Esophageal adenocarcinoma relapse after chemoradiation is dominated by a basal-like phenotype
Incidence of esophageal adenocarcinoma (EAC) is rising in Western countries over the last decades. It is a deadly disease where 80% of patients die within the first five years after diagnosis. Neoadjuvant chemoradiation therapy (RCT) is standard of care but response varies dramatically across patients and early relapse is a clinical challenge. Treatment resistance - acquired under therapy as well as primary - is a major problem. In the present study, we aimed at identifying the molecular mechanisms that lead to RCT resistance. We established a mouse xenograft RCT model with human EAC cell lines representing different response groups. Since EAC is characterized by a high level of genomic instability, we enhanced in parallel experiments genomic instability as a potential evolutionary engine by reducing BRCA2 function. We observed a strong transcriptomic and proteomic phenotype by BRCA2 knock down in xenografts and increased genomic instability. In BRCA2 proficient xenografts, we found after RCT a recurrent copy gain on chromosome 19q with BCL2L12 as a potential oncogenic driver. Relapsed xenografts after RCT displayed an upregulation of stress response keratins, including KRT6 and KRT16 connected with a basal-like transcriptomic/proteomic phenotype. Taking KRT6 as a marker for this phenotype, we screened our cohort of 840 EAC and found widespread KRT6 expression in 9.6% of tumors. High KRT6 expressing EACs were significantly associated with short overall survival and this associatin was driven by patients with neoadjuvant treatment (p = 0.00071). Overall, we identify a basal-like cell state in EAC that reflects RCT relapse. The basal-like phenotype is a marker for treatment failure and provides a new avenue for translational research to overcome RCT resistance.