Science

Targeting immune pathways in aggressive pancreatic cancer

Researchers at the University of New Mexico have found extensive insights into the immune and inflammatory responses associated with pancreatic ductal adenocarcinoma (PDAC), a notoriously active cancer with limited treatment options. The research, led by Dr. Ian Rabinowitz, and his team, including Kathryn Brayer, Dr. Joshua Hanson, Dr. Shashank Cingam, Cathleen Dr. Martinez and Scott Ness, Ph.D., used RNA sequences to analyze tumor and normal pancreatic tissue, pancreatic tissue, and normal pancreatic tissue, revealing key differences that may pave the way for new therapeutic strategies. This work has been published in the peer-reviewed journal PLOS One.

Pancreatic ductal adenocarcinoma is one of the most deadly cancers, and the survival rate of five-year patients is very low for patients in stage 4. The main motivation of the study is to understand the role of the pancreatic microbiome, especially the presence of the fungus malacia in the progression of PDAC. The team found Malassezia RNA in cancerous and normal pancreatic tissue, although its presence was not related to tumor growth. However, they found a significantly upregulated group of immune and inflammatory genes in PDAC tissue compared to normal tissues, suggesting a key role in cancer progression.

“The presence of malacia alone has nothing to do with tumor growth, but the inflammatory response it triggers may be key to understanding PDAC progression,” explains Dr. Rabinowitz. By adopting gene set enrichment analysis, the researchers found complement cascades and inflammation,” he said. The activation of the PDAC sample is evident. These findings suggest that these pathways may be critical to promoting the aggressiveness of this cancer.

The team conducted a comprehensive analysis of matched tumor normal tissue samples, indicating that tumor samples exhibited a more heterogeneous gene expression pattern compared to relatively homogeneous normal samples. Thousands of genes were found to be differentially expressed, about half upregulated and half downregulated in tumors. It is worth noting that genes related to complement cascades, complement activation and inflammatory responses were significantly enriched in tumor samples.

“Our differential gene expression analysis demonstrates that the tumor microenvironment in PDAC has a high degree of immunosuppression, supporting tumor proliferation and survival. This highlights the potential for complement and inflammatory pathways targeting the development of new therapies.”

The study also highlighted the overexpression of key genes (such as C2, dectin-1 and lectectin-3) in tumor samples. Galectin-3 is particularly associated with tumor cell adhesion, proliferation, differentiation and metastasis. Upregulation of galactocytocin 3 and Dectin-1 in PDAC tissues suggests that these molecules can promote tumor progression through inflammation and immune evasion mechanisms.

“Our findings on Galectin-3 and Dectin-1 emphasize their potential as therapeutic targets for PDAC,” said Dr. Rabinowitz. “By suppressing these molecules, we may be able to disrupt the tumor’s ability to manipulate the immune system and promote its own growth.”

The team also explored gene expression curves associated with the KRAS signaling pathway, known for their role in PDAC. They identified several genes overlap between the KRAS pathway and the complement and inflammatory pathways, suggesting that these signaling networks have complex interactions in driving pancreatic cancer.

Dr. Rabinowitz added: “The interaction between KRAS signaling and immune pathways such as complement cascades and inflammation points to a multifaceted approach to addressing PDAC. Targeting these interconnected pathways can produce more effective therapeutic outcomes.”

All in all, this pioneering study provides key insights into the immune and inflammatory situation of pancreatic cancer. By identifying key pathways and molecules involved in PDAC progression, the researchers have laid the foundation for future research to develop targeted therapies that could improve the prognosis of patients with this devastating disease.

https://www.youtube.com/watch?v=xyowxoda9v0

Journal Reference

Brayer, KJ, Hanson, JA, Cingam, S., Martinez, C., Ness, SA, and Rabinowitz, I. (2023). “Inflammatory responses in human pancreatic cancer samples compared to normal controls.” PLOS ONE, 18(11), E0284232. doi: https://doi.org/10.1371/journal.pone.0284232

About the Author

Dr. Ian Rabinowitz and Dr. Shashank Cingam It’s a doctor. And serves as a medical hematologist/medical oncologist. Dr. Cingam is a cross-plate clip of bone marrow, while Dr. Rabinowitz’s therapy is more average. Dr. Rabinowitz has participated in many of the most important clinical trials. His main basic scientific work was to identify mutations in von Wieler’s disease. Dr. Kathryn Brayer and Dr. Scott NESS have worked in the laboratory in molecular medicine, focusing on the role of C-MYB in salivary adenoid cystic carcinoma. They generously contributed their time and expertise to the project.

All authors are related to the University of New Mexico (UNM).

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