Depletion of FOXM1 via MET Targeting Underlies Establishment of a DNA Damage-Induced Senescence Program in Gastric Cancer.

Francica, Paola; Nisa Hernandez, Lluis; Aebersold, Daniel; Langer, Rupert; Bladt, Friedhelm; Blaukat, Andree; Keogh-Stroka, Deborah M.; Martínez, María Rodríguez; Zimmer, Yitzhak; Medova, Michaela (2016). Depletion of FOXM1 via MET Targeting Underlies Establishment of a DNA Damage-Induced Senescence Program in Gastric Cancer. Clinical cancer research, 22(21), pp. 5322-5336. American Association for Cancer Research 10.1158/1078-0432.CCR-15-2987

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PURPOSE

Deregulated signaling via the MET receptor tyrosine kinase is abundant in gastric tumors, with up to 80% of cases displaying aberrant MET expression. A growing body of evidence suggests MET as a potential target for tumor radiosensitization.

EXPERIMENTAL DESIGN

Cellular proliferation and DNA damage-induced senescence were studied in a panel of MET-overexpressing human gastric cancer cell lines as well as in xenograft models after MET inhibition and/or ionizing radiation. Pathways activation and protein expression were assessed by immunoblotting and immunohistochemistry. Tumor tissue microarrays (91 gastric cancer patients) were generated and copy number alteration (178 patients) and gene expression (373 patients) data available at The Cancer Genome Atlas were analyzed to assess the coalterations of MET and FOXM1.

RESULTS

MET targeting administered before ionizing radiation instigates DNA damage-induced senescence (∼80%, P < 0.001) rather than cell death. MET inhibition-associated senescence is linked to the blockade of MAPK pathway, correlates with downregulation of FOXM1, and can be abrogated (11.8% vs. 95.3%, P < 0.001) by ectopic expression of FOXM1 in the corresponding gastric tumor cells. Cells with ectopic FOXM1 expression demonstrate considerable (∼20%, P < 0.001) growth advantage despite MET targeting, suggesting a novel clinically relevant resistance mechanism to MET inhibition as the copresence of both MET and FOXM1 protein (33%) and mRNA (30%) overexpression as well as gene amplification (24,7%) are common in patients with gastric cancer.

CONCLUSIONS

FOXM1, a negative regulator of senescence, has been identified as a key downstream effector and potential clinical biomarker that mediates MET signaling following infliction of DNA damage in gastric tumors. Clin Cancer Res; 22(21); 5322-36. ©2016 AACR.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Viszeralchirurgie 04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Visceral Surgery 04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Radiation Oncology 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Radio-Onkologie 04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Radio-Onkologie 04 Faculty of Medicine > Service Sector > Institute of Pathology
Graduate School:	Graduate School for Cellular and Biomedical Sciences (GCB)
UniBE Contributor:	Francica, Paola, Nisa Hernandez, Lluis, Aebersold, Daniel Matthias, Langer, Rupert, Stroka, Deborah, Zimmer, Yitzhak, Medova, Michaela
Subjects:	600 Technology > 610 Medicine & health 500 Science > 570 Life sciences; biology
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Language:	English
Submitter:	Doris Haefelin
Date Deposited:	22 Dec 2016 13:08
Last Modified:	02 Mar 2023 23:28
Publisher DOI:	10.1158/1078-0432.CCR-15-2987
PubMed ID:	27185371
URI:	https://boris.unibe.ch/id/eprint/92027