Abstract 3096: Multi-region patient-derived xenograft models from non-small cell lung cancer patients enrolled in lung TRACERx
Authors: Hynds Robert E. , Pearce David R. , Akarca Ayse U. , Ward Sophia , Huebner Ariana , Pich Oriol , Wilson Gareth A. , Gowers Kate H. , Towns Rebecca , Aissa Assma Ben , Veeriah Selvaraju , Quezada Sergio A. , Jamal-Hanjani Mariam , Janes Sam M. , McGranahan Nicholas , Moore David A. , Marafioti Teresa , Swanton Charles 
Published: June 2022

Patient-derived xenograft (PDX) models have become important models in cancer biology. They are thought to mimic tumor biology more closely than traditional cell lines as a consequence of their in vivo heterocellularity and cell-matrix interactions, their 3D architecture and their relatively recent derivation. The genomic fidelity of PDXs is integral to their applications in both basic research and in translational medicine. We derived multi-region PDX models from patients enrolled in TRACERx - a study of the evolutionary dynamics of non-small cell lung cancer (NSCLC) that uses a multi-region deep whole-exome sequencing (WES) approach - using more extensive spatial sampling to better understand the histological and genomic fidelity of the PDX approach.

We transplanted regional NSCLC tumor tissue subcutaneously into immunocompromised NSG mice. 134 regions were attempted, resulting in 60 passagable xenografts (44.8%). Of these, 44 regional xenografts (32.8% of all regions) were NSCLC-derived, while 16 (11.9% of all regions) were B-cell lymphoproliferative disease. Multi-region sampling revealed heterogeneous success of PDX derivation between regions within individual patient tumors. There was correlation between PDX derivation and tumor purity by WES. Overall, NSCLC PDX models were established for 22 patients (50%; range 1-5 regional models per patient; Table 1). Histologically, broad similarity was observed between PDX models and corresponding patient tumor regions, although in a small number of models, variability was noted between the patient tumor and the corresponding PDX model, or during PDX passaging. PDXs were subjected to WES for comparison with matched patient tumor regions.

Overall, our study demonstrates the feasibility of systematic multi-region PDX derivation and suggests that multiple spatial sampling of tumors could improve PDX take rates and generate PDXs that represent the intratumor diversity of heterogenous NSCLCs.

Table 1. Engraftment rates of multiple spatial regions from non-small cell lung cancer tumors. Attempted NSCLC PDX B-Lymphoproliferations No Xenograft: Regions No Xenograft: Any Region LUAD 48 (21) 12 (7) 9 (7) 27 (10) LUSC 61 (17) 20 (11) 6 (5) 35 (4) Other 25 (6) 12 (4) 1 (1) 12 (1) TOTAL 134 (44) 44 (22) 16 (13) 74 (15)

Citation Format: Robert E. Hynds, David R. Pearce, Ayse U. Akarca, Sophia Ward, Ariana Huebner, Oriol Pich, Gareth A. Wilson, Kate H. Gowers, Rebecca Towns, Assma Ben Aissa, Selvaraju Veeriah, Sergio A. Quezada, Mariam Jamal-Hanjani, Sam M. Janes, Nicholas McGranahan, David A. Moore, Teresa Marafioti, Charles Swanton. Multi-region patient-derived xenograft models from non-small cell lung cancer patients enrolled in lung TRACERx [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3096.