The study of malignant transformation and vulnerability of mutated-RAS carcinomas defined by epithelial-mesenchymal transition and susceptibility to ferroptosis

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07680
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Tohoku University
• Principal Investigator: MATSUMOTO Mitsuyo 東北大学, 医学系研究科, 助教 (80400448)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: BACH1 / 膵臓癌 / Ferroptosis / EMT / RAS

Outline of Final Research Achievements

We recently found that the transcription factor BACH1 promotes epithelial-mesenchymal transition (EMT) of pancreatic ductal adenocarcinoma (PDAC) cells leading to stronger metastatic potential. In PDAC, 90% of which have RAS mutations, we analyzed, proved and reported that a gene regulatory network of BACH1 downstream target contributes to the malignant transformation of PDAC by regulating EMT. We also elucidated that ferroptosis is under the control of BACH1 where it promotes ferroptosis in mouse embryonic fibroblasts. Cancer cells with RAS mutations are known to be highly susceptible to the ferroptosis inducer erastin. Furthermore, we reported that this ferroptosis can be spread from the ferroptotic cells to the surrounding healthy cells by the chain propagation of lipid peroxidation reactions.

Free Research Field

分子腫瘍学

Academic Significance and Societal Importance of the Research Achievements

膵臓癌は難治性がんの１つである。BACH1が膵臓癌の予後不良因子であり、上皮系遺伝子の発現を抑制し、転移を促進するという今回の発見と論文での報告、およびBACH1がフェロトーシス誘導剤感受性を促進するという発見と論文での報告は、新規治療標的もしくは新規治療診断判別法を開発する礎となる可能性がある。また、癌遺伝子RAS活性型変異を持つ癌は約30%にもおよぶことから、フェロトーシス誘導剤による癌治療を考えた時、今後更なる検討が必要ではあるものの、その波及効果は大きいと期待している。