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Gene expression profiles of the original tumors influence the generation of PDX models of lung squamous cell carcinoma

Abstract

Patient-derived xenograft (PDX) murine models are employed for preclinical research on cancers, including non-small cell lung cancers (NSCLCs). Even though lung squamous cell carcinomas (LUSCs) show the highest engraftment rate among NSCLCs, half of them nevertheless show PDX failure in immunodeficient mice. Here, using immunohistochemistry and RNA sequencing, we evaluated the distinct immunohistochemical and gene expression profiles of resected LUSCs that showed successful engraftment. Among various LUSCs, including the basal, classical, secretory, and primitive subtypes, those in the non-engrafting (NEG) group showed gene expression profiles similar to the pure secretory subtype with positivity for CK7, whereas those in the engrafting (EG) group were similar to the mixed secretory subtype with positivity for p63. Pathway analysis of 295 genes that demonstrated significant differences in expression between NEG and EG tumors revealed that the former had enriched expression of genes related to the immune system, whereas the latter had enriched expression of genes related to the cell cycle and DNA replication. Interestingly, NEG tumors showed higher infiltration of B cells (CD19+) and follicular dendritic cells (CD23+) in lymph follicles than EG tumors. Taken together, these findings suggest that the PDX cancer model of LUSC represents only a certain population of LUSCs and that CD19- and CD23-positive tumor-infiltrating immune cells in the original tumors may negatively influence PDX engraftment in immunodeficient mice.

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Fig. 1: Workflow for PDX generation.
Fig. 2: PDX engraftment is associated with a subtype of lung squamous cell carcinoma.
Fig. 3: Distinct gene expression profile of patient-derived tumors is associated with PDX engraftment.
Fig. 4: PDX engraftment-associated genes show links to various cellular pathways.
Fig. 5: PDX engraftment is associated with tumor-infiltrating immune cells in CD19+ lymph follicles or CD23+ secondary lymph follicles.

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Acknowledgements

We express our appreciation to Professor Masafumi Muratani (Department of Genome Biology, Faculty of Medicine, University of Tsukuba and Tsukuba Transborder Medical Center) for research support and kind advice. We thank also Tsukuba Human Biobank Center for sample supply.

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Correspondence to Yunjung Kim.

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Kim, Y., Shiba-Ishii, A., Nakagawa, T. et al. Gene expression profiles of the original tumors influence the generation of PDX models of lung squamous cell carcinoma. Lab Invest 101, 543–553 (2021). https://doi.org/10.1038/s41374-021-00529-1

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