Abstract
Neoadjuvant chemotherapy (NAC) followed by surgery is a standard approach for management of locally advanced esophageal squamous cell carcinoma (ESCC). Patients who do not respond well to NAC have a poor prognosis. Despite extensive research, the mechanisms of chemoresistance in ESCC remain largely unknown. Here, we established paired tumor organoids—designated as PreNAC-O and PostNAC-O—from one ESCC patient before and after NAC, respectively. Although the two organoids did not exhibit significant differences in proliferation, morphology or drug sensitivity in vitro, the tumorigenicity of PostNAC-O in vivo was significantly higher than that of PreNAC-O. Xenografts from PreNAC-O tended to exhibit keratinization, while those from PostNAC-O displayed conspicuous necrotic areas. The tumorigenicity of PostNAC-O xenografts during the chemotherapy was comparable to that of PreNAC-O without treatment. Furthermore, the gene expression profiles of the xenografts suggested that expression of genes involved in the EMT and/or hypoxia response might be related to the tumorigenicity of PostNAC-O. Our data suggested that the tumorigenicity of residual cancer had been enhanced, outweighing the effects of chemotherapy, rather than being attributable to intrinsic chemoresistance. Further studies are required to clarify the extent to which residual cancers share a common mechanism similar to that revealed here.
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Data availability
The data that support the findings of this study are available from the corresponding authors upon reasonable request. Microarray data are available in the GEO database. The GEO accession numbers for xenografts and organoids in vitro are GSE243145 and GSE243146, respectively.
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Acknowledgements
We would like to thank Ms. Kanako Ito, Ms. Yoko Kudo, Ms. Mami Kimoto and Ms. Kei Shimizu for their excellent technical assistance.
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This work was supported by Oita University President’s Strategic Discretionary Fund (2022 and 2023), and by JSPS KAKENHI Grant Number JP21H02703, JP20K07394.
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Conceptualization TF, YT, and NH; Experiments and investigation TF, SK, YT, KK, YH, CN and NH; Data analysis TU. TM, and YY; Writing-original draft preparation TF, YT, and NH; Writing-review and editing MF, KT, KF, RO, KMi, MK, and KMu.; Funding acquisition YT, MI, KMu, and NH; Resources; TS, SF, HF, YI, KS. HS, and MI; Supervision MI, KMu, MM, and NH; All authors have approved the final version of the paper.
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The study protocol was performed in accordance with the revised Helsinki Declaration of 2008 and approved by the Institutional Review Board of the Faculty of Medicine, University of Oita (approval No. 1496). All animal experiments in this study were approved by the Oita University Animal Ethics Committee (Approval No.220802A and 230801) and were conducted in accordance with ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines (https://arriveguidelines.org/).
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Fuchino, T., Kurogi, S., Tsukamoto, Y. et al. Characterization of residual cancer by comparison of a pair of organoids established from a patient with esophageal squamous cell carcinoma before and after neoadjuvant chemotherapy. Human Cell 37, 491–501 (2024). https://doi.org/10.1007/s13577-023-01020-3
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DOI: https://doi.org/10.1007/s13577-023-01020-3