Kounosuke Watabe, PhD
The studies of our laboratory focus on the molecular mechanism of tumor metastasis in breast and prostate cancers. Although the overall incidence of these cancers is gradually declining, more than 90% of cancer death is still attributable directly to the metastatic disease. Therefore, understanding the pathological mechanism of metastatic process is urgently needed in order to identify better therapeutic targets of this devastating disease. Our lab is working on the following four key areas, by particularly focusing on tumor microenvironment, cancer stem cells and non-coding RNAs.
Wu K, Fukuda K, Xing F, Zhang Y, Sharma S, Liu Y, Chan M, Zhou X, Qasem S, Pochampally R, Mo YY, Watabe K. Roles of the cyclooxygenase 2-matrix metalloproteinase 1 pathway in brain metastasis of breast cancer. J Biol Chem. 2015;290(15):9842-9854.
Xing F, Sharma S, Liu Y, Mo YY, Wu K, Zhang YY, Pochampally R, Martinez LA, Lo HW, Watabe K. miR-509 suppresses brain metastasis of breast cancer cells by modulating RhoC and TNF-alpha. Oncogene. 2015;():.
Paw I, Carpenter RC [sic] [Carpenter RL], Watabe K, Debinski W, Lo HW.Mechanisms regulating glioma invasion. Cancer Lett. 2015;362(1):1-7.
Carpenter RL, Paw I, Sirkisoon S, Xing F, Gibo D, Watabe K, Debinski W, Lo HW.The gain-of-function truncated GLI1 (TGLI1) promotes glioblastoma angiogenesis by direct upregulation of VEGF-C and TEM7 expression [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research (AACR); 2015 Apr 18-22; Philadelphia (PA). 2015;():A4165.
Johnson AG, Ruiz J, Hughes R, Page BR, Isom S, Lucas JT, McTyre ER, Houseknecht KW, Ayala-Peacock DN, Bourland DJ, Hinson WH, Laxton AW, Tatter SB, Debinski W, Watabe K, Chan MD. Impact of systemic targeted agents on the clinical outcomes of patients with brain metastases. Oncotarget. 2015;6(22):18945-55.
Tumor microenvironment of metastasis in the bone and the brainTumor metastasis occurs in a relatively organ-specific manner, and the tumor microenvironment in each organ plays important roles. Our research particularly focuses on both brain and bone metastasis of breast and prostate cancers. We identified specific components of host cells in these organs and clarified signaling networks in cancer stem cells and microenvironmental cells, which led to discoveries of several novel therapeutic targets and small molecules for potential clinical use. Selected publications:
- Okuda, H., Kobayashi, A., Xia, B., Watabe, M., Pai, S.K., Hirota, S., Xing, F., Liu, W., Pandey, P.R., Fukuda, K., Modur, V., Ghosh, A., Wilber, A., and Watabe, K. (2011) HAS2 promotes metastasis by stimulating interaction of breast cancer stem cells with macrophage and stromal cells in the bone. Cancer Res. 72, 537
- Kobayashi, A., Okuda, H., Pandey, P.R., Watabe, M., Hirota, S., Pai, S.K., Xing, F., Liu, W., Fukuda, K., Chambers, C., and Watabe, K. (2011) Roles of BMP7 in dormancy and recurrence of prostate cancer stem-like cell in bone. J. Exp. Med. 208, 2641 (ISMCBBPR due to this discovery) (BMP7 was selected as “Molecule of the year in 2011”)
- Xing, F., Okuda, H., Kobayashi, A., Watabe, M., Pai, S.K., Pandey, P.R., Hirota, S., Moore, B.E., Liu, W., Fukuda, K., Modur, V., Iiizumi, M., Wilber, A., Peralta, E., and Watabe, K. (2013). Reactive astrocytes promote the growth of cancer stem-like cells of metastatic breast tumor by activating Notch signaling in brain. EMBO Mol. Med. 5, 384 (cover story) (Faculty 1000)
- Wu, K., Fukuda, K., Xing, F., Zhan, Y., Liu, Y., Sharma, S., Mo, Y., Pochampally, R., and Watabe, K. (2015) Cooperative roles of Cox2 and MMP1 in brain metastasis of breast cancer. J. Biol. Chem. 290, 9842
Roles of microRNAs in tumor progressionMicroRNAs play critical roles in tumor progression at various stages. We are particularly interested in the roles of microRNAs in cancer stem cells in tumor metastasis. Our results revealed that different microRNAs promote metastasis of cancer stem cells in organ and stage specific manners. We also clarified how the expressions of these microRNAs are regulated through interaction with microenvironmental cells. Selected publications:
- Sachdeva, M., Zhu, S., Wu, F., Wu, H., Walia, V., Kumar, S., Elble, R., Watabe, K., and Mo, Y.-Y. (2009) p53 represses c-Myc through induction of the tumor suppressor miR-145. Proc. Natl. Acad. Sci. USA. 106, 3207
- Okuda, H., Xing, F., Pandey, P.R., Sharma, S., Watabe, M., Pai, S.K., Mo, Y.-Y., Iiizumi-Gairani, M., Hirota, S., and Watabe, K. (2013) miR-7 suppresses brain metastasis of cancer stem-like cells by modulating Kruppel-like factor 4 in breast cancer. Cancer Res. 73, 1434 (Cover story) (citation in Discover Magazine as top 100 science discovery in 2013)
- Xing, F., Sharma, S., Liu, Y., Mo Y., Wu K., Mo Y., Pochampally R., Lo, H.W., and Watabe, K. (2015) miR509 suppresses brain metastasis of breast cancer cells by modulating RhoC and TNF alpha. Oncogene. In press
Fatty acid metabolism in tumor initiation and progressionFatty acid synthesis plays a pivotal role in tumor initiation and progression by providing energy and cell membrane components to rapidly growing cancer cells. De novo synthesis of lipid is quite specific to cancer cells and blocking this process induces apoptosis to them. Thus the fatty acid synthase (FAS) is considered to be an excellent therapeutic target. In a series of publications, we reported (i) how FAS expression is regulated, (ii) what is the role of FAS in cancer stem cells, and (iii) molecular mechanism of FAS-mediated apoptosis. Our finding led to discoveries of additional targets in this pathway and provided a strong rationale for using FAS pathway inhibitors for the treatment of both early and late stages of cancer as well as recurrence disease. Selected publications:
- Bandyopadhyay, S., Fulk R.S., Pai, SK., Gross, SC., Hirota, S., Hosobe, S., Tsukada, T., Miura, K., Saito, K., Watabe, M., Wang Y., Huggenvik, J. Pauza, ME, Iiizumi, M. and Watabe K. (2005) FAS expression inversely correlates with PTEN level in prostate cancer and an Akt inhibitor synergizes with FAS siRNA to induce apoptosis. Oncogene, 24, 5389
- Bandyopadhyay, S., Zhan, R., Wang, Y., Pai, SK., Hirota, S., Hosobe, S., Takano, Y., Saito, K., Furuta, E., Iiizumi, M., Mohinta, S., Watabe, M., Chalfant, C., and Watabe, K. (2006) Mechanism of apoptosis induced by the inhibition of Fatty Acid Synthase in breast cancer cells. Cancer Res. 66, 5934
- Furuta, E., Pai, SK., Zhan, R., Bandyopadhyay, S., Watabe, M., Iiizumi, M., Liu, W., Mo, Y-Y., Hirota, S., Hosobe, S.,Tsukada,T., Miura,K., Kamada, S., Saito, K. and Watabe, K. (2008) Fatty acid synthase gene is up-regulated by hypoxia via activation of Akt and SREBP. Cancer Res. 68, 1003
- Pandey, P.R., Xing, F., Sharma, S., Watabe, M., Pai, S.K., Iiizumi- Gairani, M., Fukuda, K., Hirota, S., Mo, Y.-Y., and Watabe, K. (2012) Elevated lipogenesis in epithelial stem-like cell confers survival advantage in ductal carcinoma in situ of breast cancer. Oncogene, 10, 519
Identification of tumor metastasis suppressor genes and elucidating their functionsThe existence of tumor metastasis suppressor genes was long been predicted and they were expected to suppress only metastatic process but not tumor initiation. We identified several chromosomal regions of metastasis suppression in prostate and breast cancers. We also clarified the function of two key metastasis suppressor genes, KAI1 and NDRG1, their signaling pathways and mechanism by which they cross-talk each other. We then showed several small molecules that potentially activate these genes and suppress recurrence. Selected publications:
- Mashimo, T., Watabe, M., Hirota, S., Hosobe, S., Tagtmeyer, P., Rinker-Schaeffer, C. and Watabe, K. (1998). The expression of the KAI1 gene, a tumor metastasis suppressor, is directly activated by P53. Proc. Natl. Acad. Sci. USA. 95, 11307-11311
- Bandyopadhyay, S., Zhan, R., Chaudhuri, A., Watabe, M., Pai, S.K., Hirota, S., Hosobe, S., Tsukada, T., Miura, K., Takano, Y., Saito, K., Pauza, M.E., Hayashi, S., Wang, Y., Mohinta, S., Mashimo, T., Iiizumi, M., Furuta, E., and Watabe, K. (2006) Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression. Nature Med. 12, 933-9388
- Bandyopadhyay, S., Wang, Y., Zhan, R., Pai, S.K., Watabe, M., Iiizumi, M., Furuta, E., Mohinta, S., Liu, W., Hirota, S., Hosobe, S., Tsukada, T., Miura, K., Takano, Y., Saito, K., Commes, T., Piquemal, D., Hai, T., and Watabe, K. (2006) The tumor metastasis suppressor gene Drg-1 down regulates the expression of ATF3 in prostate cancer. Cancer Res. 66(24),11983-90
- Liu, W., Iiizumi-Gairani, M., Okuda, H., Watabe, M., Pai, S.K., Pandey, P.R., Hirota, S., Xing, F., Kobayashi, A., Mo, Y.-Y. Fukuda, K., Li, Y., and Watabe, K. (2012) Metastasis suppressor, NDRG1, pleiotropically inhibits tumor metastasis by modulating Wnt-β-catenin signaling: Targeting Wnt-NDRG1 pathway as a potential therapeutic opportunity. EMBO Mol. Med. 4, 93