Metastatic breast cancer is a leading health burden worldwide. Previous studies have shown that metadherin (MTDH) promotes breast cancer initiation, metastasis and therapy resistance; however, the therapeutic potential of targeting MTDH remains largely unexplored. Here, we used genetically modified mice and demonstrate that genetic ablation of Mtdh inhibits breast cancer development through disrupting the interaction with staphylococcal nuclease domain-containing 1 (SND1), which is required to sustain breast cancer progression in established tumors. We performed a small-molecule compound screening to identify a class of specific inhibitors that disrupts the protein-protein interaction (PPI) between MTDH and SND1 and show that our lead candidate compounds C26-A2 and C26-A6 suppressed tumor growth and metastasis and enhanced chemotherapy sensitivity in preclinical models of triple-negative breast cancer (TNBC). Our results demonstrate a significant therapeutic potential in targeting the MTDH-SND1 complex and identify a new class of therapeutic agents for metastatic breast cancer.
Endonucleases/metabolism , Membrane Proteins/metabolism , Micrococcal Nuclease , RNA-Binding Proteins/metabolism , Triple Negative Breast Neoplasms , Animals , Cell Adhesion Molecules/genetics , Humans , Membrane Proteins/genetics , Mice , RNA-Binding Proteins/genetics , Transcription Factors
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 in vitro and in vivo. 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.
Adenocarcinoma/therapy , Colorectal Neoplasms/therapy , Lung Neoplasms/therapy , Membrane Proteins/antagonists & inhibitors , Oligonucleotides, Antisense/therapeutic use , RNA-Binding Proteins/antagonists & inhibitors , Adenocarcinoma/genetics , Adenocarcinoma/pathology , Animals , Cell Movement/drug effects , Cell Movement/genetics , Cell Proliferation/drug effects , Cell Proliferation/genetics , Cells, Cultured , Colorectal Neoplasms/genetics , Colorectal Neoplasms/pathology , Disease Progression , Gene Expression Regulation, Neoplastic/drug effects , Genetic Therapy/methods , HEK293 Cells , Humans , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Membrane Proteins/genetics , Mice , Mice, Inbred C57BL , Molecular Targeted Therapy/methods , Neoplasm Metastasis , Oligonucleotides/pharmacology , Oligonucleotides/therapeutic use , Oligonucleotides, Antisense/pharmacology , RNA-Binding Proteins/genetics , Xenograft Model Antitumor Assays
