What Drives Pancreatic Cancer Spread?

Cancer cells play by their own rules.

Although cancers aren’t identical, their cells have one goal in common—to grow and divide, relentlessly. Some of those cells will eventually metastasize, leaving their starting point in the pancreas, for example, and spreading to another organ like the liver. 

Metastasis, or cancer spread, is very complex. Researchers still need to learn about the intricate mechanisms that fuel this spread. In a study published in September 2023 in the journal Cell Reports, scientists from the Mayo Clinic in Rochester, Minnesota, may have come one step closer by identifying a cell-signaling protein called DOCK8 that drives pancreatic cancer cell growth. The hope is that this signaling protein could eventually be a potential therapeutic target.

In her lab at Mayo, Gina Razidlo, Ph.D., the study’s senior author, uses both cell biology and biochemical strategies to investigate the mechanism of tumor cell invasion and migration. “We need to have a fundamental understanding of what is happening in terms of migration and metastasis and there are still many questions with not a lot of answers,” she says. Razidlo leads the Cell Biology of Metastasis Laboratory at Mayo. “The majority of cancer deaths are associated with metastasis, but there is not one drug in use that inhibits the process. We want to change that but first we need to better understand the entire process.”

Unanswered Questions

Indeed, there are many unanswered questions as to what makes the metastatic process so powerful. For example, scientists still need to learn how to accurately identify when and where metastasis occurs and to get a better handle on the specific molecular changes that enable cancer cells to spread, Razidlo explains.

“Another area of research is learning more about the role of the microenvironment and how it supports metastatic growth,” she notes. “Pancreatic cancer is a very difficult disease to treat and obviously earlier detection is vital. But today most people are still diagnosed with disease that is in its later stages, and that makes it even tougher to treat. So, if we can find some clues about the basic biology of metastasis then we could potentially find a target. And that would be a real game changer for patients.”

DOCK8 as the Cell-Signaling Protein in Metastasis

Pancreatic cancer thrives in a harsh, nutrient-deprived setting. Its cells grow in a microenvironment encapsulated in a dense, mesh-like network made of secreted proteins and other non-cancer cells called the stroma. Blood flow is restricted, and because of that restriction, the cancer cells have limited access to nutrients. But pancreatic cancer still grows and spreads at an alarming rate.

Like other cancer cells, pancreatic cancer cells rewire their metabolism to meet their energy needs. One way in which the cancer cell accomplishes this task is to hijack metabolic pathways. The cancer cell’s target is a tiny membrane-bound organelle called a lysosome. These organelles contain digestive enzymes that are involved with various cell processes. They break down excess or worn-out cell parts and they may be used to neutralize signals and sense the nutrient environment.

“In a way, the pancreatic cancer cell hijacks lysosomes, which normally function kind of like a cell’s stomach,” explains Razidlo. “The digestive enzymes in the lysosome break down proteins, lipids, and nutrients that fuel cells to grow. There’s been a lot of research showing that amplified lysosome activity is a key indicator of several forms of cancer.”

Razidlo and her team, including lead author Omar Gutierrez-Ruiz, Ph.D., examined lysosomes in pancreatic cancer cells that were driven by mutations in the oncogene KRAS, which is present in more than 90 percent of pancreatic cancers. The first step was to compare the lysosomes from pancreatic cancer cells expressing mutated KRAS with lysosomes from cells with healthy KRAS. Among the 52 proteins they found that had changed on the surface of lysosomes in pancreatic cancer cells, there was one protein that caught their attention. That protein is dubbed dedicator of cytokinesis 8 or, more simply, DOCK8.

“DOCK 8 is best studied in our immune cells,” Razidlo says. “One role is to help immune cells fight infection by clearing a way for the immune cell to get to its target.” But DOCK8 was also found on lysosomes in pancreatic cancer cells. After examining pancreatic cancer cells more closely, the researchers saw that DOCK8 uses lysosomes to break down the extracellular environment around the cancer cell, helping it to spread. “We studied images and videos of the pancreatic cancer cells from our cell signaling center,” she adds. “We were pretty amazed to consider how it resembled DOCK8’s role in the immune response.”

To confirm DOCK8 was involved in tumor progression, the team used CRISPR technology to eliminate pancreatic cancer cells in preclinical models. Their findings show DOCK8-depleted lysosomes were slow-moving, resulting in slowed tumor growth and decreased metastasis. In clinical models, the researchers found that DOCK8 was present in about 20 percent of patients with pancreatic cancer whose cells were studied.

The Next Step

Currently, there is no drug to inhibit DOCK8, but all clinical strategies and our understanding of diseases like pancreatic cancer come from discovery science. “Any drugs or therapies that we have now first started in the lab,” Razidlo says. “DOCK8 may be an answer or it may not. But we need to investigate it more.”

Razidlo has worked in pancreatic cancer research for about 16 years. She is heartened by the recent progress in the disease. “When I started, we never thought KRAS could be targeted. It was considered ‘undruggable,’” she notes. “But now we have KRAS inhibitors. It’s going to be a long road, but I’m hopeful we are going to be able to do the same and target metastasis.”