, Korona B, Whiteman P, Chillakuri C, Holt L, Handford PA et al (2017) Structural and functional dissection of the interplay between lipid and Notch binding by human Notch ligands. EMBO J 36:2204–2215
Sugimoto K, Maekawa Y, Kitamura A, Nishida J, Koyanagi A, Yagita H et al (2010) Notch2 signaling is required for potent antitumor immunity in vivo. J Immunol 184:4673–4678
Tanis KQ, Podtelezhnikov AA, Blackman SC, Hing J, Railkar RA, Lunceford J et al (2016) An accessible pharmacodynamic transcriptional biomarker for Notch target engagement. Clin Pharmacol Ther 99:370–380
Tchekneva EE, Goruganthu MUL, Uzhachenko RV, Thomas PL, Antonucci A, Chekneva I et al (2019) Determinant roles of dendritic cell-expressed Notch Delta-like and Jagged ligands on anti-tumor T cell immunity. J Immunother Cancer 7:95
Thounaojam MC, Dudimah DF, Pellom ST, Uzhachenko RV, Carbone DP, Dikov MM et al (2015) Bortezomib enhances expression of effector molecules in anti-tumor CD8+ T lymphocytes by promoting Notch-nuclear factor-κB crosstalk. Oncotarget 6:32439–32455
Toda S, Blauch LR, Tang SKY, Morsut L, Lim WA (2018) Programming self-organizing multicellular structures with synthetic cell-cell signaling. Science 361:156–162
Vaccari T, Lu H, Kanwar R, Fortini ME, Bilder D (2008) Endosomal entry regulates Notch receptor activation in Drosophila melanogaster. J Cell Biol 180:755–762
Vaccari T, Duchi S, Cortese K, Tacchetti C, Bilder D (2010) The vacuolar ATPase is required for physiological as well as pathological activation of the Notch receptor. Development 137:1825–1832
Vijayan D, Young A, Teng MWL, Smyth MJ (2017) Targeting immunosuppressive adenosine in cancer. Nat Rev Cancer 17:709–724
Villalobos VM, Hall F, Jimeno A, Gore L, Kern K, Cesari R et al (2018) Long-term follow-up of Desmoid fibromatosis treated with PF-03084014, an oral gamma secretase inhibitor. Ann Surg Oncol 25:768–775
Waickman AT, Alme A, Senaldi L, Zarek PE, Horton M, Powell JD (2012) Enhancement of tumor immunotherapy by deletion of the A2A adenosine receptor. Cancer Immunol Immunother 61:917–926
Wang Q, Lu Q (2017) Plasma membrane-derived extracellular microvesicles mediate non-canonical intercellular NOTCH signaling. Nat Commun 8:709
Wang Y-C, He F, Feng F, Liu X-W, Dong G-Y, Qin H-Y et al (2010) Notch signaling determines the M1 versus M2 polarization of macrophages in antitumor immune responses. Cancer Res 70:4840–4849
Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D et al (2011) The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35:871–882
Wang Z, Hu Y, Xiao D, Wang J, Liu C, Xu Y et al (2017) Stabilization of Notch1 by the Hsp90 chaperone is crucial for T-cell leukemogenesis. Clin Cancer Res 23:3834–3846
Wharton KA, Johansen KM, Xu T, Artavanis-Tsakonas S (1985) Nucleotide sequence from the neurogenic locus Notch implies a gene product that shares homology with proteins containing EGF-like repeats. Cell 43:567–581
Wilkin MB, Carbery A-M, Fostier M, Aslam H, Mazaleyrat SL, Higgs J et al (2004) Regulation of notch endosomal sorting and signaling by Drosophila Nedd4 family proteins. Curr Biol 14:2237–2244
Wilkin M, Tongngok P, Gensch N, Clemence S, Motoki M, Yamada K et al (2008) Drosophila HOPS and AP-3 complex genes are required for a Deltex-regulated activation of notch in the endosomal trafficking pathway. Dev Cell 15:762–772
Willingham SB, Ho PY, Hotson A, Hill C, Piccione EC, Hsieh J et al (2018) A2AR antagonism with CPI-444 induces antitumor responses and augments efficacy to anti-PD-(L)1 and anti-CTLA-4 in preclinical models. Cancer Immunol Res 6:1136. https://doi.org/10.1158/2326-6066.CIR-18-0056
Xu J, Chi F, Guo T, Punj V, Lee WNP, French SW et al (2015) NOTCH reprograms mitochondrial metabolism for proinflammatory macrophage activation. J Clin Invest 125:1579–1590
Yamada K, Fuwa TJ, Ayukawa T, Tanaka T, Nakamura A, Wilkin MB et al (2011) Roles of Drosophila Deltex in Notch receptor endocytic trafficking and activation. Genes Cells 16:261–272
Yamamoto N, Yamamoto S, Inagaki F, Kawaichi M, Fukamizu A, Kishi N et al (2001) Role of Deltex-1 as a transcriptional regulator downstream of the Notch receptor. J Biol Chem 276:45031–45040
Yan M (2011) Therapeutic promise and challenges of targeting DLL4/NOTCH1. Vasc Cell 3:17
Yao W, Shan Z, Gu A, Fu M, Shi Z, Wen W (2018) WW domain-mediated regulation and activation of E3 ubiquitin ligase Suppressor of Deltex. J Biol Chem 293:16697–16708
Yen WC, Fischer MM, Axelrod F, Bond C, Cain J, Cancilla B et al (2015) Targeting notch signaling with a Notch2/Notch3 antagonist (Tarextumab) inhibits tumor growth and decreases tumor-initiating cell frequency. Clin Cancer Res 21:2084–2095
Zhang J, Shao X, Sun H, Liu K, Ding Z, Chen J et al (2016) NUMB negatively regulates the epithelial-mesenchymal transition of triple-negative breast cancer by antagonizing Notch signaling. Oncotarget 7:61036–61053
Zhao Z-L, Zhang L, Huang C-F, Ma S-R, Bu L-L, Liu J-F et al (2016a) NOTCH1 inhibition enhances the efficacy of conventional chemotherapeutic agents by targeting head neck cancer stem cell. Sci Rep 6:24704
Zhao E, Maj T, Kryczek I, Li W, Wu K, Zhao L et al (2016b) Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction. Nat Immunol 17:95–103
Zhou R, Wang S, Wen H, Wang M, Wu M (2019) The bispecific antibody HB-32, blockade of both VEGF and DLL4 shows potent anti-angiogenic activity in vitro and anti-tumor activity in breast cancer xenograft models. Exp Cell Res 380:141–148
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Monticone, G., Miele, L. (2021). Notch Pathway: A Journey from Notching Phenotypes to Cancer Immunotherapy. In: Reichrath, J., Reichrath, S. (eds) Notch Signaling in Embryology and Cancer. Advances in Experimental Medicine and Biology, vol 1287. Springer, Cham. https://doi.org/10.1007/978-3-030-55031-8_13
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