Interconnected cellular pathways symbolizing the Notch signaling pathway in pancreatic cancer cells.

Unlocking Pancreatic Cancer: The Role of Notch Receptors and Ligands

Samir D’Costa in Health & Wellness November 2025 • 4 min read.

"A deep dive into how understanding Notch signaling pathways can revolutionize diagnosis and treatment of pancreatic ductal adenocarcinoma (PDAC)."

Pancreatic cancer, particularly pancreatic ductal adenocarcinoma (PDAC), stands as a formidable health challenge, ranking as the fourth leading cause of cancer-associated mortality in developed nations. PDAC's aggressive nature and often late diagnosis contribute to its dismal prognosis, underscoring the urgent need for innovative diagnostic and therapeutic approaches.

Central to understanding PDAC's complexities is the Notch signaling pathway, a crucial regulator of embryonic development and tumorigenesis. This pathway involves four Notch receptors (Notch1-4) and five ligands (Jagged1, Jagged2, DLL1, DLL3, and DLL4). The intricacies of Notch signaling in PDAC—whether it acts as an oncogene or a tumor suppressor—depend heavily on the specific tissue type, highlighting the need to unravel the distinct roles of Notch receptors within the same tissue.

Recent research has focused on mapping the expression of all Notch receptors and their ligands in PDAC tissues and cells to address this critical gap. By employing immunohistochemistry to analyze paraffin-embedded PDAC tissue samples and immunofluorescence to examine pancreatic cancer cell lines (HPAC and PANC-1), scientists aim to clarify how these molecular players contribute to PDAC development and progression, paving the way for more targeted interventions.

Decoding Notch Receptors: What Does Their Expression Tell Us About Pancreatic Cancer?

Interconnected cellular pathways symbolizing the Notch signaling pathway in pancreatic cancer cells.

The study meticulously examined the expression of Notch receptors and their ligands in PDAC, yielding several key insights. Immunohistochemical analysis revealed increased levels of Notch1 and Notch3 in PDAC tissues, whereas Notch2 and Notch4 levels were decreased. These findings suggest that Notch1 and Notch3 may play pivotal roles in promoting PDAC, while Notch2 and Notch4 might have different, potentially tumor-suppressive functions.

Consistent with the tissue analysis, the expression of Notch receptors in HPAC and PANC-1 cell lines mirrored the patterns observed in PDAC tissues. Furthermore, the ligands DLL1, DLL3, and DLL4 showed elevated levels in both HPAC and PANC-1 cells, as well as in PDAC tissue samples, reinforcing their potential involvement in PDAC pathogenesis. Conversely, the expression of Jagged1 and Jagged2 remained low, indicating that these ligands might not be as critical in PDAC development.

Notch1 and Notch3: Increased in PDAC tissues, suggesting oncogenic roles.
Notch2 and Notch4: Decreased in PDAC tissues, indicating potential tumor-suppressive functions.
DLL1, DLL3, and DLL4: Elevated in HPAC and PANC-1 cells and PDAC tissue samples.
Jagged1 and Jagged2: Low expression, suggesting a less critical role in PDAC development.

A noteworthy observation was the positive correlation between the expression of Notch1 and Notch3, as well as between Notch1 and the ligands DLL1, DLL3, and DLL4. This suggests that the interaction of Notch1 and Notch3 with these specific ligands may be essential for maintaining the tumor phenotype in pancreatic cancer. In contrast, Notch2, Notch4, Jagged1, and Jagged2 did not show such correlations, further highlighting the distinct roles of different Notch receptors and ligands in PDAC.

The Future of Pancreatic Cancer Treatment: Targeting Notch Signaling

These findings underscore the potential of targeting Notch1 and Notch3, along with their ligands DLL1, DLL3, and DLL4, as a therapeutic strategy for pancreatic cancer. By selectively modulating the Notch signaling pathway, researchers hope to disrupt the mechanisms that drive tumor growth and metastasis, offering new hope for patients battling this devastating disease. Future studies focusing on larger patient cohorts and in-depth molecular analyses will further refine our understanding of the Notch signaling pathway in PDAC, ultimately leading to more effective and personalized treatment approaches.

About this Article -

This article was crafted using a human-AI hybrid and collaborative approach. AI assisted our team with initial drafting, research insights, identifying key questions, and image generation. Our human editors guided topic selection, defined the angle, structured the content, ensured factual accuracy and relevance, refined the tone, and conducted thorough editing to deliver helpful, high-quality information.See our About page for more information.

This article is based on research published under:

DOI-LINK: 10.3892/etm.2018.6172, Alternate LINK

Title: Expression Of Notch Receptors And Their Ligands In Pancreatic Ductal Adenocarcinoma

Subject: Cancer Research

Journal: Experimental and Therapeutic Medicine

Publisher: Spandidos Publications

Authors: Hai‑Yan Song, Ying Wang, Hong Lan, Yu‑Xiang Zhang

Published: 2018-05-16

Everything You Need To Know

How do the expression levels of different Notch receptors, specifically Notch1, Notch2, Notch3, and Notch4, typically differ in pancreatic ductal adenocarcinoma (PDAC) tissues, and what implications does this have?

In pancreatic ductal adenocarcinoma (PDAC), research indicates that Notch1 and Notch3 are often found at increased levels within PDAC tissues, suggesting they may promote tumor development. Conversely, Notch2 and Notch4 are typically found at decreased levels, which might indicate they have tumor-suppressing roles in PDAC. These differences highlight how individual Notch receptors can have opposing effects in the same cancer type.

What role do the ligands DLL1, DLL3, and DLL4 play in pancreatic ductal adenocarcinoma (PDAC), and what is the significance of their elevated levels in pancreatic cancer cell lines and tissue samples?

DLL1, DLL3, and DLL4 are ligands that have shown elevated levels in both HPAC and PANC-1 pancreatic cancer cell lines, as well as in PDAC tissue samples. This suggests that these ligands might play a significant role in the development and progression of PDAC. Targeting these ligands could potentially disrupt the Notch signaling pathway and inhibit tumor growth.

Why are Jagged1 and Jagged2 considered less critical in the development of pancreatic ductal adenocarcinoma (PDAC) compared to other Notch ligands, based on their expression levels?

Jagged1 and Jagged2 showed low expression in the analyzed PDAC tissues and cell lines. This suggests that these ligands may not be as critical in the development of pancreatic ductal adenocarcinoma compared to DLL1, DLL3, and DLL4. Therefore, therapeutic strategies might prioritize targeting the DLL ligands over Jagged ligands in PDAC.

What does the correlation between Notch1 and Notch3, as well as between Notch1 and the ligands DLL1, DLL3, and DLL4, reveal about potential therapeutic targets in pancreatic ductal adenocarcinoma (PDAC)?

The research found a positive correlation between Notch1 and Notch3, as well as between Notch1 and the ligands DLL1, DLL3, and DLL4, in PDAC. This suggests that the interaction between Notch1 and Notch3 with these specific DLL ligands may be particularly important for maintaining the tumor phenotype in pancreatic cancer. Disrupting these specific interactions could be a promising therapeutic approach.

What are the potential therapeutic implications of targeting specific Notch receptors and ligands like Notch1, Notch3, DLL1, DLL3, and DLL4 in pancreatic cancer treatment, and what further research is needed?

Targeting Notch1 and Notch3, along with their ligands DLL1, DLL3, and DLL4, holds promise as a therapeutic strategy for pancreatic cancer. By selectively modulating the Notch signaling pathway, researchers aim to disrupt the mechanisms that drive tumor growth and metastasis. However, further research is needed to fully understand the specific roles of each Notch receptor and ligand in PDAC, as well as to develop safe and effective therapies that target these molecules.