Soft tissue sarcoma (STS) is a highly malignant tumor with limited targeted therapies. A novel anaplastic lymphoma kinase (ALK) transcript, ALKATI, was identified recently and could be targeted by ALK inhibitors in melanoma. However, the clinical and functional role of aberrant ALKATI expression in STS remains unknown. Here we demonstrate that as a new ALK transcript, ALKATI is frequently found in STS. ALKATI expression correlates with a lower probability of progression-free survival in STS patients. Compared with the other ALK isoforms, ALKATI expresses not only in the cytoplasm, but also in the nucleus of sarcoma cells. Functionally, overexpression of ALKATI promoted cancer stem cell (CSC)-like properties in sarcoma cells by promoting sphere formation and upregulating the expression of stem cell markers. Moreover, the ALK inhibitors not only suppressed the oncogenic functions of ALKATI but also attenuated ALKATI-induced CSC-like properties by reducing the expression of stem cell markers such as c-Myc, ABCG2, BMI1, and OCT4 both in vitro and in vivo. Furthermore, ALKATI interacted with c-Myc and increased the binding of c-Myc to the ABCG2 promoter, resulting in the induction of stem cell-like properties. Together, these findings indicate that ALKATI may be a potential prognostic marker and therapeutic target for STS patients harboring such ALK aberrations.
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Toro JR, Travis LB, Wu HJ, Zhu K, Fletcher CD, Devesa SS. Incidence patterns of soft tissue sarcomas, regardless of primary site, in the surveillance, epidemiology and end results program, 1978–2001: an analysis of 26,758 cases. Int J Cancer. 2006;119:2922–30.
Pisters PW, Leung DH, Woodruff J, Shi W, Brennan MF. Analysis of prognostic factors in 1041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol. 1996;14:1679–89.
Lewis JJ, Leung D, Heslin M, Woodruff JM, Brennan MF. Association of local recurrence with subsequent survival in extremity soft tissue sarcoma. J Clin Oncol. 1997;15:646–52.
FDA Approval for Pazopanib Hydrochloride. U.S. National Institutes of Health, 2013. https://www.cancer.gov/about-cancer/treatment/drugs/fda-pazopanibhydrochloride. Accessed 28 Sep 2017.
FDA approves new therapy for certain types of advanced soft tissue sarcoma. U.S. Food and Drug Administration, 2015. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm468832.htm. Accessed 18 Aug 2017.
FDA approves first drug to show survival benefit in liposarcoma. U.S. Food and Drug Administration, 2016. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm483714.htm. Accessed 18 Aug 2017.
FDA grants accelerated approval to new treatment for advanced soft tissue sarcoma. U.S. Food and Drug Administration, 2016. www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm525878.htm. Accessed 18 Aug 2017.
Sheng JY, Movva S. Systemic therapy for advanced soft tissue sarcoma. Surg Clin North Am. 2016;96:1141–56.
Grande E, Bolos MV, Arriola E. Targeting oncogenic ALK: a promising strategy for cancer treatment. Mol Cancer Ther. 2011;10:569–79.
Armstrong F, Lamant L, Hieblot C, Delsol G, Touriol C. TPM3-ALK expression induces changes in cytoskeleton organisation and confers higher metastatic capacities than other ALK fusion proteins. Eur J Cancer. 2007;43:640–6.
Shaw AT, Yeap BY, Mino-Kenudson M, Digumarthy SR, Costa DB, Heist RS, et al. Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27:4247–53.
Van Roosbroeck K, Cools J, Dierickx D, Thomas J, Vandenberghe P, Stul M, et al. ALK-positive large B-cell lymphomas with cryptic SEC31A-ALK and NPM1-ALK fusions. Haematologica. 2010;95:509–13.
Janoueix-Lerosey I, Lequin D, Brugieres L, Ribeiro A, de Pontual L, Combaret V, et al. Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. Nature. 2008;455:967–70.
Bonvini P, Zin A, Alaggio R, Pawel B, Bisogno G, Rosolen A. High ALK mRNA expression has a negative prognostic significance in rhabdomyosarcoma. Br J Cancer. 2013;109:3084–91.
Ishibashi Y, Miyoshi H, Hiraoka K, Arakawa F, Haraguchi T, Nakashima S, et al. Anaplastic lymphoma kinase protein expression, genetic abnormalities, and phosphorylation in soft tissue tumors: Phosphorylation is associated with recurrent metastasis. Oncol Rep. 2015;33:1667–74.
Kimbara S, Takeda K, Fukushima H, Inoue T, Okada H, Shibata Y, et al. A case report of epithelioid inflammatory myofibroblastic sarcoma with RANBP2-ALK fusion gene treated with the ALK inhibitor, crizotinib. Jpn J Clin Oncol. 2014;44:868–71.
Jiang Q, Tong HX, Hou YY, Zhang Y, Li JL, Zhou YH, et al. Identification of EML4-ALK as an alternative fusion gene in epithelioid inflammatory myofibroblastic sarcoma. Orphanet J Rare Dis. 2017;12:97.
Mansfield AS, Murphy SJ, Harris FR, Robinson SI, Marks RS, Johnson SH, et al. Chromoplectic TPM3-ALK rearrangement in a patient with inflammatory myofibroblastic tumor who responded to ceritinib after progression on crizotinib. Ann Oncol. 2016;27:2111–7.
Subbiah V, McMahon C, Patel S, Zinner R, Silva EG, Elvin JA, et al. STUMP un“stumped”: anti-tumor response to anaplastic lymphoma kinase (ALK) inhibitor based targeted therapy in uterine inflammatory myofibroblastic tumor with myxoid features harboring DCTN1-ALK fusion. J Hematol Oncol. 2015;8:66.
Lee JC, Li CF, Huang HY, Zhu MJ, Marino-Enriquez A, Lee CT, et al. ALK oncoproteins in atypical inflammatory myofibroblastic tumours: novel RRBP1-ALK fusions in epithelioid inflammatory myofibroblastic sarcoma. J Pathol. 2017;241:316–23.
Wiesner T, Lee W, Obenauf AC, Ran L, Murali R, Zhang QF, et al. Alternative transcription initiation leads to expression of a novel ALK isoform in cancer. Nature. 2015;526:453–7.
Busam KJ, Vilain RE, Lum T, Busam JA, Hollmann TJ, Saw RP, et al. Primary and metastatic cutaneous melanomas express ALK through alternative transcriptional initiation. Am J Surg Pathol. 2016;40:786–95.
Clevers H. The cancer stem cell: premises, promises and challenges. Nat Med. 2011;17:313–9.
Beck B, Blanpain C. Unravelling cancer stem cell potential. Nat Rev Cancer. 2013;13:727–38.
Deshmukh A, Deshpande K, Arfuso F, Newsholme P, Dharmarajan A. Cancer stem cell metabolism: a potential target for cancer therapy. Mol Cancer. 2016;15:69.
Xie X, Ye Z, Yang D, Tao H. Effects of combined c-myc and Bmi-1 siRNAs on the growth and chemosensitivity of MG-63 osteosarcoma cells. Mol Med Rep. 2013;8:168–72.
Gravina GL, Festuccia C, Popov VM, Di Rocco A, Colapietro A, Sanita P, et al. c-Myc sustains transformed phenotype and promotes radioresistance of embryonal rhabdomyosarcoma cell lines. Radiat Res. 2016;185:411–22.
Schulte JH, Bachmann HS, Brockmeyer B, Depreter K, Oberthur A, Ackermann S, et al. High ALK receptor tyrosine kinase expression supersedes ALK mutation as a determining factor of an unfavorable phenotype in primary neuroblastoma. Clin Cancer Res. 2011;17:5082–92.
Zhou JX, Yang H, Deng Q, Gu X, He P, Lin Y, et al. Oncogenic driver mutations in patients with non-small-cell lung cancer at various clinical stages. Ann Oncol. 2013;24:1319–25.
Todaro M, Francipane MG, Medema JP, Stassi G. Colon cancer stem cells: promise of targeted therapy. Gastroenterology. 2010;138:2151–62.
Dandawate PR, Subramaniam D, Jensen RA, Anant S. Targeting cancer stem cells and signaling pathways by phytochemicals: novel approach for breast cancer therapy. Semin Cancer Biol. 2016;40-41:192–208.
Brown HK, Tellez-Gabriel M, Heymann D. Cancer stem cells in osteosarcoma. Cancer Lett. 2017;386:189–95.
Fujiwara T, Ozaki T. Overcoming therapeutic resistance of bone sarcomas: overview of the molecular mechanisms and therapeutic targets for bone sarcoma stem cells. Stem Cells Int. 2016;2016:2603092.
Kuo CY, Ann DK. When fats commit crimes: fatty acid metabolism, cancer stemness and therapeutic resistance. Cancer Commun (Lond). 2018;38:47.
Riggi N, Cironi L, Provero P, Suva ML, Kaloulis K, Garcia-Echeverria C, et al. Development of Ewing’s sarcoma from primary bone marrow-derived mesenchymal progenitor cells. Cancer Res. 2005;65:11459–68.
Haldar M, Hancock JD, Coffin CM, Lessnick SL, Capecchi MR. A conditional mouse model of synovial sarcoma: insights into a myogenic origin. Cancer Cell. 2007;11:375–88.
Feng BH, Liu AG, Gu WG, Deng L, Cheng XG, Tong TJ, et al. CD133+ subpopulation of the HT1080 human fibrosarcoma cell line exhibits cancer stem-like characteristics. Oncol Rep. 2013;30:815–23.
Huang FF, Wu DS, Zhang L, Yu YH, Yuan XY, Li WJ, et al. Inactivation of PTEN increases ABCG2 expression and the side population through the PI3K/Akt pathway in adult acute leukemia. Cancer Lett. 2013;336:96–105.
Xia P, Xu XY. PI3K/Akt/mTOR signaling pathway in cancer stem cells: from basic research to clinical application. Am J Cancer Res. 2015;5:1602–9.
Kim J, Woo AJ, Chu J, Snow JW, Fujiwara Y, Kim CG, et al. A Myc network accounts for similarities between embryonic stem and cancer cell transcription programs. Cell. 2010;143:313–24.
Lin CY, Loven J, Rahl PB, Paranal RM, Burge CB, Bradner JE, et al. Transcriptional amplification in tumor cells with elevated c-Myc. Cell. 2012;151:56–67.
Wang Y, Cheng J, Xie D, Ding X, Hou H, Chen X, et al. NS1-binding protein radiosensitizes esophageal squamous cell carcinoma by transcriptionally suppressing c-Myc. Cancer Commun (Lond). 2018;38:33.
Porro A, Iraci N, Soverini S, Diolaiti D, Gherardi S, Terragna C, et al. c-MYC oncoprotein dictates transcriptional profiles of ATP-binding cassette transporter genes in chronic myelogenous leukemia CD34+ hematopoietic progenitor cells. Mol Cancer Res. 2011;9:1054–66.
Porro A, Haber M, Diolaiti D, Iraci N, Henderson M, Gherardi S, et al. Direct and coordinate regulation of ATP-binding cassette transporter genes by Myc factors generates specific transcription signatures that significantly affect the chemoresistance phenotype of cancer cells. J Biol Chem. 2010;285:19532–43.
This work was supported by the National Key Research and Development Program (2017YFA0505600) and the National Natural Science Foundation of China Programs (Grant Nos 81772863 and 81572403). We thank Dr Deng Xianming (Principal Investigator for Chemical Biology and Medicinal Chemistry School of Life Sciences, Xiamen University, China) for generously providing the plasmids.
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Xu, B., Chen, H., Que, Y. et al. ALKATI interacts with c-Myc and promotes cancer stem cell-like properties in sarcoma. Oncogene 39, 151–163 (2020). https://doi.org/10.1038/s41388-019-0973-5