Involvement of Hippo pathway in epigenetic control in lung cancer

• Project/Area Number: 16K08672
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Jichi Medical University
• Principal Investigator: Matsubara Daisuke 自治医科大学, 医学部, 准教授 (80415554)
• Project Period (FY): 2016-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: Hippo pathway / LATS2 / YAP1 / CADM1 / 神経内分泌分化 / Non-TRU / TTF-1 / Neuroendocrine / Lung adenocarcinoma / TFF-1 / Non-TRU type / TTF-1/NKX2-1 mutations / SCLC / LCNEC / chemosensitivity / 癌 / 肺癌 / エピゲノム

Outline of Final Research Achievements

We revealed that CADM1 forms complexes with Hippo pathway core molecules like MST1/2 and LATS1/2 at the cell membrane, and co-expressions of CADM1 and LATS2 in membrane correlated with better prognosis in primary lung adenocarcinomas (2019, Cancer Sci). We also revealed that loss of YAP1 was characteristics to neuroendocrine tumors of the lung, and YAP1 was correlated with resistance to chemotherapy, and Knock down of YAP1 induced the expression of RAB3A, a neuroendocrine marker (2016, Cancer Sci).

Academic Significance and Societal Importance of the Research Achievements

CADM1は腫瘍抑制因子として良く知られるが、接着分子であるCADM1がなぜ腫瘍抑制的に働くのか、その機序の解明は不十分であった。我々は、CADM1がHippo pathwayを介して、腫瘍抑制に働くことを見出した。さらに、Hippo pathwayのターゲット分子であるYAP1のLossが小細胞癌などの神経内分泌腫瘍において特徴的に認められることを見出したのは、我々の報告が最初である。YAP1は細胞分化にも関与している可能性が示された。

Research Products

• [Journal Article] A Non-smoking Woman with Anti-phospholipid Antibodies Proved to Have Thromboangiitis Obliterans (2020)
  • Author(s): Shima Natsuki、Akiyama Yoichiro、Yamamoto Shotaro、Kokuzawa Ayako、Nagatani Katsuya、Iwamoto Masahiro、Matsubara Daisuke、Kawai Shigeo、Sato Kojiro、Minota Seiji
  • Journal Title: Internal Medicine Volume: 59 Issue: 3 Pages: 439-443
  • DOI: 10.2169/internalmedicine.3372-19
  • NAID: 130007793779
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2020-02-01
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reciprocal expression of trefoil factor‐1 and thyroid transcription factor‐1 in lung adenocarcinomas (2020)
  • Author(s): Matsubara Daisuke、Yoshimoto Taichiro、Soda Manabu、Amano Yusuke、Kihara Atsushi、Funaki Toko、Ito Takeshi、Sakuma Yuji、Shibano Tomoki、Endo Shunsuke、Hagiwara Koichi、Ishikawa Shumpei、Fukayama Masashi、Murakami Yoshinori、Mano Hiroyuki、Niki Toshiro
  • Journal Title: Cancer Science Volume: 111 Issue: 6 Pages: 1-13
  • DOI: 10.1111/cas.14403
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Desmoplastic small round cell tumor showing solid proliferation with limited desmoplasia and confusing immunohistochemical findings: an autopsy report (2020)
  • Author(s): Kihara Atsushi、Takahashi Kazuya、Ishikawa Ayataka、Amano Yusuke、Matsubara Daisuke、Kanda Hiroaki、Sata Naohiro、Fukushima Noriyoshi、Niki Toshiro
  • Journal Title: Medical Molecular Morphology Volume: 1 Issue: 3 Pages: 1-6
  • DOI: 10.1007/s00795-019-00242-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CADM1 associates with Hippo pathway core kinases; membranous coexpression of CADM1 & LATS2 in lung tumors predicts good prognosis. (2019)
  • Author(s): Takeshi Ito Atsuko Nakamura Ichidai Tanaka Yumi Tsuboi Teppei Morikawa Jun Nakajima Daiya Takai Masashi Fukayama Yoshitaka Sekido Toshiro Niki Daisuke Matsubara（Corresponding author） Yoshinori Murakami
  • Journal Title: Cancer Science Volume: in press Issue: 7 Pages: 2284-2295
  • DOI: 10.1111/cas.14040
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Massively parallel sequencing of tenosynovial giant cell tumors reveals novel CSF1 fusion transcripts and novel somatic CBL mutations (2019)
  • Author(s): Tsuda Yusuke、Matsubara Daisuke (5th) etc
  • Journal Title: International Journal of Cancer Volume: 145 Issue: 12 Pages: 3276-3284
  • DOI: 10.1002/ijc.32421
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Mucin 21 is a key molecule involved in the incohesive growth pattern in lung adenocarcinoma (2019)
  • Author(s): Yoshimoto Taichiro、Matsubara Daisuke、Soda Manabu、Ueno Toshihide、Amano Yusuke、Kihara Atsushi、Sakatani Takashi、Nakano Tomoyuki、Shibano Tomoki、Endo Shunsuke、Hagiwara Koichi、Fukayama Masashi、Denda‐Nagai Kaori、Irimura Tatsuro、Mano Hiroyuki、Niki Toshiro
  • Journal Title: Cancer Science Volume: 110 Issue: 9 Pages: 3006-3011
  • DOI: 10.1111/cas.14129
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Stromal p16 Expression Helps Distinguish Atypical Polypoid Adenomyoma From Myoinvasive Endometrioid Carcinoma of the Uterus (2019)
  • Author(s): Kihara Atsushi、Amano Yusuke、Yoshimoto Taichiro、Matsubara Daisuke、Fukushima Noriyoshi、Fujiwara Hiroyuki、Niki Toshiro
  • Journal Title: The American Journal of Surgical Pathology Volume: 43 Issue: 11 Pages: 1526-1535
  • DOI: 10.1097/pas.0000000000001320
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Integrated exome and RNA sequencing of dedifferentiated liposarcoma (2019)
  • Author(s): Hirata Makoto、Matsubara Daisuke (21th) etc
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 1-12
  • DOI: 10.1038/s41467-019-13286-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Liver heterotopia associated with congenital diaphragmatic hernia (2019)
  • Author(s): Mito Kumiko、Amano Yusuke、Oshiro Hisashi、Matsubara Daisuke、Fukushima Noriyoshi、Ono Shigeru
  • Journal Title: Medicine Volume: 98 Issue: 4 Pages: e14211-e14211
  • DOI: 10.1097/md.0000000000014211
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ras activation in retinal progenitor cells induces tumor formation in the eye (2019)
  • Author(s): Koso Hideto、Tsuhako Asano、Matsubara Daisuke、Fujita Yasuyuki、Watanabe Sumiko
  • Journal Title: Experimental Eye Research Volume: 180 Pages: 39-42
  • DOI: 10.1016/j.exer.2018.11.025
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Duodenal gastrointestinal stromal tumors appear similar to pancreatic neuroendocrine tumors: A case report (2018)
  • Author(s): Futo Yurie、Saito Shin、Miyato Hideyo、Sadatomo Ai、Kaneko Yuki、Kono Yoshihiko、Matsubara Daisuke、Horie Hisanaga、Lefor Alan Kawarai、Sata Naohiro
  • Journal Title: International Journal of Surgery Case Reports Volume: 53 Pages: 358-361
  • DOI: 10.1016/j.ijscr.2018.11.011
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pediatric ovarian dysgerminoma with highly elevated serum neuron-specific enolase (2018)
  • Author(s): Hayase Tomomi、Matsubara Daisuke、Maeda Kosaku、Aihara Toshinori、Morimoto Akira
  • Journal Title: Pediatrics International Volume: 60 Issue: 10 Pages: 982-983
  • DOI: 10.1111/ped.13676
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Expression of protein arginine methyltransferase-5 in oral squamous cell carcinoma and its significance in epithelial-to-mesenchymal transition. (2018)
  • Author(s): Amano Y, Matsubara D, Yoshimoto T, Tamura T, Nishino H, Mori Y, Niki T
  • Journal Title: Pathol int Volume: Mar 30 Issue: 6 Pages: 1-8
  • DOI: 10.1111/pin.12666
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Establishment and analysis of a novel mouse line carrying a conditional knockin allele of a cancer-specific FBXW7 mutation. (2018)
  • Author(s): Ikenoue T, Terakado Y, Zhu C, Liu X, Ohsugi T, Matsubara D, Fujii T, Kakuta S,Kubo S, Shibata T, Yamaguchi K, Iwakura Y, Furukawa Y.
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 2021-2021
  • DOI: 10.1038/s41598-018-19769-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Synchronous gastric leiomyoma and intramuscular abdominal wall granular cell tumor with similar imaging features: A case report. (2018)
  • Author(s): Saito S, Yan C, Fukuda H, Hosoya Y, Matsumoto S, Matsubara D, Kitayama J,Lefor AK, Sata N.
  • Journal Title: Int J Surg Case Rep Volume: 44 Pages: 207-211
  • DOI: 10.1016/j.ijscr.2018.03.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] An isolated metachronous metastasis to the adrenal gland from a pancreatic neuroendocrine tumor: A case report. (2017)
  • Author(s): Sakuma Y, Sata N, Endo K, Yasuda Y, Yokota S, Hosoya Y, Shimizu A, Fujii H,Matsubara D, Fukushima N, Asakawa S, Shimada YK, Lefor CK, Lefor AK.
  • Journal Title: Int J Surg Case Rep Volume: 41 Pages: 169-173
  • DOI: 10.1016/j.ijscr.2017.10.017
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Establishment of highly metastatic KRAS mutant lung cancer cell sublines in long-term three-dimensional low attachment cultures. (2017)
  • Author(s): Nakano T, Kanai Y, Amano Y, Yoshimoto T, Matsubara D, Shibano T, Tamura T, Oguni S, Katashiba S, Ito T, Murakami Y, Fukayama M, Murakami T, Endo S, Niki T.
  • Journal Title: Plos One Volume: 12 Issue: 8 Pages: e0181342-e0181342
  • DOI: 10.1371/journal.pone.0181342
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inactivating mutations and hypermethylation of the NKX2-1/TTF-1 gene in non-terminal respiratory unit-type lung adenocarcinomas. (2017)
  • Author(s): Matsubara D, Soda M, Yoshimoto T, Amano Y, Sakuma Y, Yamato A, Ueno T, Kojima S, Shibano T, Hosono Y, Kawazu M, Yamashita Y, Endo S, Hagiwara K, Fukayama M,Takahashi T, Mano H, Niki T.
  • Journal Title: Cancer Sci Volume: 108 Issue: 9 Pages: 1888-1896
  • DOI: 10.1111/cas.13313
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A case of primary aldosteronism caused by unilateral multiple adrenocortical micronodules presenting as muscle cramps at rest: The importance of functional histopathology for identifying a culprit lesion. (2017)
  • Author(s): Ito A, Yamazaki Y, Sasano H, Matsubara D, Fukushima N, Tamba M, Tabata K, Ashizawa K, Takei A, Koizumi M, Sakuma Y, Sata N, Oshiro H.
  • Journal Title: Pathol Int. Volume: 67 Issue: 4 Pages: 214-221
  • DOI: 10.1111/pin.12521
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of cell-type-specific mutations in nodal T-cell lymphomas. (2017)
  • Author(s): Nguyen TB, Sakata-Yanagimoto M, Asabe Y, Matsubara D, Kano J, Yoshida K, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Izutsu K, Nakamura N, Takeuchi K, Miyoshi H, Ohshima K, Minowa T, Ogawa S, Noguchi M, Chiba S.
  • Journal Title: Blood Cancer Journal Volume: 7 Issue: 1 Pages: e516-e516
  • DOI: 10.1038/bcj.2016.122
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pancreatic neuroendocrine tumor with metastasis to the spleen: a case report. (2017)
  • Author(s): Sakuma Y, Yasuda Y, Sata N, Hosoya Y, Shimizu A, Fujii H, Matsubara D, Fukushima N, Miki A, Maeno M, Lefor AK.
  • Journal Title: BMC Cancer Volume: 17 Issue: 1 Pages: 37-37
  • DOI: 10.1186/s12885-016-3020-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Crohn's disease presenting as a ceco-urachal fistula. (2017)
  • Author(s): Tsukui H, Koinuma K, Morimoto M, Horie H, Lefor AK, Kagaya Y, Takahashi H, Yano T, Matsubara D, Yamamoto H, Sata N.
  • Journal Title: Clin J Gastroenterol Volume: 10 Issue: 1 Pages: 32-36
  • DOI: 10.1007/s12328-016-0691-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Addiction to the IGF2-ID1-IGF2 circuit for maintenance of the breast cancer stem-like cells (2017)
  • Author(s): Tominaga K, Shimamura T, Kimura N, Murayama T, Matsubara D, Kanauchi H, Niida A, Shimizu S, Nishioka K, Tsuji EI, Yano M, Sugano S, Shimono Y, Ishii H, Saya H, Mori M, Akashi K, Tada KI, Ogawa T, Tojo A, Miyano S, Gotoh N
  • Journal Title: Oncogene Volume: 36(9) Issue: 9 Pages: 1276-1286
  • DOI: 10.1038/onc.2016.293
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 胸部の原発不明がんの鑑別 (2017)
  • Author(s): 松原大祐
  • Journal Title: 病理と臨床 Volume: 35 Pages: 152-159
• [Journal Article] 胸部の原発不明癌の鑑別 (2017)
  • Author(s): 松原 大祐
  • Journal Title: 病理と臨床 Volume: 35 Pages: 152-159
• [Journal Article] Loss of YAP1 defines neuroendocrine differentiation of lung tumors. (2016)
  • Author(s): Ito T, Matsubara D, Tanaka I, Makiya K, Tanei ZI, Kumagai Y, Shiu SJ, Nakaoka HJ, Ishikawa S, Isagawa T, Morikawa T, Shinozaki-Ushiku A, Goto Y, Nakano T, Tsuchiya T, Tsubochi H, Komura D, Aburatani H, Dobashi Y, Nakajima J, Endo S, Fukayama M, Sekido Y, Niki T, Murakami Y.
  • Journal Title: Cancer Science Volume: 107 Issue: 10 Pages: 1527-1538
  • DOI: 10.1111/cas.13013
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] p53 is a Host Cell Regulator during Herpes Simplex Encephalitis. (2016)
  • Author(s): Maruzuru Y, Koyanagi N, Takemura N, Uematsu S, Matsubara D, Suzuki Y, Arii J, Kato A, Kawaguchi Y.
  • Journal Title: J Virol. Volume: 90(15) Issue: 15 Pages: 6738-6745
  • DOI: 10.1128/jvi.00846-16
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A novel mouse model of intrahepatic cholangiocarcinoma induced by liver-specific Kras activation and Pten deletion. (2016)
  • Author(s): Ikenoue T, Terakado Y, Nakagawa H, Hikiba Y, Fujii T, Matsubara D, Noguchi R, Zhu C, Yamamoto K, Kudo Y, Asaoka Y, Yamaguchi K, Ijichi H, Tateishi K, Fukushima N, Maeda S, Koike K, Furukawa Y
  • Journal Title: Sci Rep Volume: 印刷中 Issue: 1 Pages: 23899-23899
  • DOI: 10.1038/srep23899
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 肺腺癌における細胞分化とゲノム異常 (2020)
  • Author(s): 松原 大祐
  • Organizer: 第109回日本病理学会総会
  • Invited
• [Presentation] TFF-1 (trefoil factor-1) as a Marker for Non-TRU (terminal respiratory unit) Type Lung Adenocarcinoma with Gastrointestinal Features (2020)
  • Author(s): Daisuke Matsubara
  • Organizer: USCAP 2020 Annual Meeting
  • Int'l Joint Research
• [Presentation] CADM1 associates with Hippo pathway core kinases; membranous co-expression of CADM1 & LATS2 in lung tumors predicts good prognosis. (2019)
  • Author(s): 松原 大祐
  • Organizer: 第65回日本病理学会秋期特別総会
• [Presentation] TFF-1 as a potential molecular target for non-TRU type lung adenocarcinoma (2018)
  • Author(s): 松原 大祐
  • Organizer: 第107回日本病理学会総会 札幌
• [Presentation] Reciprocal expressions of TFF-1 and TTF-1 in lung adenocarcinomas. (2018)
  • Author(s): Daisuke Matsubara
  • Organizer: AACR Annual Meeting 2018
• [Presentation] ドライバー変異に依存しない肺腺癌における細胞分化と分子異常の研究（A演説） (2018)
  • Author(s): 松原 大祐
  • Organizer: 第64回日本病理学会学術総会、呉
• [Presentation] Reciprocal expressions of TFF-1 and TTF-1 in lung adenocarcinomas (2018)
  • Author(s): Matsubara D
  • Organizer: .AACR Annual Meeting 2018 in Chicago
• [Presentation] Knockdown of BRM Causes Epithelial-Mesenchymal Transition in Lung Adenocarcinoma Cell Line H1975 (2017)
  • Author(s): Matsubara D
  • Organizer: IASLC 18th World Conference on Lung Cancer in Yokohama
• [Presentation] 高悪性度神経内分泌腫瘍におけるYAP1 の欠失は，神経内分泌分化と薬剤感受性を決定づける (2016)
  • Author(s): 松原 大祐
  • Organizer: 第５７回 日本肺癌学会
  • Place of Presentation: 福岡国際学会(福岡県福岡市)
  • Year and Date: 2016-12-19
• [Presentation] 形態学的アプローチに基づくNon-TRU type 肺腺癌の解析：TFF-1 とTTF-1 の相互排他的な関係性について (2016)
  • Author(s): 松原 大祐
  • Organizer: 第５７回 日本肺癌学会
  • Place of Presentation: 福岡国際学会(福岡県福岡市)
  • Year and Date: 2016-12-19
• [Presentation] Inactivating mutations of the NKX2-1 gene in non-TRU-type lung cancer:identification through histology-driven approach (2016)
  • Author(s): 松原 大祐
  • Organizer: 第７５回 日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Remarks] 自治医科大学 病理学講座 統合病理学部門 ホームページ
  • URL: http://www.jichi.ac.jp/pathol/
• [Remarks] 自治医大統合病理学部門
  • URL: http://www.jichi.ac.jp/pathol/
• [Remarks] 自治医科大学病理学講座統合病理学部門ホームページ
  • URL: http://www.jichi.ac.jp/pathol/