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:

Multiple intratumoral sources of kit ligand promote gastrointestinal stromal tumor

Oncogene volume 42, pages 2578–2588 (2023)Cite this article

Subjects

Abstract

Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and is typically driven by a single mutation in the Kit or PDGFRA receptor. While highly effective, tyrosine kinase inhibitors (TKIs) are not curative. The natural ligand for the Kit receptor is Kit ligand (KitL), which exists in both soluble and membrane-bound forms. While KitL is known to stimulate human GIST cell lines in vitro, we used a genetically engineered mouse model of GIST containing a common human KIT mutation to investigate the intratumoral sources of KitL, importance of KitL during GIST oncogenesis, and contribution of soluble KitL to tumor growth in vivo. We discovered that in addition to tumor cells, endothelia and smooth muscle cells produced KitL in KitV558Δ/+ tumors, even after imatinib therapy. Genetic reduction of total KitL in tumor cells of KitV558Δ/+ mice impaired tumor growth in vivo. Similarly, genetic reduction of tumor cell soluble KitL in KitV558Δ/+ mice decreased tumor size. By RNA sequencing, quantitative PCR, and immunohistochemistry, KitL expression was heterogeneous in human GIST specimens. In particular, PDGFRA-mutant tumors had much higher KitL expression than Kit-mutant tumors, suggesting the benefit of Kit activation in the absence of mutant KIT. Serum KitL was higher in GIST patients with tumors resistant to imatinib and in those with tumors expressing more KitL RNA. Overall, KitL supports the growth of GIST at baseline and after imatinib therapy and remains a potential biomarker and therapeutic target.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Kit ligand promotes oncogenic signaling in the presence of kinase inhibition.
Fig. 2: Multiple cell types within GIST produce Kit ligand.
Fig. 3: KitL is expressed in GIST despite tyrosine kinase inhibition.
Fig. 4: Human KitL expression varies by GIST mutation and treatment status.
Fig. 5: Kit ligand promotes GIST growth in vivo.

Similar content being viewed by others

Data availability

ScRNAseq data presented in this work are submitted through the Sequencing Read Archive under the accession number PRJNA945239. The remaining data generated and/or analyzed during the current study are available within the article and its Supplementary Data files or are available from the corresponding author upon reasonable request.

References

  1. Joensuu H, DeMatteo RP. The management of gastrointestinal stromal tumors: a model for targeted and multidisciplinary therapy of malignancy. Annu Rev Med. 2012;63:247–58.

    Article  CAS  PubMed  Google Scholar 

  2. Antonescu CR, Besmer P, Guo T, Arkun K, Hom G, Koryotowski B, et al. Acquired resistance to imatinib in gastrointestinal stromal tumor occurs through secondary gene mutation. Clin Cancer Res. 2005;11:4182–90.

    Article  CAS  PubMed  Google Scholar 

  3. Agaram NP, Besmer P, Wong GC, Guo T, Socci ND, Maki RG, et al. Pathologic and molecular heterogeneity in imatinib-stable or imatinib-responsive gastrointestinal stromal tumors. Clin Cancer Res. 2007;13:170–81.

    Article  CAS  PubMed  Google Scholar 

  4. Lyman SD, Jacobsen SE. c-kit ligand and Flt3 ligand: stem/progenitor cell factors with overlapping yet distinct activities. Blood. 1998;91:1101–34.

    Article  CAS  PubMed  Google Scholar 

  5. Huang E, Nocka K, Beier DR, Chu TY, Buck J, Lahm HW, et al. The hematopoietic growth factor KL is encoded by the Sl locus and is the ligand of the c-kit receptor, the gene product of the W locus. Cell 1990;63:225–33.

    Article  CAS  PubMed  Google Scholar 

  6. Lennartsson J, Ronnstrand L. Stem cell factor receptor/c-Kit: from basic science to clinical implications. Physiol Rev. 2012;92:1619–49.

    Article  CAS  PubMed  Google Scholar 

  7. Reber L, Da Silva CA, Frossard N. Stem cell factor and its receptor c-Kit as targets for inflammatory diseases. Eur J Pharm. 2006;533:327–40.

    Article  CAS  Google Scholar 

  8. Huang EJ, Nocka KH, Buck J, Besmer P. Differential expression and processing of two cell associated forms of the kit-ligand: KL-1 and KL-2. Mol Biol Cell. 1992;3:349–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Heissig B, Hattori K, Dias S, Friedrich M, Ferris B, Hackett NR, et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell. 2002;109:625–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Miyazawa K, Williams DA, Gotoh A, Nishimaki J, Broxmeyer HE, Toyama K. Membrane-bound Steel factor induces more persistent tyrosine kinase activation and longer life span of c-kit gene-encoded protein than its soluble form. Blood. 1995;85:641–9.

    Article  CAS  PubMed  Google Scholar 

  11. Yasuda A, Sawai H, Takahashi H, Ochi N, Matsuo Y, Funahashi H, et al. Stem cell factor/c-kit receptor signaling enhances the proliferation and invasion of colorectal cancer cells through the PI3K/Akt pathway. Dig Dis Sci. 2007;52:2292–300.

    Article  CAS  PubMed  Google Scholar 

  12. Zhang W, Stoica G, Tasca SI, Kelly KA, Meininger CJ. Modulation of tumor angiogenesis by stem cell factor. Cancer Res. 2000;60:6757–62.

    CAS  PubMed  Google Scholar 

  13. Hida T, Ueda R, Sekido Y, Hibi K, Matsuda R, Ariyoshi Y, et al. Ectopic expression of c-kit in small-cell lung cancer. Int J Cancer Suppl. 1994;8:108–9.

    Article  CAS  PubMed  Google Scholar 

  14. Krystal GW, Hines SJ, Organ CP. Autocrine growth of small cell lung cancer mediated by coexpression of c-kit and stem cell factor. Cancer Res. 1996;56:370–6.

    CAS  PubMed  Google Scholar 

  15. Hayashi Y, Asuzu DT, Gibbons SJ, Aarsvold KH, Bardsley MR, Lomberk GA, et al. Membrane-to-nucleus signaling links insulin-like growth factor-1- and stem cell factor-activated pathways. PLoS One. 2013;8:e76822.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bono P, Krause A, von Mehren M, Heinrich MC, Blanke CD, Dimitrijevic S, et al. Serum KIT and KIT ligand levels in patients with gastrointestinal stromal tumors treated with imatinib. Blood. 2004;103:2929–35.

    Article  CAS  PubMed  Google Scholar 

  17. Hirano K, Shishido-Hara Y, Kitazawa A, Kojima K, Sumiishi A, Umino M, et al. Expression of stem cell factor (SCF), a KIT ligand, in gastrointestinal stromal tumors (GISTs): a potential marker for tumor proliferation. Pathol Res Pract. 2008;204:799–807.

    Article  CAS  PubMed  Google Scholar 

  18. Theou-Anton N, Tabone S, Brouty-Boye D, Saffroy R, Ronnstrand L, Lemoine A, et al. Co expression of SCF and KIT in gastrointestinal stromal tumours (GISTs) suggests an autocrine/paracrine mechanism. Br J Cancer. 2006;94:1180–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sommer G, Agosti V, Ehlers I, Rossi F, Corbacioglu S, Farkas J, et al. Gastrointestinal stromal tumors in a mouse model by targeted mutation of the Kit receptor tyrosine kinase. Proc Natl Acad Sci USA. 2003;100:6706–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hou XW, Bai CG, Liu XH, Qiu C, Huang L, Xu JJ, et al. Expression of stem cell factor in gastrointestinal stromal tumors: Implications for proliferation and imatinib resistance. Oncol Lett. 2013;5:552–8.

    Article  CAS  PubMed  Google Scholar 

  21. Kim TS, Cavnar MJ, Cohen NA, Sorenson EC, Greer JB, Seifert AM, et al. Increased KIT inhibition enhances therapeutic efficacy in gastrointestinal stromal tumor. Clin Cancer Res. 2014;20:2350–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ding L, Saunders TL, Enikolopov G, Morrison SJ. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature. 2012;481:457–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Da Silva CA, Heilbock C, Kassel O, Frossard N. Transcription of stem cell factor (SCF) is potentiated by glucocorticoids and interleukin-1beta through concerted regulation of a GRE-like and an NF-kappaB response element. FASEB J. 2003;17:2334–6.

    Article  PubMed  Google Scholar 

  24. Grimaldi P, Capolunghi F, Geremia R, Rossi P. Cyclic adenosine monophosphate (cAMP) stimulation of the kit ligand promoter in sertoli cells requires an Sp1-binding region, a canonical TATA box, and a cAMP-induced factor binding to an immediately downstream GC-rich element. Biol Reprod. 2003;69:1979–88.

    Article  CAS  PubMed  Google Scholar 

  25. Hue J, Kim A, Song H, Choi I, Park H, Kim T, et al. IL-18 enhances SCF production of melanoma cells by regulating ROI and p38 MAPK activity. Immunol Lett. 2005;96:211–7.

    Article  CAS  PubMed  Google Scholar 

  26. Hollenbeck ST, Sakakibara K, Faries PL, Workhu B, Liu B, Kent KC. Stem cell factor and c-kit are expressed by and may affect vascular SMCs through an autocrine pathway. J Surg Res. 2004;120:288–94.

    Article  CAS  PubMed  Google Scholar 

  27. Tieniber AD, Hanna AN, Do K, Wang L, Rossi F, DeMatteo RP. Molecular and immunologic techniques in a genetically engineered mouse model of gastrointestinal stromal tumor. J Vis Exp. 2022.

  28. Rossi F, Ehlers I, Agosti V, Socci ND, Viale A, Sommer G, et al. Oncogenic Kit signaling and therapeutic intervention in a mouse model of gastrointestinal stromal tumor. Proc Natl Acad Sci USA. 2006;103:12843–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Vitiello GA, Bowler TG, Liu M, Medina BD, Zhang JQ, Param NJ, et al. Differential immune profiles distinguish the mutational subtypes of gastrointestinal stromal tumor. J Clin Investig. 2019;129:1863–77.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Han ZB, Ren H, Zhao H, Chi Y, Chen K, Zhou B, et al. Hypoxia-inducible factor (HIF)-1 alpha directly enhances the transcriptional activity of stem cell factor (SCF) in response to hypoxia and epidermal growth factor (EGF). Carcinogenesis. 2008;29:1853–61.

    Article  CAS  PubMed  Google Scholar 

  31. Cohen NA, Zeng S, Seifert AM, Kim TS, Sorenson EC, Greer JB, et al. Pharmacological inhibition of KIT activates MET signaling in gastrointestinal stromal tumors. Cancer Res. 2015;75:2061–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Treff NR, Dement GA, Adair JE, Britt RL, Nie R, Shima JE, et al. Human KIT ligand promoter is positively regulated by HMGA1 in breast and ovarian cancer cells. Oncogene. 2004;23:8557–62.

    Article  CAS  PubMed  Google Scholar 

  33. Balachandran VP, Cavnar MJ, Zeng S, Bamboat ZM, Ocuin LM, Obaid H, et al. Imatinib potentiates antitumor T cell responses in gastrointestinal stromal tumor through the inhibition of Ido. Nat Med. 2011;17:1094–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Asik M, Karakus S, Haznedaroglu IC, Goker H, Ozatli D, Buyukasik Y, et al. Bone marrow and peripheral blood C-kit ligand concentrations in patients with thrombocytosis and thrombocytopenia. Hematology. 2003;8:369–73.

    Article  CAS  PubMed  Google Scholar 

  35. Horvath VJ, Vittal H, Lorincz A, Chen H, Almeida-Porada G, Redelman D, et al. Reduced stem cell factor links smooth myopathy and loss of interstitial cells of cajal in murine diabetic gastroparesis. Gastroenterology. 2006;130:759–70.

    Article  CAS  PubMed  Google Scholar 

  36. Tajima Y, Moore MA, Soares V, Ono M, Kissel H, Besmer P. Consequences of exclusive expression in vivo of Kit-ligand lacking the major proteolytic cleavage site. Proc Natl Acad Sci USA. 1998;95:11903–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hynes NE, Lane HA. ERBB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer. 2005;5:341–54.

    Article  CAS  PubMed  Google Scholar 

  38. Matsumoto K, Umitsu M, De Silva DM, Roy A, Bottaro DP. Hepatocyte growth factor/MET in cancer progression and biomarker discovery. Cancer Sci. 2017;108:296–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Okamoto W, Okamoto I, Tanaka K, Hatashita E, Yamada Y, Kuwata K, et al. TAK-701, a humanized monoclonal antibody to hepatocyte growth factor, reverses gefitinib resistance induced by tumor-derived HGF in non-small cell lung cancer with an EGFR mutation. Mol Cancer Ther. 2010;9:2785–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yee NS, Hsiau CW, Serve H, Vosseller K, Besmer P. Mechanism of down-regulation of c-kit receptor. Roles of receptor tyrosine kinase, phosphatidylinositol 3'-kinase, and protein kinase C. J Biol Chem. 1994;269:31991–8.

    Article  CAS  PubMed  Google Scholar 

  41. Shimizu Y, Ashman LK, Du Z, Schwartz LB. Internalization of Kit together with stem cell factor on human fetal liver-derived mast cells: new protein and RNA synthesis are required for reappearance of Kit. J Immunol. 1996;156:3443–9.

    Article  CAS  PubMed  Google Scholar 

  42. Lemmon MA, Pinchasi D, Zhou M, Lax I, Schlessinger J. Kit receptor dimerization is driven by bivalent binding of stem cell factor. J Biol Chem. 1997;272:6311–7.

    Article  CAS  PubMed  Google Scholar 

  43. Liu H, Chen X, Focia PJ, He X. Structural basis for stem cell factor-KIT signaling and activation of class III receptor tyrosine kinases. EMBO J. 2007;26:891–901.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yuzawa S, Opatowsky Y, Zhang Z, Mandiyan V, Lax I, Schlessinger J. Structural basis for activation of the receptor tyrosine kinase KIT by stem cell factor. Cell. 2007;130:323–34.

    Article  CAS  PubMed  Google Scholar 

  45. Krimmer SG, Bertoletti N, Suzuki Y, Katic L, Mohanty J, Shu S, et al. Cryo-EM analyses of KIT and oncogenic mutants reveal structural oncogenic plasticity and a target for therapeutic intervention. Proc Natl Acad Sci USA. 2023;120:e2300054120.

    Article  CAS  PubMed  Google Scholar 

  46. Huang Z, Ruan HB, Xian L, Chen W, Jiang S, Song A, et al. The stem cell factor/Kit signalling pathway regulates mitochondrial function and energy expenditure. Nat Commun. 2014;5:4282.

    Article  CAS  PubMed  Google Scholar 

  47. Merchant JL, Du M, Todisco A. Sp1 phosphorylation by Erk 2 stimulates DNA binding. Biochem Biophys Res Commun. 1999;254:454–61.

    Article  CAS  PubMed  Google Scholar 

  48. Minet E, Ernest I, Michel G, Roland I, Remacle J, Raes M, et al. HIF1A gene transcription is dependent on a core promoter sequence encompassing activating and inhibiting sequences located upstream from the transcription initiation site and cis elements located within the 5'UTR. Biochem Biophys Res Commun. 1999;261:534–40.

    Article  CAS  PubMed  Google Scholar 

  49. Toyota M, Hinoda Y, Takaoka A, Makiguchi Y, Takahashi T, Itoh F, et al. Expression of c-kit and kit ligand in human colon carcinoma cells. Tumour Biol. 1993;14:295–302.

    Article  CAS  PubMed  Google Scholar 

  50. Bai C, Liu X, Qiu C, Zheng J. FoxM1 is regulated by both HIF-1alpha and HIF-2alpha and contributes to gastrointestinal stromal tumor progression. Gastric Cancer. 2019;22:91–103.

    Article  CAS  PubMed  Google Scholar 

  51. Huynh K. Meteorin-like protein repairs the ischaemic heart via receptor KIT in endothelial cells. Nat Rev Cardiol. 2022;19:575.

    PubMed  Google Scholar 

  52. Medina BD, Liu M, Vitiello GA, Seifert AM, Zeng S, Bowler T, et al. Oncogenic kinase inhibition limits Batf3-dependent dendritic cell development and antitumor immunity. J Exp Med. 2019;216:1359–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Tieniber AD, Hanna AN, Medina BD, Vitiello GA, Etherington MS, Liu M, et al. Tyrosine kinase inhibition alters intratumoral CD8 + T-cell subtype composition and activity. Cancer Immunol Res. 2022;10:1210–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Medina BD, Liu M, Vitiello GA, Seifert AM, Zeng S, Bowler T, et al. Oncogenic kinase inhibition limits Batf3-dependent dendritic cell development and antitumor immunity. J Exp Med. 2019;216:1359–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Seifert AM, Zeng S, Zhang JQ, Kim TS, Cohen NA, Beckman MJ, et al. PD-1/PD-L1 blockade enhances T-cell activity and antitumor efficacy of imatinib in gastrointestinal stromal tumors. Clin Cancer Res. 2017;23:454–65.

    Article  CAS  PubMed  Google Scholar 

  56. Vitiello GA, Medina BD, Zeng S, Bowler TG, Zhang JQ, Loo JK, et al. Mitochondrial inhibition augments the efficacy of imatinib by resetting the metabolic phenotype of gastrointestinal stromal tumor. Clin Cancer Res. 2018;24:972–84.

    Article  CAS  PubMed  Google Scholar 

  57. Satija R, Farrell JA, Gennert D, Schier AF, Regev A. Spatial reconstruction of single-cell gene expression data. Nat Biotechnol. 2015;33:495–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Hafemeister C, Satija R. Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression. Genome Biol. 2019;20:296.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Liu M, Etherington MS, Hanna A, Medina BD, Vitiello GA, Bowler TG, et al. Oncogenic KIT modulates Type I IFN-mediated antitumor immunity in GIST. Cancer Immunol Res. 2021;9:542–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

The investigators were supported by NIH grants R01 CA102613 and T32 CA251063 (RPD).

Author information

Author notes

  1. These authors contributed equally: Andrew D. Tieniber, Ferdinando Rossi.

Authors and Affiliations

  1. Department of Surgery, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

    Andrew D. Tieniber, Ferdinando Rossi, Andrew N. Hanna, Marion Liu, Mark S. Etherington, Jennifer K. Loo, Nesteene Param, Shan Zeng, Kevin Do, Laura Wang & Ronald P. DeMatteo

Authors
  1. Andrew D. Tieniber
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ferdinando Rossi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrew N. Hanna
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marion Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mark S. Etherington
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jennifer K. Loo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nesteene Param
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shan Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kevin Do
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Laura Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Ronald P. DeMatteo
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ADT: Conceptualization, data curation, formal analysis, validation, investigation, methodology, writing–original draft, writing—review and editing. FR: Conceptualization, data curation, formal analysis, validation, investigation, methodology, writing–original draft, writing–review and editing. ANH: Conceptualization, data curation, formal analysis, validation, writing–review and editing. ML: Conceptualization, Data curation, formal analysis. MSE: Data curation, formal analysis. JKL: Data curation, formal analysis. N. Param: Data curation, formal analysis. SZ: Data curation, formal analysis. KJD: Data curation, validation. LW: Data curation, validation. RPD: Conceptualization, resources, supervision, funding acquisition, writing–original draft, project administration, writing–review and editing.

Corresponding author

Correspondence to Ronald P. DeMatteo.

Ethics declarations

Competing interests

Research grant from BluePrint Medicines (RPD). The authors declare no potential conflicts of interest.

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

Tieniber, A.D., Rossi, F., Hanna, A.N. et al. Multiple intratumoral sources of kit ligand promote gastrointestinal stromal tumor. Oncogene 42, 2578–2588 (2023). https://doi.org/10.1038/s41388-023-02777-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-023-02777-5

Search

Advanced search

Quick links