Journal
CANCER BIOLOGY & MEDICINE
Volume 18, Issue 1, Pages 184-+Publisher
CHINA ANTI-CANCER ASSOC
DOI: 10.20892/j.issn.2095-3941.2020.0012
Keywords
Patient-derived xenograft (PDX); non-small cell lung cancer (NSCLC); tumor heterogeneity
Categories
Funding
- National Natural Science Foundation of China [81101143, 81572617, 81630101]
- Sichuan Province Science and Technology Support Program [2019JDRC0019, 2018SZ0009]
- 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University [ZYJC18026]
- Science and Technology Project of the Health Planning Committee of Sichuan [19PJ242]
- Chengdu science and technology Support Program [2019-YFYF-00090-SN]
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A large collection of serially transplantable PDX models for NSCLC were successfully developed, faithfully reproducing the molecular, histopathological, and therapeutic characteristics, as well as the corresponding tumor heterogeneities of primary tumors. PDX models responded differentially to the standard of care treatment, including chemo-, targeted and immuno-therapeutics, similar to clinical patients.
Objective: Patient-derived xenograft (PDX) models have shown great promise in preclinical and translational applications, but their consistency with primary tumors in phenotypic, genetic, and pharmacodynamic heterogeneity has not been well-studied. This study aimed to establish a PDX repository for non small cell lung cancer (NSCLC) and to further elucidate whether it could preserve the heterogeneity within and between tumors in patients. Methods: A total of 75 surgically resected NSCLC specimens were implanted into immunodeficient NOD/SCDD mice. Based on the successful establishment of the NSCLC PDX model, we compared the expressions of vimentin, Ki67, EGER, and PD-L1 proteins between cancer tissues and PDX models using hematoxylin and eosin staining and immunohistochemical staining. In addition, we detected whole gene expression profiling between primary tumors and PDX generations. We also performed whole exome sequencing (WES) analysis in 17 first generation xenografts to further mess whether PDXs retained the patient heterogeneities. Finally, paclitaxel, cisplatin, doxortibicin, atezolizumab, afatininb, and AZD4547 were used to evaluate the responses of PDX models to the standard-of-care agents. Results: A large collection of serially transplantable PDX models for NSCLC were successfully developed. The histology and pathological immunohistochemistry of PDX xenografts were consistent with the patients' tumor samples. WES and RNA-seq further confirmed that PDX accurately replicated the molecular heterogeneities of primary tumors. Similar to clinical patients, PDX models responded differentially to the standard of care treatment, including chemo-, targeted and immuno-therapeutics. Conclusions: Our established PDX models of NSCLC faithfully reproduced the molecular, histopathological, and therapeutic characteristics, as well as the corresponding tumor heterogeneities, which provides a clinically relevant platform for drug screening, biomarker discovery, and translational research.
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