NCKU and CCU Collaborate on Pancreatic Cancer Research Published in a Top Journal-國立成功大學永續發展SDGs

Pancreatic cancer, often referred to as the "king of cancers," is a highly aggressive malignant tumor. Due to the lack of early diagnostic biomarkers, it is often diagnosed at an advanced stage, making surgical removal impossible and showing poor response to chemotherapy. As a result, the survival rate of patients remains below 10%. Therefore, identifying the mechanisms behind the malignant transformation of pancreatic cancer is of utmost importance.  


After years of dedicated research, the pancreatic cancer research teams from National Cheng Kung University (NCKU) and National Chung Cheng University (CCU) have successfully unraveled the key mechanisms of how pancreatic cells develop into malignant cancer cells. This breakthrough was achieved through a combination of fundamental and clinical research, leveraging the latest biomedical AI big data analysis and clinical evidence-based medicine. Their findings have been published in the prestigious international journal Molecular Cancer in January 2025. Intercellular TIMP-1-CD63 signaling directs the evolution of immune escape and metastasis in KRAS-mutated pancreatic cancer cells


The KRAS oncogene mutation is a hallmark of pancreatic cancer, with approximately 90% of pancreatic cancer specimens exhibiting mutations in the KRAS gene. Traditionally, it has been believed that KRAS mutations continuously activate intracellular signaling pathways, leading to uncontrolled cell growth and division, ultimately resulting in cancer. However, this hypothesis fails to explain why pancreatic cancer predominantly occurs in older individuals (with a median onset age of 65 years) and why benign tumors with KRAS mutations take approximately 16 years to transform into malignant cancer cells.


To solve this mystery, a research team led by President Shaw-Jenq Tsai of CCU and Dean Yan-Shen Shan of the College of Medicine at NCKU spent over six years meticulously examining genetically modified mouse pancreatic specimens and performing single-cell nucleic acid sequencing analysis on early- and late-stage human pancreatic cancer samples. Their investigation uncovered a previously overlooked blind spot—although KRAS-mutated cells exhibit proliferation, they also undergo aging and apoptosis (programmed cell death). This indicates that a KRAS mutation alone is not sufficient to cause pancreatic cancer. Instead, our body possesses a protective mechanism that directs these abnormal cells toward self-destruction, preventing the onset of cancer.


If KRAS mutations alone are not sufficient to cause pancreatic cancer, then what exactly triggers the disease? And why do more than 90% of pancreatic cancer cells still carry KRAS mutations? Through extensive investigation, the research team identified the loss of another crucial gene as the key factor that allows KRAS-mutated cells to survive and continue growing. This gene is Dual specificity phosphatase-2 (DUSP2). One of the team members, Assistant Professor Chu-An Wang from the Institute of Basic Medical Sciences at NCKU, discovered through single-cell sequencing analysis that a small subset of KRAS-mutated cells increases in number as pancreatic cancer progresses. Further analysis revealed that this group of cells lacks DUSP2 expression. To verify this discovery, the research team spent 3 years developing a genetically engineered mouse model in which DUSP2 was specifically deleted in pancreatic cells, combined with a KRAS mutation. The results confirmed that these mice spontaneously develop pancreatic cancer and exhibit severe cancer cell metastasis, closely resembling human pancreatic cancer.


The next question is: What causes the suppression of DUSP2 expression? Through Cell-Chat analysis, Dr. Ya-ChinHou from NCKU Hospital and the research team identified a specific subset of macrophages within the tumor microenvironment that plays a critical role. When macrophages interact with pancreatic cancer cells, they suppress DUSP2 expression, leading to sustained activation of extracellular signal-regulated kinases. This activation drives tumor cell proliferation, metastasis, and immune evasion. Using the pancreatic cancer RNA sequencing database established at NCKU Hospital, the team discovered a novel TIMP1-CD63 signaling pathway, which serves as a key mechanism in the cross-regulation between macrophages and cancer cells. Through this signaling interaction, cancer cells gain immune privilege, allowing them to evade immune system attack and rendering cutting-edge cellular immunotherapies ineffective. This mechanism is one of the major reasons why pancreatic cancer remains highly resistant to treatment.


A more significant contribution of this research is its implication that chronic inflammation, such as pancreatitis, plays a crucial role in pancreatic cancer development. While KRAS gene mutations are inevitable spontaneous events, DUSP2 functions as a tumor suppressor gene, protecting pancreatic cells from malignant transformation. However, if inflammation is not controlled, macrophages will be recruited to the pancreatic tumor microenvironment, triggering a vicious cycle that ultimately leads to the malignant progression of pancreatic cancer. Dean Yan-Shen Shan of NCKU College of Medicine, a leading pancreatic cancer expert in Taiwan, emphasizes that understanding the complex interactions among various cells within the pancreatic tumor microenvironment is crucial for developing effective therapeutic strategies, improving early detection rates, and enhancing patient prognosis in the future.


This research was primarily funded by grants from the National Science and Technology Council and the National Health Research Institutes. The research team also appreciates the support from the core facilities of the NCKU College of Medicine and Hospital, as well as the sponsorship from the Xu Yan Education Foundation.