Generation of Non-Small Cell Lung Cancer Patient-Derived Xenografts to Study Intratumor Heterogeneity
| Autor: | Ioannis S. Pateras, Alexandra Voutsina, Margaritis Avgeris, Athina Markou, Konstantinos Vachlas, Konstantinos Potaris, Emmanouil Athanasiadis, Vassilis Georgoulias, Periklis Makrythanasis, Apostolos Klinakis, Eleni Patsea, Ioannis Vamvakaris, Athanasios Kotsakis, Evi Lianidou, Zoi Kanaki |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research DNA repair Cell intratumor heterogeneity Drug resistance Biology Article Metastasis 03 medical and health sciences 0302 clinical medicine Circulating tumor cell medicine Lung cancer Gene Exome sequencing RC254-282 non-small cell lung cancer Neoplasms. Tumors. Oncology. Including cancer and carcinogens medicine.disease 3. Good health 030104 developmental biology medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Cancer research patient-derived xenografts genetic profiling |
| Zdroj: | Cancers Volume 13 Issue 10 Cancers, Vol 13, Iss 2446, p 2446 (2021) |
| ISSN: | 2072-6694 |
| DOI: | 10.3390/cancers13102446 |
| Popis: | Simple Summary It is widely thought that tumors are composed of different subpopulations of cancer cells carrying genetic alterations with some of them being common among all cells while others are unique for each subpopulation. This variable genetic profile of tumor cells is a component of what is collectively described as intratumor heterogeneity (ITH). Surviving the immune system and therapies, and establishing metastases are forces of natural selection that act upon ITH and drive tumor evolution and, eventually, the clinical presentation of patients. The aim of this prospective study was to investigate ITH in early-stage operable non-small cell lung cancer. We directly grafted human tumors in immunosuppressed mice and compared the genetic profile of the tumors grown in mice with that of the original human tumors. We identified clinical factors that affected the ability of human tumors to grow as mouse xenografts. Abstract Recent advances in sequencing technologies have allowed the in-depth molecular study of tumors, even at the single cell level. Sequencing efforts have uncovered a previously unappreciated heterogeneity among tumor cells, which has been postulated to be the driving force of tumor evolution and to facilitate recurrence, metastasis, and drug resistance. In the current study, focused on early-stage operable non-small cell lung cancer, we used tumor growth in patient-derived xenograft (PDX) models in mice as a fast-forward tumor evolution process to investigate the molecular characteristics of tumor cells that grow in mice, as well as the parameters that affect the grafting efficiency. We found that squamous cell carcinomas grafted significantly more efficiently compared with adenocarcinomas. Advanced stage, patient age and primary tumor size were positively correlated with grafting. Additionally, we isolated and characterized circulating tumor cells (CTC) from patients’ peripheral blood and found that the presence of CTCs expressing epithelial-to-mesenchymal (EMT) markers correlated with the grafting potential. Interestingly, exome sequencing of the PDX tumor identified genetic alterations in DNA repair and genome integrity genes that were under-represented in the human primary counterpart. In conclusion, through the generation of a PDX biobank of NSCLC, we identified the clinical and molecular properties of tumors that affected growth in mice. |
| Databáze: | OpenAIRE |
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