Generation of Non-Small Cell Lung Cancer Patient-Derived Xenografts to Study Intratumor Heterogeneity.
Zoi KanakiAlexandra VoutsinaAthina N MarkouIoannis S PaterasKonstantinos PotarisMargaritis AvgerisPeriklis MakrythanasisEmmanouil I AthanasiadisIoannis VamvakarisEleni PatseaKonstantinos VachlasEvi S LianidouVassilis GeorgouliasAthanasios KotsakisApostolos KlinakisPublished in: Cancers (2021)
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.
Keyphrases
- single cell
- circulating tumor cells
- early stage
- dna repair
- rna seq
- end stage renal disease
- gene expression
- chronic kidney disease
- high fat diet induced
- small cell lung cancer
- squamous cell carcinoma
- epithelial mesenchymal transition
- bone marrow
- dna damage
- adipose tissue
- oxidative stress
- case report
- circulating tumor
- high throughput
- prognostic factors
- metabolic syndrome
- insulin resistance
- skeletal muscle
- lymph node
- climate change
- neoadjuvant chemotherapy
- copy number
- free survival
- cell free