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Intratumoral Cellular Heterogeneity: Implications for Drug Resistance in Patients with Non-Small Cell Lung Cancer
Article

Increased Tumor Growth Rate and Mesenchymal Properties of NSCLC-Patient-Derived Xenograft Models during Serial Transplantation

1
Oncogenic Signalling Laboratory, Centro de Investigación Príncipe Felipe, 46012 Valencia, Spain
2
Department of Pathology, University and Polytechnic La Fe Hospital, 46026 Valencia, Spain
3
Department of Thoracic Surgery, University and Polytechnic La Fe Hospital, 46026 Valencia, Spain
4
Department of Pulmonology, University and Polytechnic La Fe Hospital, 46026 Valencia, Spain
5
Department of Medical Oncology, University and Polytechnic La Fe Hospital, 46026 Valencia, Spain
6
Molecular Biology Unit, Service of Clinical Analysis, University and Polytechnic La Fe Hospital, 46026 Valencia, Spain
7
Department of Pathology, Hospital Universitario de la Ribera, 46600 Alzira, Spain
*
Author to whom correspondence should be addressed.
These authors equally contributed to this manuscript.
Academic Editors: Mumtaz V. Rojiani, Srikumar Chellappan and Amyn M. Rojiani
Cancers 2021, 13(12), 2980; https://doi.org/10.3390/cancers13122980
Received: 27 March 2021 / Revised: 6 June 2021 / Accepted: 9 June 2021 / Published: 14 June 2021
(This article belongs to the Special Issue Non-small Cell Lung Cancer--Tumor Biology)
Advances have been made in the study of NSCLC tumors using in vivo models, such as patient-derived xenografts (PDXs). However, the number of PDX models that can represent the heterogeneity of NSCLC between different individuals is still limited. We successfully established nine PDX mice, from which lung adenocarcinoma tumors bearing the KRAS-G12C mutation were the most frequently grafted. We show that the most aggressive tumors have a greater implantation capacity, and the success of their implantation is indicative of a poor prognosis. By using H-score to quantify cell proliferation and mesenchymal markers, we show that PDX tumors evolved towards a more proliferative and mesenchymal phenotype associated with higher protein levels of Ki67, vimentin, and ezrin, suggesting that the evaluation of their combined expression could be used as a prognostic marker to study disease progression. These PDX models provide a valuable platform for NSCLC translational research.
Non-small-cell lung cancer (NSCLC) is the leading cause of cancer death worldwide. The high mortality is very often a consequence of its late diagnosis when the cancer is already locally advanced or has disseminated. Advances in the study of NSCLC tumors have been achieved by using in vivo models, such as patient-derived xenografts. Apart from drug screening, this approach may also be useful for study of the biology of the tumors. In the present study, surgically resected primary lung cancer samples (n = 33) were implanted in immunodeficient mice, and nine were engrafted successfully, including seven adenocarcinomas, one squamous-cell carcinoma, and one large-cell carcinoma. ADC tumors bearing the KRAS-G12C mutation were the most frequently engrafted in our PDX collection. Protein expression of vimentin, ezrin, and Ki67 were evaluated in NSCLC primary tumors and during serial transplantation by immunohistochemistry, using H-score. Our data indicated a more suitable environment for solid adenocarcinoma, compared to other lung tumor subtypes, to grow and preserve its architecture in mice, and a correlation between higher vimentin and ezrin expression in solid adenocarcinomas. A correlation between high vimentin expression and lung adenocarcinoma tumors bearing KRAS-G12C mutation was also observed. In addition, tumor evolution towards more proliferative and mesenchymal phenotypes was already observed in early PDX tumor passages. These PDX models provide a valuable platform for biomarker discovery and drug screening against tumor growth and EMT for lung cancer translational research. View Full-Text
Keywords: PDX; IHC; Ki67; vimentin; ezrin; proliferation; EMT; NSCLC PDX; IHC; Ki67; vimentin; ezrin; proliferation; EMT; NSCLC
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MDPI and ACS Style

Pardo-Sánchez, J.M.; Mancheño, N.; Cerón, J.; Jordá, C.; Ansotegui, E.; Juan, Ó.; Palanca, S.; Cremades, A.; Gandía, C.; Farràs, R. Increased Tumor Growth Rate and Mesenchymal Properties of NSCLC-Patient-Derived Xenograft Models during Serial Transplantation. Cancers 2021, 13, 2980. https://doi.org/10.3390/cancers13122980

AMA Style

Pardo-Sánchez JM, Mancheño N, Cerón J, Jordá C, Ansotegui E, Juan Ó, Palanca S, Cremades A, Gandía C, Farràs R. Increased Tumor Growth Rate and Mesenchymal Properties of NSCLC-Patient-Derived Xenograft Models during Serial Transplantation. Cancers. 2021; 13(12):2980. https://doi.org/10.3390/cancers13122980

Chicago/Turabian Style

Pardo-Sánchez, José M., Nuria Mancheño, José Cerón, Carlos Jordá, Emilio Ansotegui, Óscar Juan, Sarai Palanca, Antonio Cremades, Carolina Gandía, and Rosa Farràs. 2021. "Increased Tumor Growth Rate and Mesenchymal Properties of NSCLC-Patient-Derived Xenograft Models during Serial Transplantation" Cancers 13, no. 12: 2980. https://doi.org/10.3390/cancers13122980

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