Salivary gland cancer patient-derived xenografts enable characterization of cancer stem cells and new gene events associated with tumor progression

Stephen B. Keysar, Justin R. Eagles, Bettina Miller, Brian C. Jackson, Farshad N. Chowdhury, Julie Reisinger, Tugs Saikhan Chimed, Phuong N. Le, John J. Morton, Hilary L. Somerset, Marileila Varella-Garcia, Aik Choon Tan, John I. Song, Daniel W. Bowles, Mary E. Reyland, Antonio Jimeno

    Research output: Contribution to journalArticlepeer-review

    25 Citations (Scopus)

    Abstract

    Purpose: Salivary gland cancers (SGC) frequently present with distant metastases many years after diagnosis, suggesting a cancer stem cell (CSC) subpopulation that initiates late recurrences; however, current models are limited both in their availability and suitability to characterize these rare cells. Experimental Design: Patient-derived xenografts (PDX) were generated by engrafting patient tissue onto nude mice from one acinic cell carcinoma (AciCC), four adenoid cystic carcinoma (ACC), and three mucoepidermoid carcinoma (MEC) cases, which were derived from successive relapses from the same MEC patient. Patient and PDX samples were analyzed by RNA-seq and Exome-seq. Sphere formation potential and in vivo tumorigenicity was assessed by sorting for Aldefluor (ALDH) activity and CD44-expressing subpopulations. Results: For successive MEC relapses we found a time-dependent increase in CSCs (ALDH+CD44high), increasing from 0.2% to 4.5% (P=0.033), but more importantly we observed an increase in individual CSC sphere formation and tumorigenic potential. A 50% increase in mutational burden was documented in subsequent MEC tumors, and this was associated with increased expression of tumor-promoting genes (MT1E, LGR5, and LEF1), decreased expression of tumor-suppressor genes (CDKN2B, SIK1, and TP53), and higher expression of CSC-related proteins such as SOX2, MYC, and ALDH1A1. Finally, genomic analyses identified a novel NFIB–MTFR2 fusion in an ACC tumor and confirmed previously reported fusions (NTRK3–ETV6 and MYB–NFIB). Conclusions: Sequential MEC PDX models preserved key patient features and enabled the identification of genetic events putatively contributing to increases in both CSC proportion and intrinsic tumorigenicity, which mirrored the patient's clinical course.

    Original languageEnglish
    Pages (from-to)2935-2943
    Number of pages9
    JournalClinical Cancer Research
    Volume24
    Issue number12
    DOIs
    Publication statusPublished - 2018 Jun 15

    Bibliographical note

    Funding Information:
    This work was supported by NIH grants R01-CA149456 (to A. Jimeno), R21-DE019712 (to A. Jimeno), R01-DE024371 (to A. Jimeno), P30-CA046934 (University of Colorado Cancer Center Support Grant), R01-DE015648 (to M.E. Reyland), R56-DE023245 (to M.E. Reyland and A. Jimeno), the Adenoid Cystic Carcinoma Research Foundation (to A. Jimeno and M.E. Reyland), University of Colorado Adenoid Cystic Cancer Research Fund (to D.W. Bowles), the Daniel and Janet Mordecai Foundation (to A. Jimeno), and the Peter and Rhonda Grant Foundation (to A. Jimeno). The authors wish to thank the patients who donated their tissue, blood and time, and to the clinical teams who facilitated patient informed consent, as well as sample and data acquisition.

    Publisher Copyright:
    ©2018 American Association for Cancer Research.

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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