Characterization of novel genes involved in age-related CNS disorders, such as glioma and Alzheimer disease, and the development of new therapeutic methods for these diseases.

Professor Toru KONDO, Ph.D.

original page https://www.igm.hokudai.ac.jp/stemcell/ (Japanese only)

Our research objectives are (1) to characterize the glioma-initiating cells (GIC) induced from neural stem cells (NSC) and oligodendrocyte precursor cells (OPC), find GIC-specific factors and develop new therapeutic strategies and (2) to characterize factors involved in NSC/OPC senescence and investigate the relationship between candidate factors and age-related disorders.

Characterization of glioma-initiating cells (GICs) and identification of therapeutic targets.

It has been revealed that malignant tumors contain cancer initiating cells (CICs), which express tissue-specific stem cell markers, form tumors, and are resistant to irradiation and chemotherapy, suggesting that CICs are the essential therapeutic target. To characterize CIC, we established induced mouse CIC lines from NSCs and OPCs by overexpressing an oncogene and repressing a tumor suppressor gene: They form malignant glioma even when ten cells are injected into brain of immunodeficient mice, indicating that they are enriched for bona fide CICs. Using DNA microarray analysis, RT-PCR, and/or immunochemistry, we have found potential candidate genes, which increase and decrease in GICs and non-GICs respectively, are characterizing them and are developing novel antibody-based therapeutics.

A: Therapeutic strategies targeting GIC-specific membrane proteins.

B: Identification of GIC-specific miRNAs.

Analysis of Ecrg4 peptide hormone

The esophageal cancer related gene 4(Ecrg4) encodes a putative peptide hormone, and has been shown to be a novel senescence factor in OPCs and NSCs in our laboratory. Recent increasing evidence indicates that Ecrg4 also function as a tumor suppressor gene. Using mouse induced glioma-initiating cells (GICs) derived from Ecrg4-knockout NSCs, we identified that Ecrg4(-/-) GICs generated tumors more quickly and with higher percentage in immunocompetent mice. We identified Ecrg4 receptor and are now examining molecular mechanisms in tumorigenesis. Furthermore, we are studying about the function of Ecrg4-signaling in variety of biological phenomena including age-related diseases.

A: OPCs become senescent in the presence of high concentration of FCS with the increased level of SA-beta gal activity and cell-cycle arrest.

B: Overexpression of Ecrg4 induces cell senescence in OPCs. It is detected in OPCs and NSCs in the aged brain.

Analysis of a master regulator in cancer invasion and metastasis

Overexpression of HOXD3 converts epithelial cell-like morphology (upper) of human lung cancer cells to fibroblastic morphology (bottom). This phenomenon resembles the epithelial-mesenchymal transition, an important step in an early stage of metastasis.