Pancreatic ductal adenocarcinoma accounts for 90% of all tumors that arise from the pancreas. Despite increasing knowledge and improved treatment regimens, the prognosis for patients is poor with an average 5-year survival rate of only 10%. The aggressive tumor biology of PDAC in combination with dense fibrous tissue in the tumor micro-environment are considered part of the factors that confer therapy-resistance. Looking for new therapeutic opportunities, scientists at Cancer Center Amsterdam are zooming in on the roles of cancer-associated fibroblasts in the tumor micro-environment. These cells seem to function as enigmatic ‘double agents’, displaying both tumor-promoting as well as tumor-suppressing features.

In a review published in Seminars in Cancer Biology, first author Lenka Boyd and colleagues dive into the biology of cancer-associated fibroblasts (CAFs) in the development and treatment-resistance of pancreatic ductal adenocarcinoma. The tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) is a complex matrix with a wide variety of cells like pancreatic stellate cells, fibroblasts, endothelial, and immune cells. There are also many excreted messenger molecules including cytokines, growth factors and signals packaged in extracellular vesicles.

“The tumor microenvironment has essential roles in pancreatic ductal adenocarcinoma and offers possibilities to identify new cancer biomarkers or therapeutic strategies,” explains Lenka. “However, our knowledge about it - and in particular the CAFs - is incomplete. From existing literature, we have extracted and combined crucial information about the dual roles of CAFs in PDAC pathophysiology to provide a basis for new insights and therapy development.”

Dissecting the double agents

In this review, the researchers seek to clarify the intriguing heterogeneity and plasticity of CAFs, features that are key to their diverse roles in the regulation of the proliferation and differentiation of adjacent epithelial cells and the modulation of wound healing processes. “In fact, there is a great diversity of CAF functions, and these can both promote and limit the growth of tumors,” says Lenka. “For example, CAFs can encourage oncogenesis in a number of ways such as abnormal wound healing stimuli and immune suppression. But CAFs are also capable of restraining tumor growth. Therapeutic strategies aimed at depleting CAFS have produced conflicting and controversial results.”

The better understanding of the biology and dynamics of CAFs within the tumor microenvironment will allow the use of CAFS as prognostic or predictive biomarkers which could open the door to better clinical management and personalized therapeutics.

Research activities at Cancer Center Amsterdam to clarify the dual role of CAFs in PDAC are ongoing.

For more information contact Lenka Boyd or read the Scientific Review here:

Boyd, L.N.C., et al (2022) Heterogeneity and plasticity of cancer-associated fibroblasts in the pancreatic tumor microenvironment. Seminars in Cancer Biology 82, 184-196. https://doi.org/10.1016/j.semcancer.2021.03.006

Funding for this work was provided by the Bennink Foundation and Stichting Cancer Center Amsterdam

Involved researchers at Cancer Center Amsterdam:

Lenka N.C. Boyd

Godefridus J. Peters

Geert Kazemier

Elisa Giovannetti

In collaboration with:

Katarina D. Andini, the Netherlands Cancer Institute