Inhibition of MACC1-Induced Metastasis in Esophageal and Gastric Adenocarcinomas

Christoph Treese; Jessica Werchan; Moritz von Winterfeld; Erika Berg; Michael Hummel; Lena Timm; Beate Rau; Ole Daberkow; Wolfgang Walther; Severin Daum; Dennis Kobelt; Ulrike Stein

doi:10.3390/cancers14071773

Cancers (Mar 2022)

Inhibition of MACC1-Induced Metastasis in Esophageal and Gastric Adenocarcinomas

Christoph Treese,
Jessica Werchan,
Moritz von Winterfeld,
Erika Berg,
Michael Hummel,
Lena Timm,
Beate Rau,
Ole Daberkow,
Wolfgang Walther,
Severin Daum,
Dennis Kobelt,
Ulrike Stein

Affiliations

Christoph Treese: Experimental and Clinical Research Center, Charité–Universitätsmedizin and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany
Jessica Werchan: Experimental and Clinical Research Center, Charité–Universitätsmedizin and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany
Moritz von Winterfeld: Institute of Pathology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
Erika Berg: Institute of Pathology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
Michael Hummel: Institute of Pathology, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
Lena Timm: Experimental and Clinical Research Center, Charité–Universitätsmedizin and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany
Beate Rau: Department of Surgery, Campus Virchow-Klinikum and Campus Mitte, Charité–Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, 10117 Berlin, Germany
Ole Daberkow: EPO Experimentelle Pharmakologie & Onkologie, 13125 Berlin, Germany
Wolfgang Walther: Experimental and Clinical Research Center, Charité–Universitätsmedizin and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany
Severin Daum: Department of Gastroenterology, Infectious Diseases and Rheumatology, Campus Benjamin Franklin, Charité–Universitätsmedizin Berlin, Corporate Member Freie Universität Berlin and Humboldt-Universität zu Berlin, 12203 Berlin, Germany
Dennis Kobelt: Experimental and Clinical Research Center, Charité–Universitätsmedizin and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany
Ulrike Stein: Experimental and Clinical Research Center, Charité–Universitätsmedizin and Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany

DOI: https://doi.org/10.3390/cancers14071773
Journal volume & issue: Vol. 14, no. 7
p. 1773

Abstract

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Esophageal and Gastric Adenocarcinomas (AGE/S) are characterized by early metastasis and poor survival. MACC1 (Metastasis Associated in Colon Cancer 1) acts in colon cancer as a metastasis inducer and is linked to reduced survival. This project illuminates the role and potential for the inhibition of MACC1 in AGE/S. Using 266 of 360 TMAs and survival data of AGE/S patients, we confirm the value of MACC1 as an independent negative prognostic marker in AGE/S patients. MACC1 gene expression is correlated with survival and morphological characteristics. In vitro analysis of lentivirally MACC1-manipulated subclones of FLO-1 and OE33 showed enhanced migration induced by MACC1 in both cell line models, which could be inhibited by the MEK1 inhibitor selumetinib. In vivo, the efficacy of selumetinib on tumor growths and metastases of MACC1-overexpressing FLO-1 cells xenografted intrasplenically in NOG mice was tested. Mice with high-MACC1-expressing cells developed faster and larger distant metastases. Treatment with selumetinib led to a significant reduction in metastasis exclusively in the MACC1-positive xenografts. MACC1 is an enhancer of tumor aggressiveness and a predictor of poor survival in AGE/S. This effect can be inhibited by selumetinib.

Published in Cancers

ISSN: 2072-6694 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Medicine: Internal medicine: Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Website: https://www.mdpi.com/journal/cancers/

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