Study offers insights into how pancreatic cancer develops

Aug. 23, 2022
Atlas of pancreas tumors reveals important new findings in treatment resistance, possible new therapies.

A new study from Washington University School of Medicine in St. Louis has revealed the details of two key transition points in the development of pancreatic cancer.

The study provides insights into treatment resistance and how immunotherapy could be harnessed to treat this aggressive tumor type. Shown is a human pancreatic tumor. Cell nuclei are in blue; cell membranes are in red; proliferating cell nuclei are in cyan. Other colors highlight different kinds of immune cells and cells of connective tissue.

The study, published Aug. 22 in the journal Nature Genetics, is part of the Human Tumor Atlas Network, funded by the National Cancer Institute’s Cancer Moonshot program, all part of the National Institutes of Health (NIH).

Also, as part of an ongoing phase 1 immunotherapy clinical trial at Siteman Cancer Center — based at Barnes-Jewish Hospital and Washington University School of Medicine — the researchers are conducting the same detailed analyses performed in the current study to see how tumors from patients respond to two investigational drugs that prime the immune system to attack the cancer.

The researchers conducted a deep analysis of the genetics and protein manufacturing of 83 pancreatic tumor samples donated by 31 patients who participated in the study. They noted how the tumors differed across the volume of the tumor and at various times as the patients underwent treatment.

Ding, Fields and their colleagues, including fellow co-senior author David G. DeNardo, PhD, a professor of medicine, mapped out two key transition points in the development of pancreatic cancer. One involves the shift normal pancreatic cells make as they become precancerous. And the second transition point involves the shift from precancerous cells to early cancer cells. Future studies will focus on a third key transition point: that of the original tumor shifting to metastatic disease, which spreads to other parts of the body.

Beyond maps of the transitions, Ding and her colleagues determined the characteristics of cells in these transitory states, opening the door to future strategies to detect cells that are not yet cancerous but are on their way, which could lead to the development of ways to prevent the onset of cancer.

Another key finding relates to a new strategy for so-called checkpoint immunotherapy, which has proven ineffective in attacking pancreatic tumors. The researchers identified a new combination of signaling molecules that could potentially prove useful in targeting T cells to pancreatic tumor cells. Such a treatment would also “take the brakes off” the T cells to kill those cancer cells.

Over time, most pancreatic tumors develop resistance to chemotherapy, and the new study reveals what Ding calls a chemo-resistance signature that characterizes how the tumors change and adapt to survive even in the face of chemotherapy.

The researchers found that a threefold increase in inflammatory cells surrounding the tumor — called inflammatory cancer-associated fibroblasts — is strongly associated with resistance to chemotherapy.

Washington University School of Medicine in St. Louis release