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

Sascha Hoppe; Soha Noseir; Ali M. Yazbeck; Nestor Zaburannyi; Jan Großbach; Su Ir Lyu; Oscar Velázquez Camacho; Stefan Müller; Florian Gebauer; Vanessa Richartz; Barbara Holz; Johannes Berg; Viktor Achter; Janine Altmüller; Kerstin Becker; Christoph Arolt; Lydia Meder; Yue Zhao; Hans Schlößer; Wolfgang W. Baus; Florian Kamp; Christian Baues; Andreas Beyer; Margarete Odenthal; Alexander Quaas; Reinhard Büttner; Axel M. Hillmer

doi:10.1101/2025.01.28.635332

Cancer BiologybioRxivJan 28, 2025

Preprint

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

Sascha Hoppe iD, Soha Noseir, Ali M. Yazbeck iD, Nestor Zaburannyi iD, Jan Großbach iD, Su Ir Lyu iD, Oscar Velázquez Camacho iD, Stefan Müller iD, Florian Gebauer iD, Vanessa Richartz, Barbara Holz, Johannes Berg iD, Viktor Achter iD, Janine Altmüller iD, Kerstin Becker iD, Christoph Arolt iD, Lydia Meder iD, Yue Zhao, Hans Schlößer iD, Wolfgang W. Baus, Florian Kamp, Christian Baues iD, Andreas Beyer iD, Margarete Odenthal iD, Alexander Quaas iD, , Axel M. Hillmer iD

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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