Notch signaling drives stemness and tumorigenicity of esophageal adenocarcinoma

Zhiqiang Wang, Thiago G. Da Silva, Ke Jin, Xiaoqing Han, Prathibha Ranganathan, Xiaoxia Zhu, Avencia Sanchez-Mejias, Feng Bai, Bin Li, Dennis Liang Fei, Kelly Weaver, Rodrigo Vasquez-Del Carpio, Anna E. Moscowitz, Vadim P. Koshenkov, Lilly Sanchez, Lynne Sparling, Xin Hai Pei, Dido Franceschi, Afonso Ribeiro, David J. RobbinsAlan S. Livingstone, Anthony J. Capobianco

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Abstract

Esophageal adenocarcinoma ranks sixth in cancer mortality in the world and its incidence has risen dramatically in the Western population over the last decades. Data presented herein strongly suggest that Notch signaling is critical for esophageal adenocarcinoma and underlies resistance to chemotherapy. We present evidence that Notch signaling drives a cancer stem cell phenotype by regulating genes that establish stemness. Using patient-derived xenograft models, we demonstrate that inhibition of Notch by gamma-secretase inhibitors (GSI) is efficacious in downsizing tumor growth. Moreover, we demonstrate that Notch activity in a patient's ultrasound-assisted endoscopic-derived biopsy might predict outcome to chemotherapy. Therefore, this study provides a proof of concept that inhibition of Notch activity will have efficacy in treating esophageal adenocarcinoma, offering a rationale to lay the foundation for a clinical trial to evaluate the efficacy of GSI in esophageal adenocarcinoma treatment.

Original languageEnglish (US)
Pages (from-to)6364-6374
Number of pages11
JournalCancer Research
Volume74
Issue number21
DOIs
StatePublished - Nov 1 2014

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Wang, Z., Da Silva, T. G., Jin, K., Han, X., Ranganathan, P., Zhu, X., Sanchez-Mejias, A., Bai, F., Li, B., Fei, D. L., Weaver, K., Vasquez-Del Carpio, R., Moscowitz, A. E., Koshenkov, V. P., Sanchez, L., Sparling, L., Pei, X. H., Franceschi, D., Ribeiro, A., ... Capobianco, A. J. (2014). Notch signaling drives stemness and tumorigenicity of esophageal adenocarcinoma. Cancer Research, 74(21), 6364-6374. https://doi.org/10.1158/0008-5472.CAN-14-2051