Elucidation of renal tumorigenesis under FLCN deficiency

• Project/Area Number: 19K09694
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56030:Urology-related
• Research Institution: Yokohama City University
• Principal Investigator: HASUMI Hisashi 横浜市立大学, 医学部, 助教 (40749876)
• Co-Investigator(Kenkyū-buntansha): 矢尾 正祐 横浜市立大学, 医学研究科, 客員教授 (00260787)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 遺伝性腎癌 / BHD症候群 / シングルセル発現解析 / がん微小環境 / 免疫チェックポイント阻害剤 / 腫瘍内不均一性 / FLCN / FLCN/FNIP1/FNIP2複合体 / 細胞内輸送 / エピゲノム

Outline of Research at the Start

家族性腎癌症候群、Birt-Hogg-Dube; (BHD)症候群の原因遺伝子として同定されたfolliculin (FLCN)は、腎臓細胞の増殖を直接制御する重要な腎癌抑制遺伝子ですが、FLCNの膜輸送における生理的意義はとても議論のあるところとなっております。そこで本研究では、哺乳動物に存在するRab GTPアーゼとFLCNの関連を網羅的に調べ、膜輸送や腎臓細胞増殖における生理的意義を検証します。以上により、FLCN欠失下の腎癌発生機序が明らかとなり、新規腎癌治療薬の開発基盤が確立されます。

Outline of Final Research Achievements

We have identified novel FLNC ineracting partners and are investigating physiological meaning of those interactions using animal models. Furthermore, we have conducted single cell RNA-seq of BHD-associated kidney cancer and found that BHD-associated kidney cancer exhibits molecular proflinig simlimar to that of intercalating cell of collecting duct, transcriptomic intratumor heterogeneity (tITH) and differentially expressed genes including SLC4A4, HERC1, PLAAT4 and MIF. We also revealed distinct tumor microenvironment which is unique to each hereditary kidney cancer. These findings provides mechanistic insights into renal tumorigenesis as well as an oppotunity to develop novel therapeutics and diagnostics to hereditary nad sporadic kidney cancers.

Academic Significance and Societal Importance of the Research Achievements

本研究により、FLCNの膜輸送における役割が解明され、今後、膜輸送という全く新しい経路を標的とした新規腎癌治療薬の開発が期待できます。さらに今回のシングルセル発現解析により、詳細な腎腫瘍化機構の解明がなされただけでなく、免疫環境を含めたがん微小環境が明らかとなりました。これらの発見は腎癌細胞に対する新規治療薬開発ならびに免疫チェックポイント阻害剤や血管新生阻害剤などの腎癌の標準薬物療法の精密化につながります。

Research Products

• [Int'l Joint Research] アメリカ国立衛生研究所(米国)
• [Int'l Joint Research] National Cancer Institute(米国)
• [Journal Article] Targeting chemoresistance in Xp11.2 translocation renal cell carcinoma using a novel polyamide?chlorambucil conjugate (2022)
  • Author(s): Funasaki Shintaro、Mehanna Sally、Ma Wenjuan、Nishizawa Hidekazu、Kamikubo Yasuhiko、Sugiyama Hiroshi、Ikeda Shuji、Motoshima Takanobu、Hasumi Hisashi、Linehan W. Marston、Schmidt Laura S.、Ricketts Chris、Suda Toshio、Oike Yuichi、Kamba Tomomi、Baba Masaya
  • Journal Title: Cancer Science Volume: n/a Issue: 7 Pages: 2352-2367
  • DOI: 10.1111/cas.15364
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Single-cell transcriptomes of hereditary kidney cancers underscore genetically defined tumor characteristics and microenvironment (2022)
  • Author(s): Ryosuke Jikuya, Hisashi Hasumi, et al.
  • Journal Title: iScience Volume: n/a
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Blood and lymphatic systems are segregated by the FLCN tumor suppressor (2020)
  • Author(s): Tai-Nagara Ikue、Hasumi Yukiko、Hasumi Hisashi、Funasaki Shintaro、Satou Yorifumi、Kubota Yoshiaki
  • Journal Title: Nature Communications Volume: 11 Pages: 6314-6314
  • Peer Reviewed
• [Journal Article] FLCN alteration drives metabolic reprogramming towards nucleotide synthesis and cyst formation in salivary gland (2020)
  • Author(s): Isono Yasuhiro、Furuya Mitsuko、Kuwahara Tatsu、Schmidt Laura S.、Linehan W. Marston、Kodama Tatsuhiko、Yao Masahiro、Oridate Nobuhiko、Hasumi Hisashi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 522 Pages: 931-938
  • Peer Reviewed
• [Journal Article] Clinicopathological and molecular features of hereditary leiomyomatosis and renal cell cancer-associated renal cell carcinomas (2020)
  • Author(s): Furuya Mitsuko、Iribe Yasuhiro、Hasumi Hisashi、Iwashita Hiromichi、Ohta Junichi、Kitamura Hiroshi、Nakajima Takahiko、Yoshida Takahiro、Nakagawa Masahiro、Tanaka Reiko、Yao Masahiro
  • Journal Title: Journal of Clinical Pathology Volume: 73 Pages: 819-825
• [Journal Article] Diagnostic Impacts of Clinical Laboratory Based p2PSA Indexes on any Grade, Gleason Grade Group 2 or Greater, or 3 or Greater Prostate Cancer and Prostate Specific Antigen below 10 ng/ml. (2020)
  • Author(s): Ito K, Yokomizo A, Tokunaga S, Arai G, Sugimoto M, Akakura K, Hasumi H, Sakai H, Ouraji A, Oki R, Kashiwagi E, Kobori Y, Hirama H, Kitoh H, Uemura H, Hakariya T, Suzuki K
  • Journal Title: J Urol. Volume: 203 Issue: 1 Pages: 83-91
  • DOI: 10.1097/ju.0000000000000495
  • Peer Reviewed
• [Journal Article] Birt‐Hogg‐Dube syndrome‐associated renal cell carcinoma: Histopathological features and diagnostic conundrum (2019)
  • Author(s): Furuya M, Hasumi Y, Yao M, Nagashima Y.
  • Journal Title: Cancer Science Volume: 111 Issue: 1 Pages: 15-22
  • DOI: 10.1111/cas.14255
  • Peer Reviewed / Open Access
• [Journal Article] TFE3 Xp11.2 translocation renal cell carcinoma mouse model reveals novel therapeutic targets and identifies GPNMB as a diagnostic marker for human disease. (2019)
  • Author(s): Baba M, Furuya M, Motoshima T, Lang M, Funasaki S, Ma W, Sun HW, Hasumi H, Huang Y, Kato I, Kadomatsu T, Satou Y, Morris N, Karim BO, Ileva L, Kalen JD, Wilan Krisna LA, Hasumi Y, Sugiyama A, Kurahashi R, Nishimoto K, Oyama M, Nagashima Y, Kuroda N, Araki K, Eto M, Yao M, Kamba T, Suda T, Oike Y, Schmidt LS, Linehan WM
  • Journal Title: Molecular Cancer Research Volume: 印刷中 Issue: 8 Pages: 1613-1626
  • DOI: 10.1158/1541-7786.mcr-18-1235
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Fluorescence Enhancement Effect of TiO2 Nanoparticles and Application for Photodynamic Diagnosis (2019)
  • Author(s): Kanehira Koki、Yano Yukiko、Hasumi Hisashi、Fukuhara Hideo、Inoue Keiji、Hanazaki Kazuhiro、Yao Masahiro
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Issue: 15 Pages: 3698-3698
  • DOI: 10.3390/ijms20153698
  • Peer Reviewed
• [Journal Article] Early assessment with 18F-2-fluoro-2-deoxyglucose positron emission tomography/computed tomography to predict short-term outcome in clear cell renal carcinoma treated with nivolumab (2019)
  • Author(s): Tabei T, Nakaigawa N, Kaneta T, Ikeda I, Kondo K, Makiyama K, Hasumi H, Hayashi N, Kawahara T, Izumi K, Osaka K, Muraoka K, Teranishi JI, Miyoshi Y, Yumura Y, Uemura H, Kobayashi K, Inoue T, Yao M.
  • Journal Title: BMC Cancer Volume: 19 Issue: 1 Pages: 298-298
  • DOI: 10.1186/s12885-019-5510-y
  • Peer Reviewed / Open Access
• [Journal Article] The Pretherapeutic Neutrophil-to-Lymphocyte Ratio for Docetaxel-Based Chemotherapy Is Useful for Predicting the Prognosis of Japanese Patients with Castration-Resistant Prostate Cancer (2019)
  • Author(s): Tatenuma Tomoyuki、Kawahara Takashi、Hayashi Narihiko、Hasumi Hisashi、Makiyama Kazuhide、Nakaigawa Noboru、Kishida Takeshi、Miyoshi Yasuhide、Yao Masahiro、Uemura Hiroji
  • Journal Title: BioMed Research International Volume: 2019 Pages: 1-5
  • DOI: 10.1155/2019/2535270
  • Peer Reviewed
• [Journal Article] 遺伝性腎がんのup-to-date (2019)
  • Author(s): 蓮見 壽史, 矢尾 正祐
  • Journal Title: 腎臓内科・泌尿器科 Volume: 9 Pages: 483-490
• [Presentation] 唾液腺においてFLCN欠失が引き起こす代謝変化とその腫瘍化における意義 (2020)
  • Author(s): 蓮見壽史、磯野泰大、古屋充子、馬場理也、矢尾正祐、折舘伸彦
  • Organizer: 第26回日本遺伝性腫瘍学会学術集会
• [Presentation] International Session I「Treatment strategy for rare hereditary RCC」 (2019)
  • Author(s): 蓮見壽史
  • Organizer: 第50回腎癌研究会
  • Invited
• [Book] Lynch Syndrome-Associated Urological Malignancies (2020)
  • Author(s): Hisashi Hasumi, Masahiro Yao
  • Total Pages: 5
  • Publisher: Springer