Diversity of molecular paths during pancreatic carcinogenesis

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K09472
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Asahikawa Medical College
• Principal Investigator: Mizukami Yusuke 旭川医科大学, 医学部, 教授 (30400089)
• Co-Investigator(Kenkyū-buntansha): 小野 裕介 医療法人徳洲会札幌東徳洲会病院医学研究所, 臨床生体情報解析部, 部門長 (40742648) ; 唐崎 秀則 医療法人徳洲会札幌東徳洲会病院医学研究所, 外科的消化器病疾患研究部, 副部門長 (50374806) ; 笹島 順平 旭川医科大学, 医学部, 客員講師 (80451467)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 膵癌 / 膵管内乳頭粘液性腫瘍 / GNAS / クローン進化

Outline of Final Research Achievements

We aimed to clarify the role of two driver genes, KRAS and GNAS, on the pancreatic carcinogenesis using surgically resected pancreatic cancers associated with intraductal papillary mucinous neoplasm (IPMN). By molecular pathological analysis, new subtypes leading to the development of pancreatic cancer were found. We also clarified pancreatobiliary-type IPMN with wild-type GNAS is prone to residual pancreatic recurrence.
We also sought to clarify the downstream pathway of mutant GNAS and the effect on tumor phenotype using genetically engineered mouse models and genome-editing experiments using primary cells derived from human IPMN-related pancreatic cancer with mutant GNAS. The driver gene plays a role in tumor progression and maintenance by regulating mucin traits and tumor metabolic paths.
These findings are useful for stratifying the progression path of pancreatic carcinogenesis in IPMN patients and predicting the risk for developing malignant progression.

Free Research Field

消化器内科、がんゲノム、遺伝学

Academic Significance and Societal Importance of the Research Achievements

本研究の成果は、膵癌の悪性化機構に関わる新知見をもたらす。膵癌の多様性を制御する分子機構への理解が深め膵癌進展ルートの層別化することで、新規バイオマーカーの発見による高リスク群のサーベイランス、早期診断を支える技術開発へと繋がる。また、特定の遺伝子異常に関わる腫瘍細胞の脆弱性を見出したことで、標準治療の在り方に変革をもたらすことが期待される。