Pancreatic desmoplasia is the dense, fibrous scar-like (fibroinflammatory) tissue that forms within and around tumors in pancreatic ductal adenocarcinoma (PDAC). It can make up to 80% to 90% of the total tumor volume
Image Credit: National Cancer Institute
Scientific Frontline: Extended "At a Glance" Summary: ASC Protein Targeting in Pancreatic Cancer
The Core Concept: Researchers have demonstrated that blocking a specific innate immune system gene, which produces the inflammasome adaptor protein ASC, can significantly reduce the formation of pancreatic cancer tumors.
Key Distinction/Mechanism: While standard chemotherapy and immunotherapies struggle to penetrate the fibrous tissue surrounding pancreatic cancer, researchers successfully used small, alpaca-derived nanobody inhibitors to bypass this barrier. These nanobodies target and block the ASC protein, which normally promotes tumor growth by acting as a molecular bridge between innate immunity and energy metabolism within cancer cells.
Major Frameworks/Components:
- Pancreatic Ductal Adenocarcinoma (PDAC): Accounts for over 90% of pancreatic cancer cases and is driven by genetic alterations and dysregulated innate immunity.
- ASC Protein: An inflammasome adaptor protein historically associated with inflammatory diseases like gout and arthritis, now identified as a critical driver of PDAC and an indicator of poor survival outcomes.
- Nanobody Inhibitors: Small therapeutic inhibitors derived from alpacas that successfully penetrate solid, fibrous cancer tissues to neutralize the ASC protein.
- Innate Immunity: The body's initial immune response, which, when dysregulated, can trigger tumor-promoting chronic inflammation.
Branch of Science: Oncology, Immunology, Molecular Biology, and Genetics.
Future Application: This ASC-blocking strategy could be combined with existing therapies to create more effective treatments, potentially improving patient response rates and long-term survival for pancreatic cancer.
Why It Matters: Pancreatic cancer is projected to become the second most lethal cancer in Western countries by 2030, with a current five-year survival rate of approximately 13%. Identifying new, targetable molecular pathways is essential for combating this aggressive and highly lethal disease.
Researchers from Adelaide University have demonstrated that blocking a specific immune system gene can reduce pancreatic cancer tumor formation.
Pancreatic cancer is predicted to be the second most lethal cancer in Western countries by 2030 and is associated with a low overall five-year survival rate of approximately 13%, in part because the cancer is often advanced by the time it is diagnosed.
Current standard-of-care chemotherapy and, more recently, immunotherapy treatments are also largely ineffective.
Professor Brendan Jenkins, program head of Tumor Inflammation and Immunotherapy at the South Australian immunoGENomics Cancer Institute (SAiGENCI), and Dr. Joshua Chey have shown that the gene that makes the ASC protein can have a significant impact on tumor formation in pancreatic cancer models.
In a multilayered study, the researchers first identified upregulation of the ASC protein in patient pancreatic cancer tissue before moving to a preclinical model to further investigate its impact on the progression of cancer.
The findings were published in the journal Nature Communications.
"More than 90% of cases present as pancreatic ductal adenocarcinoma (PDAC), which we know is driven by genetic alterations in the organ coupled with dysregulated innate immunity that triggers tumor-promoting chronic inflammation," said Professor Jenkins.
"But until now, there wasn't much known about the innate immune molecular regulators as targets in PDAC.
"We have been able to show the inflammasome adaptor protein ASC indicates poor survival outcomes in patients, and that it promotes PDAC by acting as a molecular bridge between innate immunity and energy metabolism within cancer cells.
"In our preclinical model, we showed that deletion of the gene for ASC, or using a small inhibitor (nanobody derived from alpacas) against the ASC protein, significantly reduced the formation of pancreatic tumors. This provides the rationale to therapeutically target ASC in cancers."
"The appearance of ASC has long been associated with inflammatory diseases like gout and arthritis," first author Dr. Chey said.
"In solid cancers, it can be hard to penetrate fibrous tissue surrounding cancer cells, but we found the use of small nanobodies against ASC is able to penetrate and target the ASC protein in our preclinical disease model.
"This new inhibitor drug has had success with models of inflammatory conditions, but this was the first time it has been demonstrated to have anticancer activity.
"We can see this strategy of blocking ASC working in combination with existing therapies to give patients better responses and improve the long-term survival rate."
Published in journal: Nature Communications
Authors: Yu C. J. Chey, Bassam Kashgari, Louise McLeod, Georgette A. Radford, Linden J. Gearing, Ruby E. Dawson, Malvika Kharbanda, Joanne Lundy, Daniel Croagh, Charlotte Girard-Guyonvarc’h, Cem Gabay, Brooke A. Pereira, David Herrmann, Paul Timpson, John W. Finnie, Mohamed I. Saad, Dharmesh D. Bhuva, Bernardo S. Franklin, Florian I. Schmidt, and Brendan J. Jenkins
Source/Credit: Adelaide University
Edited by: Scientific Frontline
Reference Number: ongy100926_01
