Friday, May 9, 2025
5/9/2025
Administrative Supplement: Immune Regulation of Dormancy at the Metastatic Site - PROJECT SUMMARY/ABSTRACT - No change from original submission Patients with pancreatic ductal adenocarcinoma (PDAC) and no clinically detectable metastases are treated by surgery. However, >70% of such patients later develop metastases, most frequently in the liver. This is strong evidence that metastases can originate from disseminated cancer cells (DCCs). While most DCCs are eliminated by the immune system, a few DCCs escape immune surveillance by undergoing G0/G1 cell cycle arrest. Such non-proliferating DCCs can later proliferate and form lethal metastasis. What drives the dormant DCCs to prolif- erate, escape immune surveillance, and establish metastases are poorly understood, largely due to a lack of appropriate models. Here, we have established a novel PDAC mouse model of dormant DCCs in the liver, using an immunization protocol followed by intrasplenic injection of PDAC cells, we found that most DCCs were elim- inated in such “immunized” mice, but a few survived as single, non-proliferating DDCs and stayed dormant for months. In the F99 phase, we will use this dormant PDAC mouse model to examine what could drive DCC proliferation and how immune cells regulate metastasis. Patients with PDAC have 2-fold higher glucocorticoids (GCs), an immunomodulatory stress hormone, than healthy adults. Mimicking this clinical phenomenon, we treated DCC-hosting mice with GCs, achieving a 2-fold increase of GC in mice, we found that DCCs began to proliferate. In addition, the tumor microenvironment (TME) changed upon GCs treatment: numbers of neutrophils increased while T cells and natural killer (NK) cells decreased. GCs treatment did not cause metastasis, and T cell depletion caused only a few metastases in a small fraction of mice. However, when GCs treatment was combined with T cell depletion, multiple metastases were observed in all mice examined. As proposed, we will define and target the signals that trigger DCC proliferation and elucidate the mechanisms of GCs on T cells and NK cells suppression. In the K00 phase, I plan to investigate immune-fibroblast crosstalk that regulate cancer dormancy in the context of aging. Advanced aging is the most important risk factor for cancer overall and for specific metastatic cancer types including PDAC. Aging changes the TME significantly, including immune cells distributions and effector functions, fibroblasts activities, ECM, and secreted factors. However, how these changes are relevant to the metastasis relapse from DCCs is unknown. My postdoctoral research interest is to study aging-induced changes in immune cells and fibroblasts, with a focus on the immune-fibroblast crosstalk, and their sequential influences on dormant DCCs. Eventually, I plan to become an independent investigator, lead a research team to study cancer dormancy and TME, and generate knowledge to facilitate development of target therapies that prevent metastasis and improve survival.
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