by Candace Gwaltney, Indiana University

Identification of pancreatic cancer architecture. Credit: Nature Genetics (2024). DOI: 10.1038/s41588-024-01914-4

Indiana University Melvin and Bren Simon Comprehensive Cancer Center researchers have mapped pancreatic cancer tumor ecosystems using tissue from both the primary tumor, which is where cancer first starts to grow in the body, and metastatic disease, or when cancer cells spread to different parts of the body beyond the primary tumor.

The study, recently published in Nature Genetics, uncovers notable differences between primary and metastatic pancreatic cancer, which could lead to new treatment strategies for the often-deadly disease.

Study senior author Ashiq Masood, MD, associate professor of medicine at the IU School of Medicine, used spatial transcriptomic, a method to study a region of cells and their interactions, to uncover these ecosystems of pancreatic cancer.

"In about 85% of pancreatic cancer cases, surgery is not an option because it's either too advanced or has spread to other organs such as the liver," said Masood, a researcher at the cancer center. "For that reason, it's been very difficult to get enough tumor tissue to do sequencing of both the primary and metastatic tumors."

IU and its health care partner Indiana University Health have one of the highest-volume pancreatic cancer programs in the country, with surgeons performing more pancreatic cancer surgeries than any other team in the nation. This makes IU uniquely positioned to yield diverse tumor samples that are stored in a tissue bank for cancer research.

While pancreatic cancer accounts for fewer than 4% of new cancer cases in the United States, it's the third leading cause of cancer deaths annually. The National Cancer Institute estimates more than 51,000 people in the U.S. will die of pancreatic cancer in 2024.

Using tumor tissue from surgical resections of pancreatic cancer and disease that spread to the liver, pancreas and lymph nodes, IU researchers were able to study the "neighborhoods" of pancreatic cancer.

Much of pancreatic cancer research has previously focused on the primary tumor, but understanding how the disease spreads is crucial to developing new treatments. Masood and the research team identified seven distinct spatial neighborhoods, or spatial ecotypes, in the primary tumor and metastases. Each neighborhood has a unique makeup of cells and gene activity.

"These tumors can be considered an ecosystem where cancer cells and other accessory cells—whether fibroblasts, T cells and other immune cells—are interconnected and communicate with each other and with the tumor cells," Masood said.

For example, the primary pancreatic tumor neighborhood had high numbers of fibroblast cells, which contribute to forming connective tissue. Comparatively, the metastatic tumors in the liver had more cancer cells that divide and multiply rapidly.

"What was interesting is that in the same patient, we saw these different tumor ecosystems, so we may need different therapeutic strategies to target one and then the other," Masood said.

He is now planning projects to build on this work.

"Our next objective is to study pancreatic cancer ecosystems at single-cell resolution while retaining spatial context," Masood said.

"In addition to patient samples, we will use models to explore the functions of different spatial ecotypes and investigate the presence and roles of ecotype-specific genes in all patients. Finally, we aim to determine if patient-specific ecotypes exist and their influence on prognosis and treatment response, which will be vital for developing effective combination therapies."

Additional IU cancer center authors on the study include Anita Turk, Michael House, Y. Alan Wang, Nicholas J. Zyromski, Mateusz Opyrchal, Kelvin P. Lee, and Heather O'Hagan; and additional IU authors are Ateeq M. Khaliq, Meenakshi Rajamohan, Omer Saeed, Kimia Mansouri, and Asif Adil.

More information: Ateeq M. Khaliq et al, Spatial transcriptomic analysis of primary and metastatic pancreatic cancers highlights tumor microenvironmental heterogeneity, Nature Genetics (2024). DOI: 10.1038/s41588-024-01914-4

Journal information: Nature Genetics 

Provided by Indiana University