June 21, 2024
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Science And Technology

Targeting immune pathways in aggressive pancreatic cancer

Researchers at the University of New Mexico have uncovered important insights into the immune and inflammatory responses associated with pancreatic ductal adenocarcinoma (PDAC), a notoriously aggressive cancer with limited treatment options. The study, led by Dr. Ian Rabinowitz, along with his team that included Kathryn Brayer, Dr. Joshua Hanson, Dr. Shashank Cingam, Cathleen Martinez and Dr. Scott Ness, used RNA sequencing to analyze tissues normal and tumor pancreatic cells. revealing crucial differences that could pave the way for new therapeutic strategies. The work has been published in the peer-reviewed journal PLOS ONE.

Pancreatic ductal adenocarcinoma is among the deadliest forms of cancer, with a very low five-year survival rate for stage 4 patients. The main motivation for the study was to understand the role of the pancreas microbiome, particularly the presence of the Malassezia fungus, in the progression of PDAC. The team discovered Malassezia RNA in normal and cancerous pancreatic tissues, although its presence did not correlate with tumor growth. However, they identified a set of immune and inflammatory genes significantly upregulated in PDAC tissues compared to normal ones, suggesting a critical role in cancer progression.

“The presence of Malassezia alone was not related to tumor growth, but the inflammatory response it triggers could be key to understanding the progression of PDAC,” Dr. Rabinowitz explained. Employing gene set enrichment analysis, the researchers found that complement cascade activation and inflammation were prominent in PDAC samples. These findings indicate that these pathways could be crucial in driving the aggressive nature of this cancer.

The team performed a comprehensive analysis of matched normal and tumor tissue samples, revealing that the tumor samples exhibited more heterogeneous gene expression patterns compared to the relatively homogeneous normal samples. Thousands of genes were found to be differentially expressed, about half of them upregulated and the other half downregulated in the tumors. In particular, genes involved in the complement cascade, complement activation, and inflammatory responses were significantly enriched in tumor samples.

Dr. Rabinowitz noted, “Our differential gene expression analysis showed that the tumor microenvironment in PDAC is highly immunosuppressive, favoring tumor proliferation and survival. “This highlights the potential of targeting inflammatory and complement pathways in the development of new treatments.”

The study also highlighted the overexpression of key genes such as C2, Dectin-1 and Galectin-3 in tumor samples. Galectin-3, in particular, has been associated with tumor cell adhesion, proliferation, differentiation, and metastasis. The upregulation of Galectin-3 and Dectin-1 in PDAC tissues suggests that these molecules may facilitate tumor progression through inflammation and immune evasion mechanisms.

“Our findings on Galectin-3 and Dectin-1 underscore their potential as therapeutic targets in PDAC,” said Dr. Rabinowitz. “By inhibiting these molecules, we could alter the tumor's ability to manipulate the immune system and promote its own growth.”

The research team also explored gene expression profiles associated with the KRAS signaling pathway, known for its role in PDAC. They identified several overlapping genes between the KRAS pathway and inflammatory and complement pathways, suggesting a complex interplay between these signaling networks in driving pancreatic cancer.

Dr. Rabinowitz added: “The interplay between KRAS signaling and immune pathways, such as the complement cascade and inflammation, points to a multifaceted approach to addressing PDAC. Targeting these interconnected pathways could produce more effective therapeutic results.”

In summary, this groundbreaking study provides fundamental insights into the immunological and inflammatory landscape of pancreatic cancer. By identifying key pathways and molecules involved in PDAC progression, researchers have laid the foundation for future studies aimed at developing targeted therapies that could improve the prognosis of patients with this devastating disease.

Magazine reference

Brayer, KJ, Hanson, JA, Cingam, S., Martinez, C., Ness, S.A., and Rabinowitz, I. (2023). The inflammatory response of human pancreatic cancer samples compared to normal controls. MORE ONE, 18(11), e0284232. DOI: https://doi.org/10.1371/journal.pone.0284232

About the Author

All authors are associated with the University of New Mexico (UNM).

Dr. Ian Rabinowitz and Dr. Shashank Cingam are physicians. and work as a hematologist/medical oncologist. Dr. Cingam is a bone marrow transplanter, while Dr. Rabinowitz has a more general practice. Dr. Rabinowitz has participated in many clinical trials, the most important being IRIS (Imatinib versus interferon and cytarabine) in chronic myeloid leukemia. His main work in basic science was determining the mutations in von Willebrand disease. Kathryn Brayer PhD and Scott Ness PhD work in the Molecular Medicine laboratory, focusing on the role of c-myb in adenoid cystic carcinoma of the salivary glands. They graciously contributed their time and expertise to the project.

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