Understanding communication between pancreatic cancer tumor cells and their surrounding environment
The incidence of pancreatic ductal adenocarcinoma (PDAC) is rising, and the five-year overall survival remains poor at only 13%. The two principal factors that underlie this poor prognosis is resistance to currently available therapies and early spread of cancers. The focus of our laboratory is understanding how communication in the tumor environment between cancer cells and surrounding non-cancer cells contributes to growth and spread. Using unique models of PDAC development and a rich biorepository of both patient derived tumor samples and donated normal pancreases, we have developed an atlas of cellular crosstalk which describes the complex nature of disease. Additionally, we have identified how toxins present in the environment can upset the delicate balance of cell-cell interactions, promoting tumor development, growth and eventual spread.
Our prior studies have revealed that ~60% of people harbor precancerous pancreatic intraepithelial neoplasia (PanIN) lesions, many of which contain oncogenic mutation in the KRAS gene. Despite this high prevalence, few lesions advance to invasive pancreatic ductal adenocarcinoma, and the mechanisms underlying variability in malignant progression remain unknown. The goal of our lab is to elucidate the contribution of cellular crosstalk between immune cells and epithelial cells in promoting transformation from benign neoplasia to lethal malignancy. This has important implications in the discovery of therapeutics to prevent cancer in high-risk individuals such as those with familial and chronic pancreatitis as well as the design of early diagnostic methods for pancreatic cancer.
Previous work by many laboratories, including ours, showed that inflammation promotes Kras-driven pancreatic cancer, and that interleukin 22 (IL22) is required for the formation and progression of pancreatic cancer precursor lesions. Additionally, strong evidence implicates chronic inflammation as the link between exposure to toxins and PDAC tumorigenesis, but specific immune mediators remain poorly defined. Unique among cytokines, IL22’s receptor (IL22R1) is found only on non-immune cells, positioning IL22 as a key mediator of immune-epithelial cell communication in the pancreas. A defining feature of IL22-producing cells is their reliance on aryl hydrocarbon receptor (AhR), a critical ligand-dependent transcription factor involved in both production of IL22 and cellular differentiation. Thought to represent an “environmental sensor” of the immune system, a recent study found that aryl hydrocarbon receptor ligands (AhRL) present in cigarette smoke dramatically increase IL22 in the pancreas, promoting fibrosis via activation of fibroblasts(5).
A unique partnership with our local organ procurement organization Gift of Life Michigan has given us access to tissue harboring the earliest neoplastic lesions affording us the opportunity to study cancer before it has formed. The decades-long investment in a tissue biorepository as well as establishment of a tumor derived organoid bank provides avenues to test therapeutics in preclinical models, accelerating translation of findings.
Our studies on the regulation of pancreatic injury by IL22 signaling has resulted in better understanding of the balance of tissue injury and repair and established strategies to derail often fatal pancreatic autodigestion. As acute and chronic pancreatitis are a significant burden on the healthcare system and associated with morbidity and mortality, findings in this arena could have far reaching impacts.
In partnership with Drs. Pasca di Magliano and Costas Lyssiotis, we have formed a nationally recognized Pancreatic Research Initiative at the University of Michigan which comprises eight independent investigators and over fifty scientists and trainees. Through this effort, they have produced seminal discoveries using single cell RNA sequencing to identify new networks of communication within the pancreatic cancer microenvironment including immune cells. This work has just recently been published in high impact journals including Cancer Discovery and Nature Cancer. Additionally, these findings, as well as his novel model systems, has resulted in receipt of an multiple NIH R01 and U01 grants from the National Cancer Institute (NCI) studying the role of fibroblasts in tumor/immune communication.
