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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2021 | Metastasis | Research

Establishment and characterization of patient-derived head and neck cancer models from surgical specimens and endoscopic biopsies

Authors: Daniel Strüder, Theresa Momper, Nina Irmscher, Mareike Krause, Jan Liese, Sebastian Schraven, Annette Zimpfer, Sarah Zonnur, Ann-Sophie Burmeister, Björn Schneider, Bernhard Frerich, Robert Mlynski, Christina Große-Thie, Christian Junghanss, Claudia Maletzki

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

Abstract

Background

Head and neck squamous cell carcinoma (HNSCC) is heterogeneous in etiology, phenotype and biology. Patient-derived xenografts (PDX) maintain morphology and molecular profiling of the original tumors and have become a standard “Avatar” model for human cancer research. However, restricted availability of tumor samples hindered the widespread use of PDX. Most PDX-projects include only surgical specimens because reliable engraftment from biopsies is missing. Therefore, sample collection is limited and excludes recurrent and metastatic, non-resectable cancer from preclinical models as well as future personalized medicine.

Methods

This study compares the PDX-take rate, -growth, histopathology, and molecular characteristics of endoscopic specimens with surgical specimens. HNSCC samples (n = 55) were collected ad hoc, fresh frozen and implanted into NOD.Cg-Prkdc^scidIl2rg^tm1Wjl/SzJ mice.

Results

Engraftment was successful in both sample types. However, engraftment rate was lower (21 vs. 52%) and growth delayed (11.2 vs. 6.7 weeks) for endoscopic biopsies. Following engraftment, growth kinetic was similar. Comparisons of primary tumors and corresponding PDX models confirmed preservation of histomorphology (HE histology) and molecular profile (Illumina Cancer Hotspot Panel) of the patients’ tumors. Accompanying flow cytometry on primary tumor specimens revealed a heterogeneous tumor microenvironment among individual cases and identified M2-like macrophages as positive predictors for engraftment. Vice versa, a high PD-L1 expression (combined positive score on tumor/immune cells) predicted PDX rejection.

Conclusion

Including biopsy samples from locally advanced or metastatic lesions from patients with non-surgical treatment strategies, increases the availability of PDX for basic and translational research. This facilitates (pre-) clinical studies for individual response prediction based on immunological biomarkers.

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Malone E, Siu LL. Precision medicine in head and neck cancer: myth or reality? Clin Med Insights Oncol. 2018;12:117955491877958. https://doi.org/10.1177/1179554918779581.CrossRef

Guo T, Califano JA. Molecular biology and immunology of head & neck cancer. Surg Oncol Clin N Am. 2015;24(3):397–407. https://doi.org/10.1016/j.soc.2015.03.002.CrossRefPubMedPubMedCentral

Specenier P, Vermorken JB. Optimizing treatments for recurrent or metastatic head and neck squamous cell carcinoma. Expert Rev Anticancer Ther. 2018;18(9):901–15. https://doi.org/10.1080/14737140.2018.1493925.CrossRefPubMed

Dang RP, Le VH, Miles BA, et al. Clinical outcomes in patients with recurrent or metastatic human papilloma virus-positive head and neck cancer. Anticancer Res. 2016;36(4):1703–9.PubMed

Billard-Sandu C, Tao YG, Sablin MP, Dumitrescu G, Billard D, Deutsch E. CDK4/6 inhibitors in P16/HPV16-negative squamous cell carcinoma of the head and neck. Eur Arch Oto-Rhino-Laryngol. 2020;277(5):1273–80. https://doi.org/10.1007/s00405-020-05891-2.CrossRef

Ordonez R, Otero A, Jerez I, Medina JA, Lupianez-Perez Y, Gomez-Millan J. Role of radiotherapy in the treatment of metastatic head and neck cancer. Onco Targets Ther. 2019;12:677–83. https://doi.org/10.2147/OTT.S181697.CrossRefPubMedPubMedCentral

Lai Y, Wei X, Lin S, Qin L, Cheng L, Li P. Current status and perspectives of patient-derived xenograft models in cancer research. J Hematol Oncol. 2017;10(1):106. https://doi.org/10.1186/s13045-017-0470-7.CrossRefPubMedPubMedCentral

Peng S, Creighton CJ, Zhang Y, et al. Tumor grafts derived from patients with head and neck squamous carcinoma authentically maintain the molecular and histologic characteristics of human cancers. J Transl Med. 2013;11:198. https://doi.org/10.1186/1479-5876-11-198.CrossRefPubMedPubMedCentral

Byrne AT, Alférez DG, Amant F, et al. Interrogating open issues in cancer precision medicine with patient-derived xenografts. Nat Rev Cancer. 2017;17(4):254–68. https://doi.org/10.1038/nrc.2016.140.CrossRefPubMed

10.

Karamboulas C, Bruce JP, Hope AJ, et al. Patient-derived xenografts for prognostication and personalized treatment for head and neck squamous cell carcinoma. Cell Rep. 2018;25(5):1318-1331.e4. https://doi.org/10.1016/j.celrep.2018.10.004.CrossRefPubMed

11.

12.

Woo XY, Giordano J, Srivastava A, et al. Conservation of copy number profiles during engraftment and passaging of patient-derived cancer xenografts. Nat Genet. 2021;53(1):86–99. https://doi.org/10.1038/s41588-020-00750-6.CrossRefPubMedPubMedCentral

13.

Lipner MB, Marayati R, Deng Y, et al. Metformin treatment does not inhibit growth of pancreatic cancer patient-derived xenografts. PLoS ONE. 2016;11(1): e0147113. https://doi.org/10.1371/journal.pone.0147113.CrossRefPubMedPubMedCentral

14.

Kita K, Fukuda K, Takahashi H, et al. Patient-derived xenograft models of non-small cell lung cancer for evaluating targeted drug sensitivity and resistance. Cancer Sci. 2019;110(10):3215–24. https://doi.org/10.1111/cas.14171.CrossRefPubMedPubMedCentral

15.

Choi S Il, Jeon AR, Kim MK, et al. Development of patient-derived preclinical platform for metastatic pancreatic cancer: pdox and a subsequent organoid model system using percutaneous biopsy samples. Front Oncol. 2019;9:875. https://doi.org/10.3389/fonc.2019.00875.CrossRefPubMedPubMedCentral

16.

Lee HW, Lee J Il, Lee SJ, et al. Patient-derived xenografts from non-small cell lung cancer brain metastases are valuable translational platforms for the development of personalized targeted therapy. Clin Cancer Res. 2015;21(5):1172–82. https://doi.org/10.1158/1078-0432.CCR-14-1589.CrossRefPubMed

17.

Kang HN, Choi JW, Shim HS, et al. Establishment of a platform of non-small-cell lung cancer patient-derived xenografts with clinical and genomic annotation. Lung Cancer. 2018;124:168–78. https://doi.org/10.1016/j.lungcan.2018.08.008.CrossRefPubMed

18.

Moro M, Bertolini G, Tortoreto M, Pastorino U, Sozzi G, Roz L. Patient-derived xenografts of non small cell lung cancer: resurgence of an old model for investigation of modern concepts of tailored therapy and cancer stem cells. J Biomed Biotechnol. 2012;2012: 568567. https://doi.org/10.1155/2012/568567.CrossRefPubMedPubMedCentral

19.

Ilie M, Nunes M, Blot L, et al. Setting up a wide panel of patient-derived tumor xenografts of non-small cell lung cancer by improving the preanalytical steps. Cancer Med. 2015;4(2):201–11. https://doi.org/10.1002/cam4.357.CrossRefPubMed

20.

Brown KM, Xue A, Mittal A, Samra JS, Smith R, Hugh TJ. Patient-derived xenograft models of colorectal cancer in preclinical research: a systematic review. Oncotarget. 2016;7(40):66212–25. https://doi.org/10.18632/oncotarget.11184.CrossRefPubMedPubMedCentral

21.

Pergolini I, Morales-Oyarvide V, Mino-Kenudson M, et al. Tumor engraftment in patient-derived xenografts of pancreatic ductal adenocarcinoma is associated with adverse clinicopathological features and poor survival. PLoS One. 2017;12(8):e0182855. https://doi.org/10.1371/journal.pone.0182855.CrossRefPubMedPubMedCentral

22.

Hermans E, Van der Merwe SW, Depreeuw J, et al. Successful application of endoscopic ultrasound-guided fine needle biopsy to establish pancreatic patient-derived tumor xenografts: a pilot study. Endoscopy. 2016;48(11):1016–22. https://doi.org/10.1055/s-0042-113597.CrossRefPubMed

23.

Wang Z, Fu S, Zhao J, et al. Transbronchoscopic patient biopsy-derived xenografts as a preclinical model to explore chemorefractory-associated pathways and biomarkers for small-cell lung cancer. Cancer Lett. 2019;440–441:180–8. https://doi.org/10.1016/j.canlet.2018.10.014.CrossRefPubMed

24.

Lilja-Fischer JK, Ulhøi BP, Alsner J, et al. Characterization and radiosensitivity of HPV-related oropharyngeal squamous cell carcinoma patient-derived xenografts. Acta Oncol. 2019;58(10):1489–94. https://doi.org/10.1080/0284186X.2019.1660802.CrossRefPubMed

25.

Kang HN, Kim JH, Park AY, et al. Establishment and characterization of patient-derived xenografts as paraclinical models for head and neck cancer. BMC Cancer. 2020;20(1):316. https://doi.org/10.1186/s12885-020-06786-5.CrossRefPubMedPubMedCentral

26.

Kang HN, Kim JH, Park AY, et al. Establishment and characterization of patient-derived xenografts as paraclinical models for head and neck cancer. BMC Cancer. 2020;20(1):1–12. https://doi.org/10.1186/s12885-020-06786-5.CrossRef

27.

Facompre ND, Rajagopalan P, Sahu V, et al. Identifying predictors of <scp>HPV</scp> -related head and neck squamous cell carcinoma progression and survival through patient-derived models. Int J Cancer. 2020;147(11):3236–49. https://doi.org/10.1002/ijc.33125.CrossRefPubMed

28.

Kimple RJ, Harari PM, Torres AD, et al. Development and characterization of HPV-positive and HPV-negative head and neck squamous cell carcinoma tumorgrafts. Clin Cancer Res. 2013;19(4):855–64. https://doi.org/10.1158/1078-0432.CCR-12-2746.CrossRefPubMed

29.

Klinghammer K, Raguse J-D, Plath T, et al. A comprehensively characterized large panel of head and neck cancer patient-derived xenografts identifies the mTOR inhibitor everolimus as potential new treatment option. Int J cancer. 2015;136(12):2940–8. https://doi.org/10.1002/ijc.29344.CrossRefPubMed

30.

Ny L, Rizzo LY, Belgrano V, et al. Supporting clinical decision making in advanced melanoma by preclinical testing in personalized immune-humanized xenograft mouse models. Ann Oncol. 2020. https://doi.org/10.1016/j.annonc.2019.11.002.CrossRefPubMed

31.

Dong Y, Manley BJ, Becerra MF, et al. Tumor xenografts of human clear cell renal cell carcinoma but not corresponding cell lines recapitulate clinical response to sunitinib: feasibility of using biopsy samples. Eur Urol Focus. 2017;3(6):590–8. https://doi.org/10.1016/j.euf.2016.08.005.CrossRefPubMed

32.

Roife D, Kang Y, Wang L, et al. Generation of patient-derived xenografts from fine needle aspirates or core needle biopsy. Surgery. 2017;161(5):1246–54. https://doi.org/10.1016/j.surg.2016.11.020.CrossRefPubMed

33.

Linnebacher M, Maletzki C, Ostwald C, et al. Cryopreservation of human colorectal carcinomas prior to xenografting. BMC Cancer. 2010;10:362. https://doi.org/10.1186/1471-2407-10-362.CrossRefPubMedPubMedCentral

34.

Tanaka R, Kageyama K, Kimura K, et al. Establishment of a liver transplant patient-derived tumor xenograft (PDX) model using cryopreserved pancreatic ductal adenocarcinoma. Anticancer Res. 2020;40(5):2637–44. https://doi.org/10.21873/anticanres.14234.CrossRefPubMed

35.

Hernandez MC, Yang L, Leiting JL, et al. Successful secondary engraftment of pancreatic ductal adenocarcinoma and cholangiocarcinoma patient-derived xenografts after previous failed primary engraftment. Transl Oncol. 2019;12(1):69–75. https://doi.org/10.1016/j.tranon.2018.09.008.CrossRefPubMed

36.

Guerrera F, Tabbo F, Bessone L, et al. The influence of tissue ischemia time on RNA integrity and patient-derived xenografts (PDX) engraftment rate in a non-small cell lung cancer (NSCLC) Biobank. PLoS One. 2016;11(1):0145100. https://doi.org/10.1371/journal.pone.0145100.CrossRef

37.

Jiang W, Xie S, Liu Y, Zou S, Zhu X. The application of patient-derived xenograft models in gynecologic cancers. J Cancer. 2020;11(18):5478–89. https://doi.org/10.7150/jca.46145.CrossRefPubMedPubMedCentral

38.

Cho S-Y. Patient-derived xenografts as compatible models for precision oncology. Lab Anim Res. 2020;36(1):14. https://doi.org/10.1186/s42826-020-00045-1.CrossRefPubMedPubMedCentral

39.

Fujii E, Kato A, Chen YJ, Matsubara K, Ohnishi Y, Suzuki M. The status of donor cancer tissues affects the fate of patient-derived colorectal cancer xenografts in NOG mice. Exp Anim. 2015;64(2):181–90. https://doi.org/10.1538/expanim.14-0080.CrossRefPubMedPubMedCentral

40.

Maeda R, Ishii G, Neri S, et al. Circulating CD14+CD204+ cells predict postoperative recurrence in non-small-cell lung cancer patients. J Thorac Oncol. 2014. https://doi.org/10.1097/JTO.0000000000000044.CrossRefPubMed

41.

Zhang B, Cao M, He Y, et al. Increased circulating M2-like monocytes in patients with breast cancer. Tumor Biol. 2017;39(6):1010428317711571. https://doi.org/10.1177/1010428317711571.CrossRef

42.

Yamamoto K, Makino T, Sato E, et al. Tumor-infiltrating M2 macrophage in pretreatment biopsy sample predicts response to chemotherapy and survival in esophageal cancer. Cancer Sci. 2020;111(4):1103–12. https://doi.org/10.1111/cas.14328.CrossRefPubMedPubMedCentral

43.

Badr M, Jöhrens K, Allgäuer M, et al. Morphomolecular analysis of the immune tumor microenvironment in human head and neck cancer. Cancer Immunol Immunother. 2019;68(9):1443–54. https://doi.org/10.1007/s00262-019-02378-w.CrossRefPubMed

Title: Establishment and characterization of patient-derived head and neck cancer models from surgical specimens and endoscopic biopsies
Authors: Daniel Strüder
Theresa Momper
Nina Irmscher
Mareike Krause
Jan Liese
Sebastian Schraven
Annette Zimpfer
Sarah Zonnur
Ann-Sophie Burmeister
Björn Schneider
Bernhard Frerich
Robert Mlynski
Christina Große-Thie
Christian Junghanss
Claudia Maletzki
Publication date: 01-12-2021
Publisher: BioMed Central
Keyword: Metastasis
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-021-02047-w

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Abstract

Background

Methods

Results

Conclusion

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