Development of Novel Therapies Targeting Cancer Stromal Stem Cells that Survive Long-Term in the Pancreatic Cancer Microenvironment

• Project/Area Number: 18K08610
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: Showa University
• Principal Investigator: WADA SATOSHI 昭和大学, 大学共同利用機関等の部局等, 教授 (30420102)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 膵臓がん / がん間質幹細胞 / 膵臓がんPDX / 次世代シーケンサー / CAR-T療法 / がん間質細胞 / PDXモデル / がん微小環境 / 間質幹細胞 / 遺伝子解析

Outline of Final Research Achievements

We generated 17 lines of pancreatic cancer PDX. Tumor tissues were stained with epithelial and stromal markers, and stromal marker-positive cells were sorted by FACS and analyzed by next-generation sequencing. From the results of the analysis, we identified gene X that was highly expressed in the long-succeeded PDX. The expression of gene X in cancer cells of the same PDX was analyzed, and it was found that gene X was not expressed in cancer cells at all, but only in stromal cells. Next, we performed immunostaining for gene X using tumor tissue of the same PDX, and found that gene X was expressed only in some stromal cells of the tumor. In order to start the development of therapies targeting gene X, we generated antibodies against gene X and constructed CAR molecules. The CAR-T cells were generated by gene transfer to T cells, and their anti-tumor effects were examined.

Academic Significance and Societal Importance of the Research Achievements

本研究は、難治性がんで最も予後不良である膵臓がん患者を対象とした新規治療法の開発を目的とした研究である。本研究が成功すれば、膵臓がんで苦しむ多くの患者さんに恩恵がもたらされる。これまでのがん治療は腫瘍細胞を標的とした治療法が多く開発されているが、本研究の特徴は、がん細胞を標的とするのではなく、がん間質細胞を標的とするところにある。本研究では、間質細胞の中でもがん間質幹細胞を標的とした治療法の開発であり、新しい着眼点のがん治療法開発となる。

Research Products

• [Journal Article] High expression of olfactomedin-4 is correlated with chemoresistance and poor prognosis in pancreatic cancer. (2020)
  • Author(s): Ohkuma R, Yada E, Ishikawa S, Komura D, Ishizaki H, Tamada K, Kubota Y, Hamada K, Ishida H, Hirasawa Y, Ariizumi H, Satoh E, Shida M, Watanabe M, Onoue R, Ando K, Tsurutani J, Yoshimura K, Yokobori T, Sasada T, Aoki T, Murakami M, Norose T, Ohike N, Takimoto M, Izumizaki M, Kobayashi S, Tsunoda T, Wada S.
  • Journal Title: PLoS One Volume: 10 Issue: 1 Pages: e0226707-e0226707
  • DOI: 10.1371/journal.pone.0226707
  • Peer Reviewed / Open Access / Int'l Joint Research