Current Stem Cell Research & TherapyCurrent Stem Cell Research & TherapyCurrent Stem Cell Research & Therapy1574-888X2212-3946Bentham Science64566310.2174/1574888X18666230213144531MedicineResearch ArticleSignaling Pathways in Drosophila gonadal Stem CellsEslahiMaedeinfo@benthamscience.netNematbakhshNegininfo@benthamscience.netDastmalchiNargesinfo@benthamscience.netTeimourianShahraminfo@benthamscience.netSafaralizadehRezainfo@benthamscience.netDepartment of Animal Biology, Faculty of Natural Sciences, University of TabrizDepartment of Biology, University College of Nabi AkramDepartment of Medical Genetics, Iran University of Medical Sciences0102202419215416511012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://journals.eco-vector.com/1574-888X/article/view/645663

The stem cells' ability to divide asymmetrically to produce differentiating and self-renewing daughter cells is crucial to maintain tissue homeostasis and development. Stem cell maintenance and differentiation rely on their regulatory microenvironment termed ‘niches’. The mechanisms of the signal transduction pathways initiated from the niche, regulation of stem cell maintenance and differentiation were quite challenging to study. The knowledge gained from the study of Drosophila melanogaster testis and ovary helped develop our understanding of stem cell/niche interactions and signal pathways related to the regulatory mechanisms in maintaining homeostasis of adult tissue. In this review, we discuss the role of signaling pathways in Drosophila gonadal stem cell regeneration, competition, differentiation, dedifferentiation, proliferation, and fate determination. Furthermore, we present the current knowledge on how these signaling pathways are implicated in cancer, and how they contribute as potential candidates for effective cancer treatment.

Germline stem cellssomatic stem cellsdrosophila testisdrosophila ovarybone morphogenetic protein (BMP)cancer.Wu AM, Till JE, Siminovitch L, McCulloch EA. A cytological study of the capacity for differentiation of normal hemopoietic colony-forming cells. J Cell Physiol 1967; 69(2): 177-84. doi: 10.1002/jcp.1040690208 PMID: 6033948Morrison SJ, Spradling AC. Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 2008; 132(4): 598-611. doi: 10.1016/j.cell.2008.01.038 PMID: 18295578Feng L, Shi Z, Chen X. Enhancer of polycomb coordinates multiple signaling pathways to promote both cyst and germline stem cell differentiation in the Drosophila adult testis. PLoS Genet 2017; 13(2): e1006571. doi: 10.1371/journal.pgen.1006571 PMID: 28196077de Cuevas M, Matunis EL. The stem cell niche: lessons from the Drosophila testis. Development 2011; 138(14): 2861-9. doi: 10.1242/dev.056242 PMID: 21693509Matunis EL, Stine RR, de Cuevas M. Recent advances in Drosophila male germline stem cell biology. Spermatogenesis 2012; 2(3): 137-44. doi: 10.4161/spmg.21763 PMID: 23087833Dansereau DA, Lasko P. The development of germline stem cells in Drosophila. Methods Mol Biol 2008; 450: 3-26. doi: 10.1007/978-1-60327-214-8_1Fuller MT, Spradling AC. Male and female Drosophila germline stem cells: two versions of immortality. Science 2007; 316(5823): 402-4. doi: 10.1126/science.1140861 PMID: 17446390Gönczy P, DiNardo S. The germ line regulates somatic cyst cell proliferation and fate during Drosophila spermatogenesis. Development 1996; 122(8): 2437-47. doi: 10.1242/dev.122.8.2437 PMID: 8756289Zoller R, Schulz C. The Drosophila cyst stem cell lineage. Spermatogenesis 2012; 2(3): 145-57. doi: 10.4161/spmg.21380 PMID: 23087834Singh SR, Zheng Z, Wang H, Oh SW, Chen X, Hou SX. Competitiveness for the niche and mutual dependence of the germline and somatic stem cells in the Drosophila testis are regulated by the JAK/STAT signaling. J Cell Physiol 2010; 223(2): 500-10. PMID: 20143337Yamashita YM, Jones DL, Fuller MT. Orientation of asymmetric stem cell division by the APC tumor suppressor and centrosome. Science 2003; 301(5639): 1547-50. doi: 10.1126/science.1087795 PMID: 12970569La Marca JE, Somers WG. The Drosophila gonads: models for stem cell proliferation, self-renewal, and differentiation. AIMS Genetics 2014; 1(01): 055-80. doi: 10.3934/genet.2014.1.55Tulina N, Matunis E. Control of stem cell self-renewal in Drosophila spermatogenesis by JAK-STAT signaling. Science 2001; 294(5551): 2546-9. doi: 10.1126/science.1066700 PMID: 11752575Kawase E, Wong MD, Ding BC, Xie T. Gbb/Bmp signaling is essential for maintaining germline stem cells and for repressing bam transcription in the Drosophila testis. Development 2004; 131(6): 1365-75.Kalderon D. The mechanism of hedgehog signal transduction. Biochem Soc Trans 2005; 33(6): 1509-12. doi: 10.1042/BST0331509 PMID: 16246157Lusk J, Lam V, Tolwinski N. Epidermal growth factor pathway signaling in Drosophila embryogenesis: tools for understanding cancer. Cancers (Basel) 2017; 9(12): 16. doi: 10.3390/cancers9020016 PMID: 28178204Waghmare I, Page-McCaw A. Wnt signaling in stem cell maintenance and differentiation in the Drosophila Germarium. Genes (Basel) 2018; 9(3): 127. doi: 10.3390/genes9030127 PMID: 29495453Greenspan LJ, de Cuevas M, Matunis E. Genetics of gonadal stem cell renewal. Annu Rev Cell Dev Biol 2015; 31(1): 291-315. doi: 10.1146/annurev-cellbio-100913-013344 PMID: 26355592Bate M, Arias AM. The development of Drosophila melanogaster. Cold Spring Harbor Laboratory Press New York 1993.Greenspan LJ, Matunis EL. Retinoblastoma intrinsically regulates niche cell quiescence, identity, and niche number in the adult Drosophila testis. Cell Rep 2018; 24(13): 3466-76. doi: 10.1016/j.celrep.2018.08.083Voog J, D’Alterio C, Jones DL. Multipotent somatic stem cells contribute to the stem cell niche in the Drosophila testis. Nature 2008; 454(7208): 1132-6. doi: 10.1038/nature07173 PMID: 18641633Zhao T, Xiao Y, Huang B, et al. A dual role of lola in Drosophila ovary development: regulating stem cell niche establishment and repressing apoptosis. Cell Death Dis 2022; 13(9): 756. doi: 10.1038/s41419-022-05195-9 PMID: 36056003Greenspan LJ, de Cuevas M, Le KH, Viveiros JM, Matunis EL. Activation of the EGFR/MAPK pathway drives transdifferentiation of quiescent niche cells to stem cells in the Drosophila testis niche. eLife 2022; 11: e70810. doi: 10.7554/eLife.70810 PMID: 35468055White-Cooper H. Molecular mechanisms of gene regulation during Drosophila spermatogenesis. Reproduction 2010; 139(1): 11-21. doi: 10.1530/REP-09-0083 PMID: 19755484Zhang H, Cai Y. Signal transduction pathways regulating Drosophila ovarian germline stem cells. Curr Opin Insect Sci 2020; 37: 1-7. doi: 10.1016/j.cois.2019.10.002 PMID: 31726320Kirilly D, Xie T. The Drosophila ovary: an active stem cell community. Cell Res 2007; 17(1): 15-25. doi: 10.1038/sj.cr.7310123 PMID: 17199109Sahai-Hernandez P, Castanieto A, Nystul TG. Drosophila models of epithelial stem cells and their niches. Wiley Interdiscip Rev Dev Biol 2012; 1(3): 447-57. doi: 10.1002/wdev.36 PMID: 23801493Kirilly D, Wang S, Xie T. Self-maintained escort cells form a germline stem cell differentiation niche. Development 2011; 138(23): 5087-97. doi: 10.1242/dev.067850 PMID: 22031542Xie T, Spradling AC. A niche maintaining germ line stem cells in the Drosophila ovary. Science 2000; 290(5490): 328-30. doi: 10.1126/science.290.5490.328 PMID: 11030649Decotto E, Spradling AC. The Drosophila ovarian and testis stem cell niches: similar somatic stem cells and signals. Dev Cell 2005; 9(4): 501-10. doi: 10.1016/j.devcel.2005.08.012 PMID: 16198292Song X, Zhu CH, Doan C, Xie T. Germline stem cells anchored by adherens junctions in the Drosophila ovary niches. Science 2002; 296(5574): 1855-7. doi: 10.1126/science.1069871 PMID: 12052957Margolis J, Spradling A. Identification and behavior of epithelial stem cells in the Drosophila ovary. Development 1995; 121(11): 3797-807. doi: 10.1242/dev.121.11.3797 PMID: 8582289Heldin CH, Miyazono K, ten Dijke P. TGF-β signalling from cell membrane to nucleus through SMAD proteins. Nature 1997; 390(6659): 465-71. doi: 10.1038/37284 PMID: 9393997Chen D, McKearin D. Dpp signaling silences bam transcription directly to establish asymmetric divisions of germline stem cells. Curr Biol 2003; 13(20): 1786-91. doi: 10.1016/j.cub.2003.09.033 PMID: 14561403Song X, Wong MD, Kawase E, et al. Bmp signals from niche cells directly repress transcription of a differentiation-promoting gene, bag of marbles, in germline stem cells in the Drosophila ovary. Development 2004; 131(6): 1353-64. doi: 10.1242/dev.01026Kirilly D, Spana EP, Perrimon N, Padgett RW, Xie T. BMP signaling is required for controlling somatic stem cell self-renewal in the Drosophila ovary. Dev Cell 2005; 9(5): 651-62. doi: 10.1016/j.devcel.2005.09.013 PMID: 16256740Liu M, Lim TM, Cai Y. The Drosophila female germline stem cell lineage acts to spatially restrict DPP function within the niche. Sci Signal 2010; 3(132): ra57. doi: 10.1126/scisignal.2000740 PMID: 20664066Raz AA, Yamashita YM. Stem cell niche signaling goes both ways. Dev Cell 2021; 56(16): 2267-8. doi: 10.1016/j.devcel.2021.08.003 PMID: 34428394Harrison DA, McCoon PE, Binari R, Gilman M, Perrimon N. Drosophila unpaired encodes a secreted protein that activates the JAK signaling pathway. Genes Dev 1998; 12(20): 3252-63. doi: 10.1101/gad.12.20.3252 PMID: 9784499Kiger AA, Jones DL, Schulz C, Rogers MB, Fuller MT. Stem cell self-renewal specified by JAK-STAT activation in response to a support cell cue. Science 2001; 294(5551): 2542-5. doi: 10.1126/science.1066707 PMID: 11752574Issigonis M, Tulina N, de Cuevas M, Brawley C, Sandler L, Matunis E. JAK-STAT signal inhibition regulates competition in the Drosophila testis stem cell niche. Science 2009; 326(5949): 153-6. doi: 10.1126/science.1176817 PMID: 19797664Arbouzova NI, Zeidler MP. JAK/STAT signalling in Drosophila: Insights into conserved regulatory and cellular functions. Development 2006; 133(14): 2605-16.Herrera SC, Bach EA. JAK/STAT signaling in stem cells and regeneration: from Drosophila to vertebrates. Development 2019; 146(2): dev167643. doi: 10.1242/dev.167643 PMID: 30696713Leatherman JL, DiNardo S. Zfh-1 controls somatic stem cell self-renewal in the Drosophila testis and nonautonomously influences germline stem cell self-renewal. Cell Stem Cell 2008; 3(1): 44-54. doi: 10.1016/j.stem.2008.05.001 PMID: 18593558Flaherty MS, Salis P, Evans CJ, et al. chinmo is a functional effector of the JAK/STAT pathway that regulates eye development, tumor formation, and stem cell self-renewal in Drosophila. Dev Cell 2010; 18(4): 556-68. doi: 10.1016/j.devcel.2010.02.006 PMID: 20412771López-Onieva L, Fernández-Miñán A, González-Reyes A. Jak/Stat signalling in niche support cells regulates dpp transcription to control germline stem cell maintenance in the Drosophila ovary. Development 2008; 135(3): 533-40.Michel M, Kupinski AP, Raabe I, Bökel C. Hh signalling is essential for somatic stem cell maintenance in the Drosophila testis niche. Development 2012; 139(15): 2663-9. doi: 10.1242/dev.075242 PMID: 22745310Zhang Z, Pan C, Zhao Y. Hedgehog in the Drosophila testis niche: what does it do there? Protein Cell 2013; 4(9): 650-5. doi: 10.1007/s13238-013-3040-y PMID: 23807635Tabata T, Kornberg TB. Hedgehog is a signaling protein with a key role in patterning Drosophila imaginal discs. Cell 1994; 76(1): 89-102. doi: 10.1016/0092-8674(94)90175-9 PMID: 8287482Chen Y, Struhl G. Dual roles for patched in sequestering and transducing Hedgehog. Cell 1996; 87(3): 553-63. doi: 10.1016/S0092-8674(00)81374-4 PMID: 8898207Alcedo J, Ayzenzon M, Von Ohlen T, Noll M, Hooper JE. The Drosophila smoothened gene encodes a seven-pass membrane protein, a putative receptor for the hedgehog signal. Cell 1996; 86(2): 221-32. doi: 10.1016/S0092-8674(00)80094-X PMID: 8706127Domínguez M, Brunner M, Hafen E, Basler K. Sending and receiving the hedgehog signal: control by the Drosophila Gli protein Cubitus interruptus. Science 1996; 272(5268): 1621-5. doi: 10.1126/science.272.5268.1621 PMID: 8658135Amoyel M, Sanny J, Burel M, Bach EA. Hedgehog is required for CySC self-renewal but does not contribute to the GSC niche in the Drosophila testis. Development 2013; 140(1): 56-65. doi: 10.1242/dev.086413 PMID: 23175633Méthot N, Basler K. Hedgehog controls limb development by regulating the activities of distinct transcriptional activator and repressor forms of Cubitus interruptus. Cell 1999; 96(6): 819-31. doi: 10.1016/S0092-8674(00)80592-9 PMID: 10102270Li S, Wang M, Chen Y, et al. Role of the hedgehog signaling pathway in regulating the behavior of germline stem cells. Stem Cells Int 2017; 2017: 5714608. doi: 10.1155/2017/5714608Forbes AJ, Lin H, Ingham PW, Spradling AC. hedgehog is required for the proliferation and specification of ovarian somatic cells prior to egg chamber formation in Drosophila. Development 1996; 122(4): 1125-35. doi: 10.1242/dev.122.4.1125 PMID: 8620839Rojas-Ríos P, Guerrero I, González-Reyes A. Cytoneme-mediated delivery of hedgehog regulates the expression of bone morphogenetic proteins to maintain germline stem cells in Drosophila. PLoS Biol 2012; 10(4): e1001298. doi: 10.1371/journal.pbio.1001298 PMID: 22509132Lai CM, Lin KY, Kao SH, Chen YN, Huang F, Hsu HJ. Hedgehog signaling establishes precursors for germline stem cell niches by regulating cell adhesion. J Cell Biol 2017; 216(5): 1439-53. doi: 10.1083/jcb.201610063 PMID: 28363970Yatsenko AS, Shcherbata HR. Distant activation of Notch signaling induces stem cell niche assembly. PLoS Genet 2021; 17(3): e1009489. doi: 10.1371/journal.pgen.1009489 PMID: 33780456Glittenberg M, Pitsouli C, Garvey C, Delidakis C, Bray S. Role of conserved intracellular motifs in Serrate signalling, cis-inhibition and endocytosis. EMBO J 2006; 25(20): 4697-706. doi: 10.1038/sj.emboj.7601337 PMID: 17006545Kitadate Y, Shigenobu S, Arita K, Kobayashi S. Boss/Sev signaling from germline to soma restricts germline-stem-cell-niche formation in the anterior region of Drosophila male gonads. Dev Cell 2007; 13(1): 151-9. doi: 10.1016/j.devcel.2007.05.001 PMID: 17609117Le Bras S, Van Doren M. Development of the male germline stem cell niche in Drosophila. Dev Biol 2006; 294(1): 92-103. doi: 10.1016/j.ydbio.2006.02.030 PMID: 16566915Brower DL, Smith RJ, Wilcox M. Differentiation within the gonads of Drosophila revealed by immunofluorescence. J Embryol Exp Morphol 1981; 63: 233-42. doi: 10.1242/dev.63.1.233Song X, Call GB, Kirilly D, Xie T. Notch signaling controls germline stem cell niche formation in the Drosophila ovary. Development 2007; 134(6): 1071-80.Zheng Q, Chen X, Qiao C, et al. Somatic CG6015 mediates cyst stem cell maintenance and germline stem cell differentiation via EGFR signaling in Drosophila testes. Cell Death Discov 2021; 7(1): 68. doi: 10.1038/s41420-021-00452-w PMID: 33824283Sahadevan M, Kumar PG. Notch signaling in spermatogenesis and male, (in), fertility Molecular Signaling in Spermatogenesis and Male Infertility. CRC Press 2019; pp. 117-32. doi: 10.1201/9780429244216-12Schulz C, Wood CG, Jones DL, Tazuke SI, Fuller MT. Signaling from germ cells mediated by the rhomboid homolog stet organizes encapsulation by somatic support cells. Development 2002; 129(19): 4523-34.Rutledge BJ, Zhang K, Bier E, Jan YN, Perrimon N. The Drosophila spitz gene encodes a putative EGF-like growth factor involved in dorsal-ventral axis formation and neurogenesis. Genes Dev 1992; 6(8): 1503-17. doi: 10.1101/gad.6.8.1503 PMID: 1644292Shilo BZ. The regulation and functions of MAPK pathways in Drosophila. Methods 2014; 68(1): 151-9. doi: 10.1016/j.ymeth.2014.01.020 PMID: 24530508Marais R, Light Y, Paterson HF, Marshall CJ. Ras recruits Raf-1 to the plasma membrane for activation by tyrosine phosphorylation. EMBO J 1995; 14(13): 3136-45. doi: 10.1002/j.1460-2075.1995.tb07316.x PMID: 7542586Oellers N, Hafen E. Biochemical characterization of rolledSem, an activated form of Drosophila mitogen-activated protein kinase. J Biol Chem 1996; 271(40): 24939-44. doi: 10.1074/jbc.271.40.24939 PMID: 8798773Gupta S, Varshney B, Chatterjee S, Ray K. Somatic ERK activation during transit amplification is essential for maintaining the synchrony of germline divisions in Drosophila testis. Open Biol 2018; 8(7): 180033. doi: 10.1098/rsob.180033 PMID: 30045884Matsuoka S, Hiromi Y, Asaoka M. Egfr signaling controls the size of the stem cell precursor pool in the Drosophila ovary. Mech Dev 2013; 130(4-5): 241-53. doi: 10.1016/j.mod.2013.01.002 PMID: 23376160Castanieto A, Johnston MJ, Nystul TG. EGFR signaling promotes self-renewal through the establishment of cell polarity in Drosophila follicle stem cells. eLife 2014; 3: e04437. doi: 10.7554/eLife.04437 PMID: 25437306Gilboa L, Lehmann R. Soma–germline interactions coordinate homeostasis and growth in the Drosophila gonad. Nature 2006; 443(7107): 97-100. doi: 10.1038/nature05068 PMID: 16936717Wang M, Luan X, Yan Y, Zheng Q, Chen W, Fang J. Wnt6 regulates the homeostasis of the stem cell niche via Rac1-and Cdc42-mediated noncanonical Wnt signalling pathways in Drosophila testis. Exp Cell Res 2021; 402(1): 112511. doi: 10.1016/j.yexcr.2021.112511 PMID: 33582096Tomlinson A, Strapps WR, Heemskerk J. Linking Frizzled and Wnt signaling in Drosophila development. Development 1997; 124(22): 4515-21. doi: 10.1242/dev.124.22.4515 PMID: 9409669Bejsovec A. Wingless/Wnt signaling in Drosophila: The pattern and the pathway. Mol Reprod Dev 2013; 80(11): 882-94. doi: 10.1002/mrd.22228 PMID: 24038436Wang S, Gao Y, Song X, et al. Wnt signaling-mediated redox regulation maintains the germ line stem cell differentiation niche. eLife 2015; 4: e08174. doi: 10.7554/eLife.08174 PMID: 26452202Song X, Xie T. Wingless signaling regulates the maintenance of ovarian somatic stem cells in Drosophila. Development 2003; 130(14): 3259-68.Luo L, Wang H, Fan C, Liu S, Cai Y. Wnt ligands regulate Tkv expression to constrain Dpp activity in the Drosophila ovarian stem cell niche. J Cell Biol 2015; 209(4): 595-608. doi: 10.1083/jcb.201409142 PMID: 26008746Reilein A, Melamed D, Park KS, et al. Alternative direct stem cell derivatives defined by stem cell location and graded Wnt signalling. Nat Cell Biol 2017; 19(5): 433-44. doi: 10.1038/ncb3505 PMID: 28414313Tu R, Duan B, Song X, Xie T. Dlp-mediated Hh and Wnt signaling interdependence is critical in the niche for germline stem cell progeny differentiation. Sci Adv 2020; 6(20): eaaz0480. doi: 10.1126/sciadv.aaz0480 PMID: 32426496Yang L, Shi P, Zhao G, et al. Targeting cancer stem cell pathways for cancer therapy. Signal Transduct Target Ther 2020; 5(1): 8. doi: 10.1038/s41392-020-0110-5 PMID: 32296030Arnold CR, Mangesius J, Skvortsova II, Ganswindt U. The role of cancer stem cells in radiation resistance. Front Oncol 2020; 10: 164. doi: 10.3389/fonc.2020.00164 PMID: 32154167Phi LTH, Sari IN, Yang YG, et al. Cancer Stem Cells (CSCs) in drug resistance and their therapeutic implications in cancer treatment. Stem Cells Int 2018; 28; 2018: 5416923.Safa AR. Resistance to cell death and its modulation in cancer stem cells. CRO 2016; 21(3-4): 203-19. doi: 10.1615/CritRevOncog.2016016976Mu J, Hui T, Shao B, et al. Dickkopf-related protein 2 induces G0/G1 arrest and apoptosis through suppressing Wnt/β-catenin signaling and is frequently methylated in breast cancer. Oncotarget 2017; 8(24): 39443-59. doi: 10.18632/oncotarget.17055 PMID: 28467796Giancotti FG. Mechanisms governing metastatic dormancy and reactivation. Cell 2013; 155(4): 750-64. doi: 10.1016/j.cell.2013.10.029 PMID: 24209616Liang J, Cao R, Wang X, et al. Mitochondrial PKM2 regulates oxidative stress-induced apoptosis by stabilizing Bcl2. Cell Res 2017; 27(3): 329-51. doi: 10.1038/cr.2016.159 PMID: 28035139Zhang K, Guo Y, Wang X, et al. WNT/β-catenin directs self-renewal symmetric cell division of hTERThigh prostate cancer stem cells. Cancer Res 2017; 77(9): 2534-47. doi: 10.1158/0008-5472.CAN-16-1887 PMID: 28209613Ji C, Yang L, Yi W, et al. Capillary morphogenesis gene 2 maintains gastric cancer stem-like cell phenotype by activating a Wnt/β-catenin pathway. Oncogene 2018; 37(29): 3953-66. doi: 10.1038/s41388-018-0226-z PMID: 29662192Schwitalla S, Fingerle AA, Cammareri P, et al. Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell 2013; 152(1-2): 25-38. doi: 10.1016/j.cell.2012.12.012 PMID: 23273993Wu F, Stutzman A, Mo Y-Y. Notch signaling and its role in breast cancer. Front Biosci 2007; 12(8-12): 4370-83. doi: 10.2741/2394 PMID: 17485381Zhou W, Fu X, Zhang L, et al. The AKT1/NF-kappaB/Notch1/PTEN axis has an important role in chemoresistance of gastric cancer cells. Cell Death Dis 2013; 4(10): e847.Zhang Y, Li B, Ji ZZ, Zheng PS. Notch1 regulates the growth of human colon cancers. Cancer 2010; 116(22): 5207-18. doi: 10.1002/cncr.25449 PMID: 20665495Konishi J, Yi F, Chen X, Vo H, Carbone DP, Dang TP. Notch3 cooperates with the EGFR pathway to modulate apoptosis through the induction of bim. Oncogene 2010; 29(4): 589-96. doi: 10.1038/onc.2009.366 PMID: 19881544Lefort K, Mandinova A, Ostano P, et al. Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCKα kinases. Genes Dev 2007; 21(5): 562-77. doi: 10.1101/gad.1484707 PMID: 17344417Gupta A, Wang Y, Browne C, et al. Neuroendocrine differentiation in the 12T-10 transgenic prostate mouse model mimics endocrine differentiation of pancreatic beta cells. Prostate 2008; 68(1): 50-60. doi: 10.1002/pros.20650 PMID: 18004726Viatour P, Ehmer U, Saddic LA, et al. Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway. J Exp Med 2011; 208(10): 1963-76. doi: 10.1084/jem.20110198 PMID: 21875955Harrison H, Farnie G, Howell SJ, et al. Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Res 2010; 70(2): 709-18. doi: 10.1158/0008-5472.CAN-09-1681 PMID: 20068161Gao AH, Hu YR, Zhu WP. IFN-γ inhibits ovarian cancer progression via SOCS1/JAK/STAT signaling pathway. Clin Transl Oncol 2022; 24(1): 57-65. doi: 10.1007/s12094-021-02668-9 PMID: 34275119Berry DC, Levi L, Noy N. Holo-retinol-binding protein and its receptor STRA6 drive oncogenic transformation. Cancer Res 2014; 74(21): 6341-51. doi: 10.1158/0008-5472.CAN-14-1052 PMID: 25237067Yang L, Dong Y, Li Y, et al. IL‐10 derived from M2 macrophage promotes cancer stemness via JAK1/STAT1/NF‐κB/Notch1 pathway in non‐small cell lung cancer. Int J Cancer 2019; 145(4): 1099-110. doi: 10.1002/ijc.32151 PMID: 30671927Brawley C, Matunis E. Regeneration of male germline stem cells by spermatogonial dedifferentiation in vivo. Science 2004; 304(5675): 1331-4. doi: 10.1126/science.1097676 PMID: 15143218Sun X, Yu Q. Intra-tumor heterogeneity of cancer cells and its implications for cancer treatment. Acta Pharmacol Sin 2015; 36(10): 1219-27. doi: 10.1038/aps.2015.92 PMID: 26388155Kumar V, Vashishta M, Kong L, et al. The role of Notch, Hedgehog, and Wnt signaling pathways in the resistance of tumors to anticancer therapies. Front Cell Dev Biol 2021; 9: 650772. doi: 10.3389/fcell.2021.650772 PMID: 33968932