Study reveals how pancreatic tumors program macrophages to build fibrotic barriers

In the presence of pancreatic tumors, certain immune cells break down structural proteins into molecules that trigger the formation of dense tissue, a known barrier to therapy, according to a new study.

Led by researchers at NYU Grossman School of Medicine, the study revolves around the dense protein mesh that supports organs and helps rebuild damaged tissue. Collagen protein fibers, the main component of the mesh, are continually broken down and replaced to maintain tensile strength and as part of the healing process.

Previous studies had shown that immune cells called macrophages contribute to a process called desmoplasia, which is caused by the abnormal turnover and excess deposition of collagen that insulates pancreatic cancer. In this environment, macrophages are also known to engulf and break down collagen through the action of a protein called the mannose receptor (MRC1).

Published online April 4 in the Proceedings of the National Academies of Sciences, the current study found that degraded collagen increased the amount of arginine, an amino acid used by the enzyme nitric oxide synthase (iNOS) to produce compounds called reactive nitrogen species (RNS). This, in turn, caused nearby supporting stellate cells to build collagen-based meshes around the tumors, the study authors explain.

“Our results revealed how pancreatic tumors program macrophages to contribute to the construction of fibrotic barriers,” says study first author Madeleine LaRue, PhD. At the time of the study, Dr. LaRue was a graduate student in the lab of lead study author Dafna Bar-Sagi, PhD, Saul J. Farber Professor of Biochemistry and Molecular Pharmacology, and Associate Dean of Science at NYU Langone Health. “This molecular framework could be exploited to counter pro-cancer changes in structural tissues surrounding tumors,” adds Dr. LaRue.

Pancreatic cancer is the third leading cause of cancer-related death in the United States, with a 5-year survival rate of 10%. Pancreatic cancer remains difficult to treat largely due to the extensive network of fibrotic tissue around tumors. This network not only blocks the access of therapies, but also promotes aggressive growth.

For the present study, experiments showed that macrophages grown in nutrient dishes (cultures) and converted to their cancer-tolerant environment (M2) broke down significantly more collagen than macrophages that attack cancer cells (M1). Additionally, the team confirmed with a series of tests that M2 macrophages have higher levels of enzymes that generate RNS, such as iNOS.

To confirm these findings in live mice, the team implanted stellate cells that were either “pre-fed” with collagen or held in a vacuum, into the flanks of study animals with pancreatic cancer cells. The team observed a 100% increase in intratumoral collagen fiber density in tumors derived from cancer cells co-implanted with collagen-pretreated stellate cells.

Importantly, the study showed for the first time that macrophages near pancreatic cancer cells not only take up and break down more collagen as part of cleaning up proteins that fuel abnormal growth, but are also changed by the cleanse so that their energy processing system (metabolism) is rewired and signals a buildup of fibrosis.

Our team has discovered a mechanism that links collagen turnover to the construction of a treatment-resistant environment around pancreatic tumors. As this dense environment is a major reason why pancreatic cancer is so deadly, a better understanding of the links between protein trapping and the building of protective barriers will be needed to improve the treatment of this devastating malignancy.”

Dafna Bar-Sagi, PhD, lead study author

Along with Dr. Bar-Sagi and Dr. LaRue, study authors from NYU Langone Health’s Department of Biochemistry and Molecular Pharmacology were Seth Parker and Joseph Puccini. Co-authors were Alec Kimmelman, MD, PhD, chairman of the Department of Radiation Oncology and a clinician and researcher at NYU Langone’s Perlmutter Cancer Center, and Michael Cammer of the Microscopy Laboratory, Division of Advanced Research Technologies, at NYU Grossman School of Medicine. The study was funded by grants T32GM066704, CA210263, P01CA117969, and CA232124 from the National Institutes of Health, as well as the Lustgarten Foundation and Stand Up To Cancer (SU2C).

Dr. Kimmelman has financial interests in Vescor Therapeutics and is listed on patents relating to KRAS-regulated metabolic pathways, redox control pathways in pancreatic cancer, targeting GOT1 as a therapeutic approach, and autophagic control of iron metabolism. Dr. Kimmelman is a member of the Scientific Advisory Board of Rafael/Cornerstone Pharmaceuticals and a consultant for Deciphera and AbbVie. Dr. Bar-Sagi is a member of the Scientific Advisory Board of Rafael/Cornerstone Pharmaceuticals and Samumed LLC, as well as the Board of Directors of the Pancreatic Cancer Action Network. These relationships are managed in accordance with NYU Langone Health policies.

Ryan H. Bowman