{"id":399,"date":"2026-02-19T00:46:22","date_gmt":"2026-02-18T15:46:22","guid":{"rendered":"https:\/\/www.med.osaka-u.ac.jp\/pub\/gh\/wp\/research\/research-detail\/research-group-4\/"},"modified":"2026-02-19T00:46:22","modified_gmt":"2026-02-18T15:46:22","slug":"research-group-4","status":"publish","type":"page","link":"https:\/\/www.med.osaka-u.ac.jp\/pub\/gh\/en\/research\/research-detail\/research-group-4\/","title":{"rendered":"Pancreatic and Hepatic Pathology Interception Research Group"},"content":{"rendered":"\n
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Pancreatic and Hepatic Pathology Interception Research Group<\/h2>\n <\/div>\n\n
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Group Leader: Yuki Makino<\/h2>\n

Concept: Elucidation of the mechanism of multi-step pathological evolution of pancreas and liver<\/h3>\n

We conduct basic research to elucidate the pathophysiology and develop treatments for phenomena such as pancreatic carcinogenesis and inflammation, fibrosis, and carcinogenesis in the liver. Both organs have many life-threatening diseases, but both often progress through stepwise pathological changes. We are analyzing the molecular changes that occur at each stage and the changes in various cellular functions with the goal of clarifying why the initial changes occur and what mechanisms are responsible for the progression of each disease to the next stage. By elucidating these changes, we aim to develop therapies that target specific molecules and cells and \u201cintercept\u201d the progression of the disease. In the pancreas and liver, effective molecular targeted therapies have been developed only for a limited number of diseases, and many diseases are still dependent on nonspecific therapies and symptomatic treatments. We aim to change the existing concept of medical treatment by developing new therapies for diseases and conditions for which effective treatments are still lacking from our unique perspective.<\/p>\n <\/div>\n\n

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Omics Analysis Reveals Mechanisms of Pancreatic Cancer Development, Progression, and Resistance to Therapy<\/h3>\n

Pancreatic cancer is difficult to detect in its early stage, and once it develops, it is the most difficult cancer to cure with a very poor prognosis. On the other hand, pancreatic cancer can be cured if it is diagnosed and treated at an early stage. Pancreatic cancer does not occur when normal epithelial cells suddenly transform into cancer cells, but in most cases, it develops through a precancerous lesion called a pancreatic intraepithelial neoplastic lesion (PanIN) or intraductal papillary mucinous tumor (IPMN). Since it is believed that it takes years for precancerous lesions to progress to cancer and acquire metastatic potential, there is an opportunity for early detection and intervention during the precancerous stage. We will analyze the process of carcinogenesis and progression of pancreatic cancer based on comprehensive analysis of clinical specimens using omics technology in collaboration with the Biliary-Pancreatic Onco-Endoscopy Group, as well as changes in cell characteristics and microenvironment associated with treatment, and verify their significance using our original disease model. We aim to reduce the ever-increasing number of pancreatic cancer deaths by linking these findings to the early detection of pancreatic cancer and the development of methods to halt the development and progression of pancreatic cancer.<\/p>\n <\/div>\n\n

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Targeting IPMN to Prevent Pancreatic Cancer<\/h3>\n

IPMN is a cystic tumor that can be detected at a precancerous stage with a simple imaging test such as ultrasonography. IPMN is a very common disease, but the risk of pancreatic cancer increases many-fold in people with IPMN compared to those without IPMN. Therefore, IPMN is a lesion that can be targeted for therapeutic intervention from the precancerous stage, but at present there is no effective treatment other than surgical resection. This is due to the fact that the pathological mechanism of IPMN is not fully understood. We have established a disease model for IPMN, and have elucidated some of the molecular mechanisms and changes in the immune microenvironment associated with the development and progression of IPMN through analysis of clinical specimens. We will further develop and deepen these findings to realize accurate malignant risk assessment and development of novel therapies for IPMN, leading to the establishment of prophylactic treatments for pancreatic cancer.<\/p>\n <\/div>\n\n

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Analysis of the mechanism of liver pathology originating from \u201cover-activity\u201d of the cancer suppressor gene p53<\/h3>\n

p53 is the most well-known cancer-suppressor gene, and its loss of function is implicated in the development of various cancers throughout the body, including the liver. On the other hand, p53 is over-activated in the liver due to stress stimuli caused by various factors such as viruses, alcohol, and autoimmune diseases. We have been studying the role of p53 for some time and found that excessive p53 activity in hepatocytes alone causes inflammation, fibrosis, and carcinogenesis of the liver. In other words, p53, which is conventionally known as a cancer suppressor gene, acts as a master regulator of liver disease progression. We are currently conducting further research on how p53 induces inflammation, fibrosis, and carcinogenesis in the liver. We will search for therapeutic targets to halt the progression of liver diseases from among these mechanisms.<\/p>\n <\/div>\n\n

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Pathophysiology of Liver Disease Focusing on Sinusoidal Endothelial Cells<\/h3>\n

Sinusoidal endothelial cells are specialized endothelial cells that make up the sinusoids, a network of capillaries unique to the liver, and are known to function differently from normal capillary endothelial cells. In particular, Fontan-associated liver disease (FALD) is a chronic and progressive liver disorder caused by a special hemodynamic mechanism, and its pathogenesis is assumed to be closely related to the function of sinusoidal endothelial cells. In recent years, FALD often becomes apparent in postoperative Fontan patients as their prognosis improves, and it is attracting attention as an important complication, but no effective treatment or disease biomarker has yet been developed. We hope to elucidate the regulatory molecules of various liver diseases, including FALD, from the viewpoint of sinusoidal endothelial cell function, and to develop novel therapies.<\/p>\n <\/div>\n <\/section>\n\n

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Future Prospects: A Paradigm Shift in the Treatment of Pancreatic Cancer and Liver Disease<\/h3>\n

I would like to introduce the concept of \"preventive treatment\" in addition to the existing \"diagnosis\" and \"treatment\" in pancreatic cancer treatment, to make pancreatic cancer a preventable disease, and to introduce new treatment methods in the field of liver disease, where adequate treatment methods do not exist.<\/p>\n <\/section>\n\n

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Major Papers<\/h3>\n
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  1. Quoc-Huy Trinh V, Ankenbauer KE, Torbit SM, Taranto CP, Liu J, Batardiere M, Kumar B, Maurer HC, Revetta F, Chen Z, Kruse ARS, Judd AM, Copeland C, Wong J, Ben -Levy O, Jarvis B, Brown M, Brown JW, Das K, Makino Y, Spraggins JM, Lau KS, Azadi P, Maitra A, Tan MCB, DelGiorno KE. Mutant GNAS drives a pyloric metaplasia Cell Rep. 2025 Dec 23;44(12):116684.<\/li>\n
  2. Makino Y, Oyama K, Sagara A, Thege FI, Maitra A. Molecular pathology of intraductal papillary mucinous neoplasms of the pancreas: current understanding and perspectives on malignant progression. J Gastroenterol. 2025 Nov 26. doi: 10.1007\/s00535-025-02328-7. Epub ahead of print. PMID: 41296011.<\/li>\n
  3. Chen Y, Ballar\u00f2 R, Sans M, Thege FI, Zuo M, Dou R, Min J, Yip-Schneider M, Zhang J, Wu R, Irajizad E, Makino Y, Rajapakshe KI, Rudsari HK, Hurd MW, Le\u00f3n- Letelier RA, Katayama H, Ostrin E, Vykoukal J, Dennison JB, Do KA, Hanash SM, Wolff RA, Guerrero PA, Kim M, Schmidt CM, Maitra A, Fahrmann JF. sulfatide enrichment is an actionable metabolic vulnerability in intraductal papillary mucinous neoplasm (IPMN)-associated pancreatic cancers. Gut. 2025 Sep 8;74(10):1638-1652.<\/li>\n
  4. Makino Y, Rajapakshe KI, Chellakkan Selvanesan B, Okumura T, Date K, Dutta P, Abou-Elkacem L, Sagara A, Min J, Sans M, Yee N, Siemann MJ, Enriquez J, Smith P, Bhattacharya P, Kim M, Dede M, Hart T, Maitra A, Thege FI. Bhattacharya P, Kim M, Dede M, Hart T, Maitra A, Thege FI. Metabolic reprogramming by mutant GNAS creates an actionable dependency in intraductal Gut. 2024 Dec 10;74(1):75-88.<\/li>\n
  5. Semaan A, Bernard V, Wong J, Makino Y, Swartzlander DB, Rajapakshe KI, Lee JJ, Officer A, Schmidt CM, Wu HH, Scaife CL, Affolter KE, Nachmanson D, Firpo MA,. Yip-Schneider M, Lowy AM, Harismendy O, Sen S, Maitra A, Jakubek YA, Guerrero PA. Integrated Molecular Characterization of Intraductal Papillary Mucinous Neoplasms: An NCI Cancer Moonshot Precancer Atlas Pilot Project. Cancer Res Commun. 2023 Oct 10;3(10):2062-2073.<\/li>\n
  6. Sans M, Makino Y, Min J, Rajapakshe KI, Yip-Schneider M, Schmidt CM, Hurd MW, Burks JK, Gomez JA, Thege FI, Fahrmann JF, Wolff RA, Kim MP, Guerrero PA, Maitra A. Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of the Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Cancer Discov. 2023 Aug 4;13(8):1844-1861.<\/li>\n
  7. Makino Y, Hikita H, Kato S, Sugiyama M, Shigekawa M, Sakamoto T, Sasaki Y, Murai K, Sakane S, Kodama T, Sakamori R, Kobayashi S, Eguchi H, Takemura N, Kokudo N Sakamoto T, Sakamoto Y, Murai K, Sakane S, Kodama T, Sakamori R, Kobayashi S, Eguchi H, Takemura N, Kokudo N, Yokoi H, Mukoyama M, Tatsumi T, Takehara T. STAT3 is Activated by CTGF-mediated Tumor-stroma Cross Talk to Promote HCC Progression. Gastroenterol Hepatol. 2023;15(1):99-119.<\/li>\n
  8. Makino Y, Hikita H, Fukumoto K, Sung JH, Sakano Y, Murai K, Sakane S, Kodama T, Sakamori R, Kondo J, Kobayashi S, Tatsumi T, Takehara T. Constitutive Activation of the Tumor Suppressor p53 in Hepatocytes Paradoxically Promotes Non-Cell Autonomous Liver Carcinogenesis. Cancer Res. 2022 Aug 16;82(16):2860-2873. Cancer Res. 2022 Aug 16;82(16):2860-2873.<\/li>\n
  9. Urabe M, Hikita H, Saito Y, Kudo S, Fukumoto K, Mizutani N, Myojin Y, Doi A, Sato K, Sakane S, Makino Y, Kodama T, Sakamori R, Tatsumi T, Takehara T. Activation of p53 After Irradiation Impairs the Regenerative Capacity of the Mouse Liver. Hepatol Commun. 2022 Feb;6(2):411-422.<\/li>\n
  10. Makino Y, Hikita H, Kodama T, Shigekawa M, Yamada R, Sakamori R, Eguchi H, Morii E, Yokoi H, Mukoyama M, Hiroshi S, Tatsumi T, Takehara T. CTGF Mediates Tumor -Stroma Interactions between Hepatoma Cells and Hepatic Stellate Cells to Accelerate HCC Progression. Cancer Res. 2018 Sep 1;78(17):4902-4914.<\/li>\n
  11. Kodama T, Takehara T, Hikita H, Shimizu S, Shigekawa M, Tsunematsu H, Li W, Miyagi T, Hosui A, Tatsumi T, Ishida H, Kanto T, Hiramatsu N, Kubota S, Takigawa M, Takigawa M, Tomimaru Y, Tomokuni A, Nagano H, Doki Y, Mori M, Hayashi N. Tomimaru Y, Tomokuni A, Nagano H, Doki Y, Mori M, Hayashi N. Increases in p53 expression induce CTGF synthesis by mouse and human hepatocytes and result in liver fibrosis in mice. J Clin Invest. 2011 Aug;121(8):3343-56.<\/li>\n <\/ol>\n <\/section>\n\n <\/div>\n<\/main>","protected":false},"excerpt":{"rendered":"

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