Scientists report how aggressive pancreatic cancer cells change their environment to enable metastasis to other parts of the body, the main cause of pancreatic cancer-related death. The international team discovered that some pancreatic tumors produce more of the molecule perlecan to remodel the environment around them, which helps cancer cells spread more easily, and also protects them against chemotherapy. In a mouse model, the researchers showed that lowering the levels of perlecan revealed a reduction in the spread of pancreatic cancer and improved response to chemotherapy.

Led by Paul Timpson, PhD, associate professor, and head of the invasion and metastasis laboratory, and Thomas Cox, PhD, leader of the matrix and metastasis group, at the Garvan Institute of Medical Research, the study (“CAF hierarchy driven by pancreatic cancer cell p53-status creates a pro-metastatic and chemoresistant environment via perlecan”), published in Nature Communications, may provide a promising new path to more effective treatment options for individuals with pancreatic and other cancers.

“Heterogeneous subtypes of cancer-associated fibroblasts (CAFs) coexist within pancreatic cancer tissues and can both promote and restrain disease progression. Here, we interrogate how cancer cells harboring distinct alterations in p53 manipulate CAFs. We reveal the existence of a p53-driven hierarchy, where cancer cells with a gain-of-function (GOF) mutant p53 educate a dominant population of CAFs that establish a pro-metastatic environment for GOF and null p53 cancer cells alike. We also demonstrate that CAFs educated by null p53 cancer cells may be reprogrammed by either GOF mutant p53 cells or their CAFs,” the investigators wrote.

“We identify perlecan as a key component of this pro-metastatic environment. Using intravital imaging, we observe that these dominant CAFs delay cancer cell response to chemotherapy. Lastly, we reveal that depleting perlecan in the stroma combined with chemotherapy prolongs mouse survival, supporting it as a potential target for anti-stromal therapies in pancreatic cancer.”

“Pancreatic cancer is very aggressive, and by the time most cases are diagnosed, the tumor is often inoperable,” said Timpson. “What we’ve discovered in this study is a two-pronged approach for treating pancreatic cancer that we believe will improve the efficiency of chemotherapy and may help reduce tumor progression and spread.”

Pancreatic cancer is one of the most lethal forms of cancer, with a five-year survival of ~9% in Australia. In its early stages, pancreatic cancers often show no obvious signs or symptoms and by the time a cancer is diagnosed, it has often begun to spread outside the pancreas.

The Garvan-led team investigated why some pancreatic cancers spread, while others appear to stay in one place. In their study, the researchers compared the tissue around tumor cells in both metastatic and non-metastatic pancreatic cancers. This tissue (matrix) acts like a glue that holds different cells in an organ or in a tumor together.

Using mouse models, the team extracted fibroblasts, which produce most of the matrix, from spreading and non-spreading pancreatic tumors. By mixing these different fibroblasts with cancer cells, the researchers found that remarkably, cancer cells from a non-spreading tumor began to spread when mixed with fibroblasts from a spreading tumor.

“Our results suggest that some pancreatic cancer cells can ‘educate’ the fibroblasts in and around the tumor. This lets the fibroblasts remodel the matrix and interact with other, less aggressive cancer cells in a way that supports the cancer cells’ ability to spread,” said first author Claire Vennin, PhD, a postdoctoral fellow at the Netherlands Cancer Institute. “This means that in a growing tumor, even a small number of aggressive metastatic cells can help increase the spread of other, less aggressive cancer cells.”

To investigate how to stop pancreatic cancer cells from remodeling the matrix around them, the team took an even closer look at the fibroblasts. Using mass spectrometry techniques, the researchers discovered several molecules that the fibroblasts from metastatic tumors produced at significantly higher levels than the fibroblasts from non-metastatic tumors.

“What we discovered is a previously unknown set of matrix molecules that aggressive pancreatic cancer cells use to shape the tissue around them, in order to both protect them from chemotherapy and enable easier escape around the body,” explained Cox.

Pancreatic cancer cells (green) spread along matrix fibers (purple) within the body. [Max Nobis]

Using gene-editing techniques, the researchers reduced the levels perlecan in mouse models of aggressive metastatic pancreatic cancer. Through advanced live imaging techniques, the researchers tracked individual cancer cells and revealed that lowering the levels of perlecan not only reduced the spread of cancer cells, but that tumors also responded better to chemotherapy.

“We believe that there would be an important benefit in targeting the fibroblasts of a tumor in combination with targeting the cancer cells themselves with chemotherapy,” said Vennin. “If we can specifically target the aggressive fibroblasts in patients harboring precise genetic changes, we can make them more susceptible to our currently approved treatments, which would significantly change how we treat this aggressive cancer.”

The researchers say that targeting perlecan, or other matrix molecules that help remodel the tissue of metastatic tumors, may be effective for not just pancreatic cancer, but also prostate and breast cancers.

“Most cancer therapies today aim to target cancer cells themselves. The environment of tumors is a potential untapped resource for cancer therapy and one which we intend to explore further,” said Timpson.

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