Therapeutic Targeting of Metadherin Suppresses Colorectal and Lung Cancer Progression and Metastasis.

TitleTherapeutic Targeting of Metadherin Suppresses Colorectal and Lung Cancer Progression and Metastasis.
Publication TypeJournal Article
Year of Publication2021
AuthorsShen, M, Xie, S, Rowicki, M, Michel, S, Wei, Y, Hang, X, Wan, L, Lu, X, Yuan, M, Jin, JF, Jaschinski, F, Zhou, T, Klar, R, Kang, Y
JournalCancer Res
Volume81
Issue4
Pagination1014-1025
Date Published2021 02 15
ISSN1538-7445
KeywordsAdenocarcinoma, Animals, Cell Movement, Cell Proliferation, Cells, Cultured, Colorectal Neoplasms, Disease Progression, Gene Expression Regulation, Neoplastic, Genetic Therapy, HEK293 Cells, Humans, Lung Neoplasms, Membrane Proteins, Mice, Mice, Inbred C57BL, Molecular Targeted Therapy, Neoplasm Metastasis, Oligonucleotides, Oligonucleotides, Antisense, RNA-Binding Proteins, Xenograft Model Antitumor Assays
Abstract

<p>Colorectal and lung cancers account for one-third of all cancer-related deaths worldwide. Previous studies suggested that metadherin (MTDH) is involved in the development of colorectal and lung cancers. However, how MTDH regulates the pathogenesis of these cancers remains largely unknown. Using genetically modified mouse models of spontaneous colorectal and lung cancers, we found that MTDH promotes cancer progression by facilitating Wnt activation and by inducing cytotoxic T-cell exhaustion, respectively. Moreover, we developed locked nucleic acid-modified (LNA) MTDH antisense oligonucleotides (ASO) that effectively and specifically suppress MTDH expression and . Treatments with MTDH ASOs in mouse models significantly attenuated progression and metastasis of colorectal, lung, and breast cancers. Our study opens a new avenue for developing therapies against colorectal and lung cancers by targeting MTDH using LNA-modified ASO. SIGNIFICANCE: This study provides new insights into the mechanism of MTDH in promoting colorectal and lung cancers, as well as genetic and pharmacologic evidence supporting the development of MTDH-targeting therapeutics.</p>

DOI10.1158/0008-5472.CAN-20-1876
Alternate JournalCancer Res
PubMed ID33239430
PubMed Central IDPMC8026491
Grant ListP30 CA072720 / CA / NCI NIH HHS / United States
R01 CA134519 / CA / NCI NIH HHS / United States