Esophageal adenocarcinoma relapse after chemoradiation is dominated by a basal-like subtype

Hoppe, S.; Noseir, S.; Yazbeck, A.; Zaburannyi, N.; Grossbach, J.; Lyu, S. I.; Camacho, O. V.; Mueller, S.; Gebauer, F.; Richartz, V.; Holz, B.; Berg, J.; Achter, V.; Altmueller, J.; Becker, K.; Arolt, C.; Meder, L.; Zhao, Y.; Schloesser, H.; Baus, W. W.; Kamp, F.; Baues, C.; Beyer, A.; Odenthal, M.; Quaas, A.; Buettner, R.; Hillmer, A. M.

doi:10.1101/2025.01.28.635332

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bioRxiv · 10.1101/2025.01.28.635332

Esophageal adenocarcinoma relapse after chemoradiation is dominated by a basal-like subtype

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Abstract

Neoadjuvant chemoradiation therapy (RCT) is a frequently used treatment regimen for esophageal adenocarcinoma (EAC); however, the response varies dramatically, and resistance is a clinical challenge. We aimed to identify the molecular mechanisms underlying RCT resistance. We established a mouse xenograft RCT model with human EAC cell lines representing different response groups, and tested enhanced genomic instability as a potential evolutionary modulator by reducing BRCA2 function. Xenografts that relapsed after RCT displayed upregulation of stress response keratins, including KRT6 and KRT16 connected with a basal-like transcriptomic/ proteomic phenotype. We screened our cohort of 728 patients with EAC and found significantly shorter overall survival for patients with KRT6-high tumors, driven by patients receiving neoadjuvant treatment. Overall, we identified a basal-like cell state in EAC that reflects RCT relapse. The basal-like subtype is a marker of treatment failure, providing a new avenue for translational research to overcome RCT resistance.

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Hoppe, S., Noseir, S., Yazbeck, A., Zaburannyi, N., Grossbach, J., Lyu, S. I., Camacho, O. V., Mueller, S., Gebauer, F., Richartz, V., Holz, B., Berg, J., Achter, V., Altmueller, J., Becker, K., Arolt, C., Meder, L., Zhao, Y., Schloesser, H., Baus, W. W., Kamp, F., Baues, C., Beyer, A., Odenthal, M., Quaas, A., Buettner, R., Hillmer, A. M.. 2025-02-01. Esophageal adenocarcinoma relapse after chemoradiation is dominated by a basal-like subtype. https://doi.org/10.1101/2025.01.28.635332

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