DEGsPPThe Laboratory for Cancer Invasion and Metastasis started in August 2022. 57Untreated+BMP-4e.g., TNF superfamily molecule(s)Glioma-Initiating Cells (GICs)BMPOur major research interest is to identify target molecules that can be used for the treatment of intractable cancers, such as glioblastoma and pancre-atic cancer. Bone morphogenetic proteins (BMPs), members of the transform-ing growth factor-β family, induce growth arrest and differentiation of glioma-initiating cells (GICs). Through RNA-sequencing analysis of GICs treated or not with BMP-4, we have identified certain genes regulated by BMPs, including Distal-less homeobox 2 (DLX2), paired related homeobox 1 (PRRX1), and her-pes virus entry mediator (HVEM; also known as tumor necrosis factor recep-tor superfamily member 14 or TNFRSF14). Expression of DLX2 and PRRX1 is induced by BMPs, whereas that of HVEM is suppressed by BMP-4 in certain glioblastoma cells. Among subtypes of glioblastoma, including proneural, classical, and mesenchymal subtypes, we have found that HVEM is highly ex-pressed in the mesenchymal subtype of human glioblastoma cells and tissues. Silencing or knockout of HVEM expression resulted in reduced proliferation and neurosphere formation by glioblastoma cells in cell culture and decreased tumorigenic ability and prolonged survival of mice after intracranial injection of the glioblastoma cells.We have generated an anti-human HVEM-VHH antibody by immunizing alpaca. The anti-human HVEM-VHH antibody was humanized and the Fc portion of human IgG was attached to obtain a longer half-life of the antibody in the blood circulation. We have succeeded in 3-dimensional analysis of the HVEM-anti-HVEM antibody complex. Pre-clinical studies of the anti-human HVEM-VHH antibody, including pharmacokinetic and safety studies, have been conducted, and further studies, including the evaluation of the effects of the antibody using patient-derived xenograft (PDX) models, are ongoing.Type I receptorPType II receptorGene(s) regulated by BMP-4Therapeutic target gene(s)Loss of stem cell-like propertiesDifferential gene expressionin malignant GBM tissuesGBM samplesFigure: TNF superfamily protein(s) as molecular targets for the mesenchymal subtype of glio-blastomaBone morphogenetic proteins (BMPs) induce differen-tiation of glioma-initiating cells (GICs). Tumor necrosis factor (TNF) superfamily molecule(s) have been identi-fied as therapeutic molecular targets for the mesenchy-mal subtype of glioblastoma multiforme (GBM).Recent Major PublicationsTokizaki S, Podyma-Inoue KA, Matsumoto T, Takahashi K, Kobayashi M, Ibi H, Uchida S, Iwabuchi S, Harada H, Hashimoto S, Miyazono K, Shirouzu M, Watabe T. Inhibi-tion of transforming growth factor-β signals suppresses tumor formation by regulation of tumor microenviron-ment networks. Cancer Sci 115, 211-226 (2023)Takahashi Kei, Abe K, Kubota SI, Fukatsu N, Morishita Y, Yoshimatsu Y, Hirakawa S, Kubota Y, Watabe T, Ehata S, Ueda HR, Shimamura T, Miyazono K. An analysis modal-ity for vascular structures combining tissue-clearing technology and topological data analysis. Nat Commun 13, 5239 (2022)Takahashi Kazuki, Podyma-Inoue KA, Saito M, Sakakitani S, Sugauchi A, Iida K, Iwabuchi S, Koinuma D, Kurioka K, Konishi T, Tanaka S, Kaida A, Miura M, Hashimoto S, Okada M, Uchihashi T, Miyazono K, Watabe T. TGF-β generates a population of cancer cells residing in G1 phase with high motility and metastatic potential via KRTAP2-3. Cell Rep 40, 111411 (2022)Invited presentationsMiyazono K. “Diverse functions of BMP signaling on glioblastoma-initiating cells” The 41st Annual Meeting the Japan Society for Neuro-Oncology (Niigata, Japan) December 2023Miyazono K. “Cancer research from the perspective of TGF-β research” The 82nd Annual Meeting of the Japa-nese Cancer Association, Special Symposium: Encounter of Cancer Research and Molecular Biology: Symposium in Commemoration of Professor Fumimaro Takaku (Yo-kohama, Japan) September 2023Miyazono K, Tanabe R, Matsumoto T. “HVEM as a molec-ular target of glioblastoma” TGF-β meeting in Uppsala 2023 (Uppsala, Sweden) August 2023Miyazono K. “BMPs: Their diverse functions and relation to disease” The 41st Annual Meeting of the Japanese Society for Bone and Mineral Research (Tokyo, Japan) July 2023Miyazono K. “Roes of TGF-β family signaling in cancer progression: Diversity and plasticity of the mesenchymal cancer cells” Rudbeck Laboratory Seminar, Uppsala Uni-versity, Sweden (Uppsala, Sweden) February 2023vsLaboratory for Cancer Invasion and MetastasisTeam Leader: Kohei Miyazono
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