Dysregulation of Liver Macrophages in Pancreatic Cancer

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is the third-leading cause of cancer-related deaths in the United States. Metastasis is the major cause of mortality for patients with PDAC and the liver is the most common site of metastatic disease. Thus, there is a clear unmet need for therapies that disrupt the metastatic process. During

cancer development, soluble factors precondition the liver for metastasis. In this process, the liver becomes a “pro-metastatic niche” that supports the seeding of disseminated tumor cells and their subsequent outgrowth in the liver. Macrophages are a prominent component of this niche, yet their role in regulating metastasis to the

liver remains poorly understood. Preliminary data suggest that liver macrophages restrict tumor cell seeding in the liver, while published data shows that liver macrophages can promote tumor outgrowth after seeding has already occurred. Given knowledge that macrophage biology is finetuned by signals received from their

surrounding environment, these data suggest that macrophages in the liver can be “educated” to possess either anti- or pro-tumor properties. Within the liver in the absence of a niche, Kupffer cells (KCs) are the dominant resident macrophage population. In contrast, bone marrow-derived macrophages (BMDMs) are recruited to the

liver in the setting of inflammation and accumulate in the liver during the formation of a pro-metastatic niche. It is currently unknown how each macrophage subset uniquely contributes to the metastatic process. The central hypothesis of this proposal is that KCs have an inherent anti-metastatic capacity that is defined by a balance

of stimulatory and inhibitory signals; however, during cancer development, this biology is undermined by an influx of BMDMs into the liver that promote metastatic seeding and outgrowth. To test this hypothesis, this proposal will incorporate strategies to selectively deplete KCs and BMDMs to study their distinct

roles in regulating cancer metastasis to the liver using mouse models of PDAC. Aim one will address the role of liver macrophage subsets in regulating the metastatic process in the liver in the presence and absence of the pro-metastatic niche. Aim two will assess the impact of stimulatory and inhibitory signals on the capacity of liver

macrophages to intervene on the metastatic cascade. Studies in this proposal will improve our understanding of pathways regulating metastasis and may identify novel therapeutic strategies for the treatment of PDAC. This project will be sponsored by an experienced investigator with skills in immunology and cancer biology as well as

a demonstrated commitment to mentorship and will occur at one of the foremost institutions for cancer immunology. This project encompasses a graduate training plan which, in addition to training in scientific research, includes didactics in the fields of immunology and cancer biology, training in scientific communication

and mentoring, and clinical training.