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OLFM4-RET fusion is an oncogenic driver in small intestine adenocarcinoma

Oncogene volume 41, pages 72–82 (2022)Cite this article

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Abstract

Small intestine adenocarcinoma is a rare intestinal malignancy with distinct clinical, pathological, and molecular characteristics. Recently, a fusion of the intestinal stem-cell marker olfactomedin 4 (OLFM4) and the proto-oncogene RET has been identified in a small intestine adenocarcinoma patient. Here we investigated the biological effects of OLFM4-RET fusion and whether it can initiate tumorigenesis in small intestine. OLFM4 expression was found to be frequently lost or reduced in human small intestine adenocarcinoma, and its downregulation correlated with high tumor grade and advanced tumor stage. Expression of OLFM4-RET fusion-induced cellular transformation in HEK293 cells and blocked RET-induced inhibition of colony growth in HuTu 80 small intestine adenocarcinoma cells. Further, expression of OLFM4-RET activated the RAS-RAF-MAPK and STAT3 cell signaling pathways in both HEK293 cells and HuTu 80 cells. OLFM4-RET expression in HEK293 cells upregulated multiple families of genes related to carcinogenesis, cancer progression, and metastasis. Targeted expression of OLFM4-RET in the small intestine led to the development of hyperplasia, adenoma, or adenocarcinoma in transgenic mice. Our study suggests that OLFM4-RET is an oncogenic driver of small intestine tumorigenesis. Therefore, the small intestine adenocarcinoma patients with OLFM4-RET fusion may benefit from treatment with RET kinase inhibitor.

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Fig. 1: OLFM4 expression in normal small intestine and small intestine adenocarcinoma.
Fig. 2: OLFM4-RET fusion expression in HEK293 cells affects cellular proliferation and colony formation.
Fig. 3: OLFM4 N-terminal coiled-coil domain mediates OLFM4 and OLFM4-RET oligomerization.
Fig. 4: OLFM4-RET expression increases RET (Y905) autophosphorylation and activates the MAPK-ERK1/2 and STAT3 signaling pathways.
Fig. 5: OLFM4-RET induces expression of genes associated with carcinogenesis and cancer progression in HEK293 cells.
Fig. 6: Differential effect of RET and OLFM4-RET expression on cell proliferation, tumorigenesis, and cell signaling in HuTu 80 small intestine adenocarcinoma cells.
Fig. 7: OLFM4-RET transgenic mice develop tumors in small intestine.

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Acknowledgements

We thank Dr. Deborah Gumucio at the University of Michigan for providing the Villin-ΔATG plasmid. We thank Ms. Huiyan Lu at the National Institute of Diabetes and Digestive and Kidney Disease, NIH for assistance in creating the Villin-OLFM4-RET transgenic mice. We thank Drs. Yuesheng Li, Poching Liu, and Yan Luo at the DNA Sequencing and Genomics Core Facility, National Heart, Lung, and Blood Institute, NIH for help with RNA sequencing and data analysis.

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  1. Molecular and Clinical Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda, MD, USA

    Wenli Liu, Hongzhen Li, Wulin Aerbajinai & Griffin P. Rodgers

  2. Laboratory of Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, 20892, USA

    Istvan Botos

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WL and GPR designed the experiments and analyzed the data. WL, HL, WA, and IB performed the experiments. WL wrote the manuscript. GPR supervised the entire study.

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Correspondence to Griffin P. Rodgers.

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Liu, W., Li, H., Aerbajinai, W. et al. OLFM4-RET fusion is an oncogenic driver in small intestine adenocarcinoma. Oncogene 41, 72–82 (2022). https://doi.org/10.1038/s41388-021-02072-1

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