According to the CDC, the general five-year survival rate for people with pancreatic cancer in the United States is 11%. Better treatments and understanding of the disease are needed. A new study in mice by researchers at Washington University School of Medicine in St. Louis reveals key transition points in the development of these tumors and may lead to the development of novel therapies.
Their study, “Spatially restricted drivers and transitional cell populations cooperate with the microenvironment in untreated and chemo-resistant pancreatic cancer,” published 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).
The study also provides insights into treatment resistance and how immunotherapy could be harnessed.
“Pancreatic ductal adenocarcinoma is a lethal disease with limited treatment options and poor survival,” wrote the researchers. “We studied 83 spatial samples from 31 patients (11 treatment-naïve and 20 treated) using single-cell/nucleus RNA sequencing, bulk-proteogenomics, spatial transcriptomics, and cellular imaging. Subpopulations of tumor cells exhibited signatures of proliferation, KRAS signaling, cell stress, and epithelial-to-mesenchymal transition. Mapping mutations and copy number events distinguished tumor populations from normal and transitional cells, including acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia.”
“Pancreatic cancer is so difficult to treat, and to develop better treatments we need to understand how normal, healthy cells in the pancreas transition to becoming cancerous,” explained co-senior author and computational biologist Li Ding, PhD, the David English Smith distinguished professor of medicine and a professor of genetics. “This marks the first time these transitions have been mapped out in such detail in human tumors. Our findings are jumping-off points for the future development of new treatment strategies for this deadly cancer.”
“We have a lot of snapshots of these tumors, but what we really need is a movie,” said co-senior author Ryan C. Fields, MD, the Kim and Tim Eberlein distinguished professor. “It’s very hard to study these tumors in patients across the spectrum of treatment. The point of the Human Tumor Atlas Network is to document the tumors across space and time so we have more of a continuous movie rather than distinct snapshots.”
The team of researchers mapped out two key transition points in the development of pancreatic cancer. One involves the shift normal pancreatic cells make as they become precancerous; the second transition point involves the shift from precancerous cells to early cancer cells.
The researchers determined the characteristics of cells in these transitory states, opening the door to future strategies to detect cells that are not yet cancerous. The researchers also discovered a new combination of signaling molecules that may be useful in targeting T cells to pancreatic tumor cells.
“The surface molecules that make traditional checkpoint inhibitors work on other cancers are simply absent in pancreatic tumors,” Ding said. “We basically found a parallel interaction using two different molecules that are present in pancreatic cancer. We are excited about the prospect of exploring this interaction as a way to develop a new type of checkpoint immunotherapy for this tumor type.”
The researchers found that a threefold increase in inflammatory cancer-associated fibroblasts is strongly associated with resistance to chemotherapy. “These findings suggest that targeting the inflammatory fibroblasts in the tumor microenvironment may be key to overcoming chemo-resistance in these treated tumors,” Ding said.
“Our study reveals a deeper understanding of the intricate substructure of pancreatic ductal adenocarcinoma tumors that could help improve therapy for patients with this disease,” concluded the researchers.