Tumors on a chip may lead to insights into pancreatic cancer

Pancreatic cancer is an often fatal disease and remains one of the most difficult cancers to treat. This year, about 67,530 people will be diagnosed with pancreatic cancer and about 52,740 people will die of pancreatic cancer, predicts the American Cancer Society.

There are several reasons for why pancreatic cancer is difficult to treat: it is often asymptomatic in the early stage, most of the mutations are of the KRAS gene, immunotherapies are less effective in this cancer, and tumors in the pancreas are able to build a thick, dense wall of collagen, blood vessels, and fibrous tissue that hinders surgery.

But now researchers may have a way to better study how pancreatic tumors evolve and how possible treatments impact these tumors. Recently researchers at the University of Texas Health Science Center at Houston created a “tumor-on-a-chip” system that recreates the environment of a pancreatic tumor. Designed to mimic natural conditions, the chip allows fluid to flow like blood and closely mirrors the behavior of human pancreatic tumors.

“Our goal was to build a model that looks and behaves much more like a real pancreatic tumor than traditional lab models,” said Faraz Bishehsari, M.D., Ph.D., director of the Gastroenterology Research Center at McGovern Medical School at UTHealth Houston. “By recreating the tumor’s environment, we can better understand the disease and test treatments in a patient-specific way.”

The chip-based model enabled researchers to track how cancer cells interact with surrounding tissues and how they respond to treatment over time. The system was able to reproduce the interactions between cancer cells and the surrounding scar-like tissue, known as desmoplastic stroma.

“We were able to monitor how cancer cells interacted with neighboring cells, how the tumor structure evolved, and how it responded to chemotherapy and other therapies,” Bishehsari said in a news release. “By targeting the stromal components in the chip, we found that standard chemotherapy became more effective, which could suggest new strategies for improving treatment response.”

In an article published recently in Advanced Science, researchers described the model, which incorporates patient-derived organoids and key components of the pancreatic cancer tumor microenvironment (TME), such as fibroblasts, endothelial cells, and immune cells, within a microfluidic system. Researchers said that with this organ-on-a-chip system, they were able to model and assess the efficacy of immune checkpoint blockade as a model for pancreatic cancer.

Researchers obtained biopsies and blood samples from patients with pancreatic ductal adenocarcinoma. The isolated cancer cells were cultured to proliferate as 3D models of the cancer that had the functional features of the tumor in vivo. From the patients’ blood cells, researchers were able to isolate peripheral blood mononuclear cells, which include immune cells such as T cells, B cells, and NK cells.

The chip consists of two chambers, one to simulate a vascular channel and one that contains the cancer cells. To evaluate whether the tumor chip model could be used for drug testing, researchers introduced gemcitabine, a chemotherapy agent that is used as a standard of care in pancreatic cancer. They found that in their chip environment, T cells migrated toward the chamber with the tumor, but the cancer-killing effect of the immune cells was blocked by the stroma.

Additionally, researchers assessed whether the chip model could be used to assess the response of immunotherapies. They introduced pembrolizumab, a monoclonal antibody that targets programmed cell death protein 1 (PD-1). They found that with a higher dose of pembrolizumab, there was an increased percentage of apoptotic tumor cells migrating toward the chamber with the tumor.

“This approach can facilitate the development of more precise, pathophysiologically relevant platforms that better replicate in vivo tumors, thereby advancing personalized therapies for PDAC, which is largely resistant to current treatments,” researchers wrote.