Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

An FGFR-p53 developmental signaling axis drives salivary cancer progression

Oncogene (2025)Cite this article

Subjects

A Correction to this article was published on 20 June 2025

This article has been updated

Abstract

Mucoepidermoid carcinoma (MEC) is the most frequently occurring salivary gland malignancy. Here, we investigated transcriptomic profiles of human fetal and adult salivary glands and MEC tumors to assess programs involved in MEC progression. Molecular and genetic analyses revealed that MEC tumors and fetal salivary glands share proliferative and developmental gene expression profiles that implicate an FGFR-p53 signaling axis in salivary MEC progression. Based on these findings, we developed a genetically engineered mouse model of advanced MEC via targeted expression of the CRTC1-MAML2 oncogene in salivary ductal cells. Specifically, CRTC1-MAML2 expression combined with p53 dysregulation in salivary ducts rewires FGF signaling to drive formation of tumors with histological and molecular features of high-grade MEC. The combined bioinformatics and mouse modeling of this study demonstrate that salivary MEC progression is underpinned by reactivation of developmental signaling programs and suggests a role for FGFR targeted therapies in the treatment of high-grade MEC.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Fetal salivary glands and salivary MEC tumors share related transcriptional programs.
Fig. 2: High-grade salivary MEC tumors and developing fetal salivary glands are characterized by dysregulation of the p53 pathway.
Fig. 3: Cell type-specific targeting of CRTC1-MAML2 to murine salivary glands identifies Krt14-positive basal epithelial progenitors that drive early ductal pathogenesis.
Fig. 4: Dysregulation of p53 cooperates with C1/M2 to promote formation of tumors that share phenotypic hallmarks of human high-grade MEC.
Fig. 5: Alternative FGFR2 isoform usage establishes a pro-tumorigenic pathway in salivary MEC versus normal salivary glands.

Similar content being viewed by others

Data availability

The datasets generated during and/or analyzed during the current study are available in the NCBI Gene Expression Omnibus repository. The normalized gene expression data matrices and clinical annotation for this study are available at the Gene Expression Omnibus under GSE143702 and GSE282430.

Code availability

All computer code employed are commercially available. No custom computer code was generated or used for the analyses performed in this study.

Change history

  • 16 June 2025

    The original online version of this article was revised: In this article the author’s name Luane J. B. Landau was incorrectly written as Luane J. B. Landuau.

  • 20 June 2025

    A Correction to this paper has been published: https://doi.org/10.1038/s41388-025-03478-x

References

  1. Lee MY. Embryonic programs in cancer and metastasis-insights from the mammary gland. Front Cell Dev Biol. 2022;10:938625.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Coghe F, Fanni D, Gerosa C, Ravarino A, Mureddu M, Cerrone G, et al. The role of fetal programming in human carcinogenesis - may the Barker hypothesis explain interindividual variability in susceptibility to cancer insurgence and progression?. Eur Rev Med Pharm Sci. 2022;26:3585–92.

    CAS  Google Scholar 

  3. Balachandran S, Narendran A. The developmental origins of cancer: a review of the genes expressed in embryonic cells with implications for tumorigenesis. Genes. 2023;14:604.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Meacham CE, Morrison SJ. Tumour heterogeneity and cancer cell plasticity. Nature. 2013;501:328–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Junttila MR, de Sauvage FJ. Influence of tumour micro-environment heterogeneity on therapeutic response. Nature. 2013;501:346–54.

    Article  CAS  PubMed  Google Scholar 

  6. Stanta G, Bonin S. Overview on clinical relevance of intra-tumor heterogeneity. Front Med (Lausanne). 2018;5:85.

    Article  PubMed  Google Scholar 

  7. Dentro SC, Leshchiner I, Haase K, Tarabichi M, Wintersinger J, Deshwar AG, et al. Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes. Cell. 2021;184:2239–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Marusyk A, Janiszewska M, Polyak K. Intratumor heterogeneity: the Rosetta Stone of therapy resistance. Cancer Cell. 2020;37:471–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Gavish A, Tyler M, Greenwald AC, Hoefflin R, Simkin D, Tschernichovsky R, et al. Hallmarks of transcriptional intratumour heterogeneity across a thousand tumours. Nature. 2023;618:598–606.

    Article  CAS  PubMed  Google Scholar 

  10. Bleckmann SC, Blendy JA, Rudolph D, Monaghan AP, Schmid W, Schütz G. Activating transcription factor 1 and CREB are important for cell survival during early mouse development. Mol Cell Biol. 2002;22:1919–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Struthers RS, Vale WW, Arias C, Sawchenko PE, Montminy MR. Somatotroph hypoplasia and dwarfism in transgenic mice expressing a non-phosphorylatable CREB mutant. Nature. 1991;350:622–4.

    Article  CAS  PubMed  Google Scholar 

  12. Rosenberg D, Groussin L, Jullian E, Perlemoine K, Bertagna X, Bertherat J. Role of the PKA-regulated transcription factor CREB in development and tumorigenesis of endocrine tissues. Ann N Y Acad Sci. 2002;968:65–74.

    Article  CAS  PubMed  Google Scholar 

  13. Sundaram N, Tao Q, Wylie C, Heasman J. The role of maternal CREB in early embryogenesis of Xenopus laevis. Dev Biol. 2003;261:337–52.

    Article  CAS  PubMed  Google Scholar 

  14. Sakamoto KM, Frank DA. CREB in the pathophysiology of cancer: implications for targeting transcription factors for cancer therapy. Clin Cancer Res: J Am Assoc Cancer Res. 2009;15:2583–7.

    Article  CAS  Google Scholar 

  15. Conkright M, Montminy M. CREB: the unindicted cancer co-conspirator. Trends Cell Biol. 2005;15:457–9.

    Article  CAS  PubMed  Google Scholar 

  16. Steven A, Heiduk M, Recktenwald CV, Hiebl B, Wickenhauser C, Massa C, et al. Colorectal Carcinogenesis: Connecting K-RAS-Induced Transformation and CREB Activity In Vitro and In Vivo. Mol Cancer Res. 2015;13:1248–62.

    Article  CAS  PubMed  Google Scholar 

  17. Li B, Zheng L, Ye J, Zhang C, Zhou J, Huang Q, et al. CREB1 contributes colorectal cancer cell plasticity by regulating lncRNA CCAT1 and NF-kappaB pathways. Sci China Life Sci. 2022;65:1481–97.

    Article  CAS  PubMed  Google Scholar 

  18. Luna MA. Salivary mucoepidermoid carcinoma: revisited. Adv Anat Pathol. 2006;13:293–307.

    Article  PubMed  Google Scholar 

  19. O’Neill ID. t(11;19) translocation and CRTC1-MAML2 fusion oncogene in mucoepidermoid carcinoma. Oral Oncol. 2009;45:2–9.

    Article  PubMed  Google Scholar 

  20. Chen Z, Ni W, Li JL, Lin S, Zhou X, Sun Y. he CRTC1-MAML2 fusion is the major oncogenic driver in mucoepidermoid carcinoma. JCI Insight. 2021;6:e139497.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Chen J, Li JL, Chen Z, Griffin JD, Wu L. Gene expression profiling analysis of CRTC1-MAML2 fusion oncogene-induced transcriptional program in human mucoepidermoid carcinoma cells. BMC Cancer. 2015;15:803.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Wu L, Liu J, Gao P, Nakamura M, Cao Y, Shen H, et al. Transforming activity of MECT1-MAML2 fusion oncoprotein is mediated by constitutive CREB activation. EMBO J. 2005;24:2391–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Komiya T, Park Y, Modi S, Coxon AB, Oh H, Kaye FJ. Sustained expression of Mect1-Maml2 is essential for tumor cell growth in salivary gland cancers carrying the t(11;19) translocation. Oncogene. 2006;25:6128–32.

    Article  CAS  PubMed  Google Scholar 

  24. Amelio AL, Fallahi M, Schaub FX, Zhang M, Lawani MB, Alperstein AS, et al. CRTC1/MAML2 gain-of-function interactions with MYC create a gene signature predictive of cancers with CREB-MYC involvement. Proc Natl Acad Sci USA. 2014;111:E3260–E8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Musicant AM, Parag-Sharma K, Gong W, Sengupta M, Chatterjee A, Henry EC, et al. CRTC1/MAML2 directs a PGC-1alpha-IGF-1 circuit that confers vulnerability to PPARgamma inhibition. Cell Rep. 2021;34:108768.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Batsakis JG. Salivary gland neoplasia: an outcome of modified morphogenesis and cytodifferentiation. Oral Surg Oral Med Oral Pathol. 1980;49:229–32.

    Article  CAS  PubMed  Google Scholar 

  27. Brandwein MS, Ivanov K, Wallace DI, Hille JJ, Wang B, Fahmy A, et al. Mucoepidermoid carcinoma: a clinicopathologic study of 80 patients with special reference to histological grading. Am J Surg Pathol. 2001;25:835–45.

    Article  CAS  PubMed  Google Scholar 

  28. Goode RK, Auclair PL, Ellis GL. Mucoepidermoid carcinoma of the major salivary glands: clinical and histopathologic analysis of 234 cases with evaluation of grading criteria. Cancer. 1998;82:1217–24.

    Article  CAS  PubMed  Google Scholar 

  29. Katabi N, Ghossein R, Ali S, Dogan S, Klimstra D, Ganly I. Prognostic features in mucoepidermoid carcinoma of major salivary glands with emphasis on tumour histologic grading. Histopathology. 2014;65:793–804.

    Article  PubMed  Google Scholar 

  30. Hicks MJ, el-Naggar AK, Byers RM, Flaitz CM, Luna MA, Batsakis JG. Prognostic factors in mucoepidermoid carcinomas of major salivary glands: a clinicopathologic and flow cytometric study. Eur J Cancer B Oral Oncol. 1994;30B:329–34.

    Article  CAS  PubMed  Google Scholar 

  31. Spiro RH, Huvos AG, Berk R, Strong EW. Mucoepidermoid carcinoma of salivary-gland origin - clinicopathologic study of 367 cases. Am J Surg. 1978;136:461–8.

    Article  CAS  PubMed  Google Scholar 

  32. Fonseca I, Clode AL, Soares J. Mucoepidermoid carcinoma of major and minor salivary glands: a survey of 43 cases with study of prognostic indicators. Int J Surg Pathol. 1993;1:3–12.

    Article  Google Scholar 

  33. Saitou M, Gaylord EA, Xu E, May AJ, Neznanova L, Nathan S, et al. Functional specialization of human salivary glands and origins of proteins intrinsic to human saliva. Cell Rep. 2020;33:108402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Chen S, Zhou Y, Chen Y, Gu J. fastp: an ultra-fast all-in-one FASTQ preprocessor. Bioinformatics. 2018;34:i884–i90.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29:15–21.

    Article  CAS  PubMed  Google Scholar 

  36. Patro R, Duggal G, Love MI, Irizarry RA, Kingsford C. Salmon provides fast and bias-aware quantification of transcript expression. Nat Methods. 2017;14:417–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Huber W, Carey VJ, Gentleman R, Anders S, Carlson M, Carvalho BS, et al. Orchestrating high-throughput genomic analysis with Bioconductor. Nat Methods. 2015;12:115–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Liberzon A, Birger C, Thorvaldsdottir H, Ghandi M, Mesirov JP, Tamayo P. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 2015;1:417–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Grossman RL, Heath AP, Ferretti V, Varmus HE, Lowy DR, Kibbe WA, et al. Toward a shared vision for cancer genomic data. N Engl J Med. 2016;375:1109–12.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Shen S, Park JW, Lu ZX, Lin L, Henry MD, Wu YN, et al. rMATS: robust and flexible detection of differential alternative splicing from replicate RNA-Seq data. Proc Natl Acad Sci. 2014;111:E5593–E601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ramirez F, Ryan DP, Gruning B, Bhardwaj V, Kilpert F, Richter AS, et al. deepTools2: a next generation web server for deep-sequencing data analysis. Nucleic Acids Res. 2016;44:W160–W5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Roulis M, Nikolaou C, Kotsaki E, Kaffe E, Karagianni N, Koliaraki V, et al. Intestinal myofibroblast-specific Tpl2-Cox-2-PGE2 pathway links innate sensing to epithelial homeostasis. Proc Natl Acad Sci USA. 2014;111:E4658–E67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Blum R, Gupta R, Burger PE, Ontiveros CS, Salm SN, Xiong X, et al. Molecular signatures of prostate stem cells reveal novel signaling pathways and provide insights into prostate cancer. PLoS One. 2009;4:e5722.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Damrauer JS, Roell KR, Smith MA, Sun X, Kirk EL, Hoadley KA, et al. Identification of a Novel Inflamed Tumor Microenvironment Signature as a Predictive Biomarker of Bacillus Calmette-Guerin Immunotherapy in Non-Muscle-Invasive Bladder Cancer. Clin Cancer Res. 2021;27:4599–609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Maruyama EO, Aure MH, Xie X, Myal Y, Gan L, Ovitt CE. Cell-specific Cre strains for genetic manipulation in salivary glands. PLoS One. 2016;11:e0146711.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Shi G, Zhu L, Sun Y, Bettencourt R, Damsz B, Hruban RH, et al. Loss of the acinar-restricted transcription factor Mist1 accelerates Kras-induced pancreatic intraepithelial neoplasia. Gastroenterology. 2009;136:1368–78.

    Article  CAS  PubMed  Google Scholar 

  49. Schaub FX, Reza MS, Flaveny CA, Li W, Musicant AM, Hoxha S, et al. Fluorophore-NanoLuc BRET reporters enable sensitive in vivo optical imaging and flow cytometry for monitoring tumorigenesis. Cancer Res. 2015;75:5023–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Carper MB, Troutman S, Wagner BL, Byrd KM, Selitsky SR, Parag-Sharma K, et al. An immunocompetent mouse model of HPV16(+) head and neck squamous cell carcinoma. Cell Rep. 2019;29:1660–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Detre S, Saclani Jotti G, Dowsett M. A “quickscore” method for immunohistochemical semiquantitation: validation for oestrogen receptor in breast carcinomas. J Clin Pathol. 1995;48:876–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Tonon G, Modi S, Wu L, Kubo A, Coxon A, Komiya T, et al. t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Nat Genet. 2003;33:208–13.

    Article  CAS  PubMed  Google Scholar 

  53. Young L, Sung J, Stacey G, Masters JR. Detection of mycoplasma in cell cultures. Nat Protoc. 2010;5:929–34.

    Article  CAS  PubMed  Google Scholar 

  54. Spike BT, Engle DD, Lin JC, Cheung SK, La J, Wahl GM. A mammary stem cell population identified and characterized in late embryogenesis reveals similarities to human breast cancer. Cell Stem Cell. 2012;10:183–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Stanger BZ, Wahl GM. Cancer as a disease of development gone awry. Annu Rev Pathol. 2024;19:397–421.

    Article  CAS  PubMed  Google Scholar 

  56. Sole L, Lobo-Jarne T, Alvarez-Villanueva D, Alonso-Maranon J, Guillen Y, Guix M, et al. p53 wild-type colorectal cancer cells that express a fetal gene signature are associated with metastasis and poor prognosis. Nat Commun. 2022;13:2866.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Janky R, Verfaillie A, Imrichova H, Van de Sande B, Standaert L, Christiaens V, et al. iRegulon: from a gene list to a gene regulatory network using large motif and track collections. PLoS Comput Biol. 2014;10:e1003731.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Pandit B, Halasi M, Gartel AL. p53 negatively regulates expression of FoxM1. Cell Cycle. 2009;8:3425–7.

    Article  CAS  PubMed  Google Scholar 

  59. Barsotti AM, Prives C. Pro-proliferative FoxM1 is a target of p53-mediated repression. Oncogene. 2009;28:4295–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH, et al. Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell. 2005;7:469–83.

    Article  CAS  PubMed  Google Scholar 

  61. Wang K, McDermott JD, Schrock AB, Elvin JA, Gay L, Karam SD, et al. Comprehensive genomic profiling of salivary mucoepidermoid carcinomas reveals frequent BAP1, PIK3CA, and other actionable genomic alterations. Ann Oncol. 2017;28:748–53.

    Article  CAS  PubMed  Google Scholar 

  62. Wang X, Bai J, Yan J, Li B. The clinical outcome, pathologic spectrum, and genomic landscape for 454 cases of salivary mucoepidermoid carcinoma. NPJ Precis Oncol. 2024;8:238.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Gomes CC, Diniz MG, Orsine LA, Duarte AP, Fonseca-Silva T, Conn BI, et al. Assessment of TP53 mutations in benign and malignant salivary gland neoplasms. PLoS One. 2012;7:e41261.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Rodriguez-Ramirez C, Zhang Z, Warner KA, Herzog AE, Mantesso A, Zhang Z, et al. p53 inhibits Bmi-1-driven self-renewal and defines salivary gland cancer stemness. Clin Cancer Res. 2022;28:4757–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Andrews A, Warner K, Rodriguez-Ramirez C, Pearson AT, Nor F, Zhang Z, et al. Ablation of cancer stem cells by therapeutic inhibition of the MDM2-p53 interaction in mucoepidermoid carcinoma. Clin Cancer Res. 2019;25:1588–600.

    Article  CAS  PubMed  Google Scholar 

  66. Jaskoll T, Htet K, Abichaker G, Kaye FJ, Melnick M. CRTC1 expression during normal and abnormal salivary gland development supports a precursor cell origin for mucoepidermoid cancer. Gene Expr Patterns. 2011;11:57–63.

    Article  CAS  PubMed  Google Scholar 

  67. Adams A, Warner K, Pearson AT, Zhang Z, Kim HS, Mochizuki D, et al. ALDH/CD44 identifies uniquely tumorigenic cancer stem cells in salivary gland mucoepidermoid carcinomas. Oncotarget. 2015;6:26633–50.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Ninche N, Kwak M, Ghazizadeh S Diverse epithelial cell populations contribute to the regeneration of secretory units in injured salivary glands. Development. 2020;147.

  69. Batsakis JG, Regezi JA, Luna MA, el-Naggar A. Histogenesis of salivary gland neoplasms: a postulate with prognostic implications. J Laryngol Otol. 1989;103:939–44.

    Article  CAS  PubMed  Google Scholar 

  70. May AJ, Cruz-Pacheco N, Emmerson E, Gaylord EA, Seidel K, Nathan S, et al. Diverse progenitor cells preserve salivary gland ductal architecture after radiation-induced damage. Development. 2018;145.

  71. Aure MH, Konieczny SF, Ovitt CE. Salivary gland homeostasis is maintained through acinar cell self-duplication. Dev Cell. 2015;33:231–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Vasioukhin V, Degenstein L, Wise B, Fuchs E. The magical touch: genome targeting in epidermal stem cells induced by tamoxifen application to mouse skin. Proc Natl Acad Sci USA. 1999;96:8551–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Nitta M, Kume T, Nogawa H. FGF alters epithelial competence for EGF at the initiation of branching morphogenesis of mouse submandibular gland. Dev Dynam. 2009;238:315–23.

    Article  CAS  Google Scholar 

  74. Aure MH, Symonds JM, Villapudua CU, Dodge JT, Werner S, Knosp WM, et al. FGFR2 is essential for salivary gland duct homeostasis and MAPK-dependent seromucous acinar cell differentiation. Nat Commun. 2023;14:6485.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Mattingly A, Finley JK, Knox SM. Salivary gland development and disease. Wiley Interdiscip Rev Dev Biol. 2015;4:573–90.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Xie Y, Su N, Yang J, Tan Q, Huang S, Jin M, et al. FGF/FGFR signaling in health and disease. Signal Transduct Target Ther. 2020;5:181.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Beenken A, Mohammadi M. The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov. 2009;8:235–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Wang S, Sekiguchi R, Daley WP, Yamada KM. Patterned cell and matrix dynamics in branching morphogenesis. J Cell Biol. 2017;216:559–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Hsu JC, Yamada KM. Salivary gland branching morphogenesis-recent progress and future opportunities. Int J Oral Sci. 2010;2:117–26.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Musselmann K, Green JA, Sone K, Hsu JC, Bothwell IR, Johnson SA, et al. Salivary gland gene expression atlas identifies a new regulator of branching morphogenesis. J Dent Res. 2011;90:1078–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Yeh BK, Igarashi M, Eliseenkova AV, Plotnikov AN, Sher I, Ron D, et al. Structural basis by which alternative splicing confers specificity in fibroblast growth factor receptors. Proc Natl Acad Sci USA. 2003;100:2266–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Finburgh EN, Mauduit O, Noguchi T, Bu JJ, Abbas AA, Hakim DF, et al. Role of FGF10/FGFR2b Signaling in Homeostasis and Regeneration of Adult Lacrimal Gland and Corneal Epithelium Proliferation. Invest Ophthalmol Vis Sci. 2023;64:21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Epstein RJ, Tian LJ, Gu YF. 2b or not 2b: how opposing FGF receptor splice variants are blocking progress in precision oncology. J Oncol. 2021;2021:9955456.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Holzmann K, Grunt T, Heinzle C, Sampl S, Steinhoff H, Reichmann N, et al. Alternative Splicing of Fibroblast Growth Factor Receptor IgIII Loops in Cancer. J Nucleic Acids. 2012;2012:950508.

    Article  PubMed  Google Scholar 

  85. Amelio AL, Caputi M, Conkright MD. Bipartite functions of the CREB co-activators selectively direct alternative splicing or transcriptional activation. EMBO J. 2009;28:2733–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Tasoulas J, Srivastava S, Xu X, Tarasova V, Maniakas A, Karreth FA, et al. Genetically engineered mouse models of head and neck cancers. Oncogene. 2023;42:2593–609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Lombaert IM, Abrams SR, Li L, Eswarakumar VP, Sethi AJ, Witt RL, et al. Combined KIT and FGFR2b signaling regulates epithelial progenitor expansion during organogenesis. Stem Cell Rep. 2013;1:604–19.

    Article  CAS  Google Scholar 

  88. Emmerson E, Knox SM. Salivary gland stem cells: a review of development, regeneration and cancer. Genesis. 2018;56:e23211.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Chatzeli L, Bordeu I, Han S, Bisetto S, Waheed Z, Koo BK, et al. A cellular hierarchy of Notch and Kras signaling controls cell fate specification in the developing mouse salivary gland. Dev Cell. 2023;58:94–109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Mantovani F, Collavin L, Del Sal G. Mutant p53 as a guardian of the cancer cell. Cell Death Differ. 2019;26:199–212.

    Article  PubMed  Google Scholar 

  91. Bieging KT, Mello SS, Attardi LD. Unravelling mechanisms of p53-mediated tumour suppression. Nat Rev Cancer. 2014;14:359–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Rodriguez-Ramirez C, Nor JE. p53 and cell fate: sensitizing head and neck cancer stem cells to chemotherapy. Crit Rev Oncog. 2018;23:173–87.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Kiyoshima T, Shima K, Kobayashi I, Matsuo K, Okamura K, Komatsu S, et al. Expression of p53 tumor suppressor gene in adenoid cystic and mucoepidermoid carcinomas of the salivary glands. Oral Oncol. 2001;37:315–22.

    Article  CAS  PubMed  Google Scholar 

  94. Katoh M, Loriot Y, Brandi G, Tavolari S, Wainberg ZA, Katoh M. FGFR-targeted therapeutics: clinical activity, mechanisms of resistance and new directions. Nat Rev Clin Oncol. 2024;21:312–29.

    Article  PubMed  Google Scholar 

  95. Shoji K, Teishima J, Hayashi T, Ohara S, McKeehan WL, Matsubara A. Restoration of fibroblast growth factor receptor 2IIIb enhances the chemosensitivity of human prostate cancer cells. Oncol Rep. 2014;32:65–70.

    Article  CAS  PubMed  Google Scholar 

  96. Matsubara A, Teishima J, Mirkhat S, Yasumoto H, Mochizuki H, Seki M, et al. Restoration of FGF receptor type 2 enhances radiosensitivity of hormone-refractory human prostate carcinoma PC-3 cells. Anticancer Res. 2008;28:2141–6.

    PubMed  Google Scholar 

  97. Varghese JJ, Schmale IL, Wang Y, Hansen ME, Newlands SD, Ovitt CE, et al. Retroductal nanoparticle injection to the murine submandibular gland. J Vis Exp. 2018;e7521. https://doi.org/10.3791/57521.

  98. Troester MA, Herschkowitz JI, Oh DS, He X, Hoadley KA, Barbier CS, et al. Gene expression patterns associated with p53 status in breast cancer. BMC Cancer. 2006;6:276.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful for the support of previous and current members of the Amelio lab, with special thanks to Dr. Harish Bharambe for his technical expertise and assistance. We would also like to thank Gabriela De La Cruz and Bentley Midkiff in the Pathology Services Core and David Corcoran in the Lineberger Bioinformatics Core of the University of North Carolina at Chapel Hill for expert technical assistance with histological staining and fluorescent imaging. The Pathology Services Core is supported in part by an NCI Center Core Support Grant (P30-CA016086). In addition, the authors would like to acknowledge Dr. Jimena Guidice and Dr. Jessica Cote for their technical assistance. This work was also supported in part by Dr. Joseph Johnson and Brooke Smedley of the Analytic Microscopy Core, Jodi Balasi of the Tissue Core, and Dr. Mikalai Budzevich and Epi Ruiz of the Small Animal Imaging Lab at the Moffitt Cancer Center and Research Institute, a comprehensive cancer center designated by the National Cancer Institute and funded in part by Moffitt’s Cancer Center Support Grant (P30-CA076292). This work was supported in part by NIH/NIGMS T32-GM007092 and NIH/NIDCR F31-DE027282 training grants (to AMM), Head and Neck Cancer Fund (to TGH and DNH), NIH/NCATS-supported UL1-TR002489 UNC Translational Team Science Award (TTSA#026P1; to TGH and ALA), Moffitt Cancer Center funds (to ALA), and NIH/NIDCR R01-DE030123 (to ALA).

Author information

Author notes

  1. These authors contributed equally: Adele M. Musicant, Julia M. R. Billington.

Authors and Affiliations

  1. Graduate Curriculum in Genetics and Molecular Biology, Biological and Biomedical Sciences Program, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Adele M. Musicant

  2. Cancer Biology PhD Program, University of South Florida, Tampa, FL, USA

    Julia M. R. Billington

  3. Department of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA

    Julia M. R. Billington, Jay H. Mehta, John Powers & Antonio L. Amelio

  4. Department of Medicine, Division of Oncology, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Jeffrey S. Damrauer

  5. Bioinformatics Core, Lineberger Comprehensive Cancer Center, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Jennifer L. Modliszewski & Yi-Hsuan Tsai

  6. Department of Biological Sciences, University at Buffalo, Buffalo, NY, USA

    Luane J. B. Landau & Omer Gokcumen

  7. Department of Pathology and Laboratory Medicine, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Renee Betancourt

  8. Center for Cancer Research, University of Tennessee Health Sciences Center, Memphis, TN, USA

    Radhika Sekhri & D. Neil Hayes

  9. Division of Diagnostic Sciences, Adams School of Dentistry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Ricardo J. Padilla

  10. Department of Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA

    Juan C. Hernandez-Prera

  11. Department of Otolaryngology/Head and Neck Surgery, School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Trevor G. Hackman

  12. Department of Cell and Tissue Biology, University of California San Francisco, San Francisco, CA, USA

    Sarah M. Knox

  13. Program in Craniofacial Biology, University of California San Francisco, San Francisco, CA, USA

    Sarah M. Knox

  14. Department of Head and Neck-Endocrine Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA

    Antonio L. Amelio

Authors
  1. Adele M. Musicant
    View author publications

    Search author on:PubMed Google Scholar

  2. Julia M. R. Billington
    View author publications

    Search author on:PubMed Google Scholar

  3. Jeffrey S. Damrauer
    View author publications

    Search author on:PubMed Google Scholar

  4. Jennifer L. Modliszewski
    View author publications

    Search author on:PubMed Google Scholar

  5. Luane J. B. Landau
    View author publications

    Search author on:PubMed Google Scholar

  6. Yi-Hsuan Tsai
    View author publications

    Search author on:PubMed Google Scholar

  7. Jay H. Mehta
    View author publications

    Search author on:PubMed Google Scholar

  8. John Powers
    View author publications

    Search author on:PubMed Google Scholar

  9. Renee Betancourt
    View author publications

    Search author on:PubMed Google Scholar

  10. Radhika Sekhri
    View author publications

    Search author on:PubMed Google Scholar

  11. Ricardo J. Padilla
    View author publications

    Search author on:PubMed Google Scholar

  12. Juan C. Hernandez-Prera
    View author publications

    Search author on:PubMed Google Scholar

  13. D. Neil Hayes
    View author publications

    Search author on:PubMed Google Scholar

  14. Trevor G. Hackman
    View author publications

    Search author on:PubMed Google Scholar

  15. Omer Gokcumen
    View author publications

    Search author on:PubMed Google Scholar

  16. Sarah M. Knox
    View author publications

    Search author on:PubMed Google Scholar

  17. Antonio L. Amelio
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Conception and design: AMM, JMRB, and ALA. Development of methodology: AMM, JMRB, JSD, JHM, LJBL, Y-HT, and ALA. Acquisition of data (provided reagents, provided facilities, etc.): AMM, JMRB, JP, RB, and RS. Interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): AMM, JMRB, JSD, JHM, LJBL, Y-HT, JM, OG, SMK, and ALA. Writing of the manuscript: AMM, JMRB, and ALA. Review and revision of the manuscript: AMM, JMRB, JSD, JHM, LJBL, Y-HT, JM, JP, RB, RS, RJP, JCH-P, DNH, TGH, OG, SMK, and ALA. Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): JM, LJBL, Y-HT, JHM, RB, RS, OG, SMK, and ALA. Study supervision: OG, SMK, and ALA. Acquisition of funding: TGH and ALA.

Corresponding author

Correspondence to Antonio L. Amelio.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval

Research involving human tissues was reviewed and approved by the Institutional Review Boards at The University of North Carolina at Chapel Hill (IRB protocols 15-1604 and 17-2947) and University of California—San Francisco (IRB protocol 10-00768) and informed consent was obtained from all participants. Research involving murine tissues was reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of The University of North Carolina Chapel Hill (IACUC protocols 17-202 and 20-142), Moffitt Cancer Center and the University of South Florida (IACUC protocols 11291 M and 11379 R). All methods were performed in accordance with relevant guidelines and regulations.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Musicant, A.M., Billington, J.M.R., Damrauer, J.S. et al. An FGFR-p53 developmental signaling axis drives salivary cancer progression. Oncogene (2025). https://doi.org/10.1038/s41388-025-03444-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41388-025-03444-7

Search

Advanced search

Quick links