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 journalArticle

6 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
Externally publishedYes

Fingerprint

Salivary Gland Neoplasms
Neoplastic Stem Cells
Heterografts
Mucoepidermoid Carcinoma
Genes
Neoplasms
Adenoid Cystic Carcinoma
Recurrence
Mucoepidermoid Tumor
Acinar Cell Carcinoma
Exome
Tumor Suppressor Genes
Nude Mice
Research Design
RNA
Neoplasm Metastasis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Salivary gland cancer patient-derived xenografts enable characterization of cancer stem cells and new gene events associated with tumor progression. / Keysar, Stephen B.; Eagles, Justin R.; Miller, Bettina; Jackson, Brian C.; Chowdhury, Farshad N.; Reisinger, Julie; Chimed, Tugs Saikhan; Le, Phuong N.; Morton, John J.; Somerset, Hilary L.; Varella-Garcia, Marileila; Tan, Aik-Choon; Song, John I.; Bowles, Daniel W.; Reyland, Mary E.; Jimeno, Antonio.

In: Clinical Cancer Research, Vol. 24, No. 12, 15.06.2018, p. 2935-2943.

Research output: Contribution to journalArticle

Keysar, SB, Eagles, JR, Miller, B, Jackson, BC, Chowdhury, FN, Reisinger, J, Chimed, TS, Le, PN, Morton, JJ, Somerset, HL, Varella-Garcia, M, Tan, A-C, Song, JI, Bowles, DW, Reyland, ME & Jimeno, A 2018, 'Salivary gland cancer patient-derived xenografts enable characterization of cancer stem cells and new gene events associated with tumor progression', Clinical Cancer Research, vol. 24, no. 12, pp. 2935-2943. https://doi.org/10.1158/1078-0432.CCR-17-3871
Keysar, Stephen B. ; Eagles, Justin R. ; Miller, Bettina ; Jackson, Brian C. ; Chowdhury, Farshad N. ; Reisinger, Julie ; Chimed, Tugs Saikhan ; Le, Phuong N. ; Morton, John J. ; Somerset, Hilary L. ; Varella-Garcia, Marileila ; Tan, Aik-Choon ; Song, John I. ; Bowles, Daniel W. ; Reyland, Mary E. ; Jimeno, Antonio. / Salivary gland cancer patient-derived xenografts enable characterization of cancer stem cells and new gene events associated with tumor progression. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 12. pp. 2935-2943.
@article{3b1c80bf2bda4c159c8357be7a6015f4,
title = "Salivary gland cancer patient-derived xenografts enable characterization of cancer stem cells and new gene events associated with tumor progression",
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.",
author = "Keysar, {Stephen B.} and Eagles, {Justin R.} and Bettina Miller and Jackson, {Brian C.} and Chowdhury, {Farshad N.} and Julie Reisinger and Chimed, {Tugs Saikhan} and Le, {Phuong N.} and Morton, {John J.} and Somerset, {Hilary L.} and Marileila Varella-Garcia and Aik-Choon Tan and Song, {John I.} and Bowles, {Daniel W.} and Reyland, {Mary E.} and Antonio Jimeno",
year = "2018",
month = "6",
day = "15",
doi = "10.1158/1078-0432.CCR-17-3871",
language = "English",
volume = "24",
pages = "2935--2943",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "12",

}

TY - JOUR

T1 - Salivary gland cancer patient-derived xenografts enable characterization of cancer stem cells and new gene events associated with tumor progression

AU - Keysar, Stephen B.

AU - Eagles, Justin R.

AU - Miller, Bettina

AU - Jackson, Brian C.

AU - Chowdhury, Farshad N.

AU - Reisinger, Julie

AU - Chimed, Tugs Saikhan

AU - Le, Phuong N.

AU - Morton, John J.

AU - Somerset, Hilary L.

AU - Varella-Garcia, Marileila

AU - Tan, Aik-Choon

AU - Song, John I.

AU - Bowles, Daniel W.

AU - Reyland, Mary E.

AU - Jimeno, Antonio

PY - 2018/6/15

Y1 - 2018/6/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85052538180&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85052538180&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-17-3871

DO - 10.1158/1078-0432.CCR-17-3871

M3 - Article

C2 - 29555661

AN - SCOPUS:85052538180

VL - 24

SP - 2935

EP - 2943

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 12

ER -