Mechanisms regulating the formation of a pro-metastatic niche and tumor cell dormancy in the liver

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ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is the third-leading cause of cancer-related deaths in the United States. For patients with PDAC, metastasis is the major cause of mortality and the liver is the most common site of metastasis. Thus, therapies capable of disrupting the metastatic process represent a clear unmet need. Recent work in the lab showed that Serum Amyloid A1/2 proteins (SAA) released during cancer development precondition the liver for metastasis. In this process, a “pro-metastatic niche” forms in the liver that supports the seeding and colonization of disseminated tumor cells (DTCs). Notably, SAA is a known determinant of liver biology acting via toll-like receptors (TLRs) expressed by innate immune cells. SAA has also been shown to orchestrate an acute phase inflammatory response and to promote tissue repair. However, the mechanisms by which SAA directs formation of a pro-metastatic niche in the liver, and the impact of this niche on the fate of DTCs seeding the liver, remain ill-defined. Thus, an understanding of this biology has strong potential to inform the development of novel strategies aimed at derailing the metastatic cascade. Preliminary data show expression of SAA receptors on macrophages isolated from normal livers, in vitro induction of TLR2 and TLR4 reporter signals by SAA, and increased expression of TLR2 and TLR4 on macrophages within the niche. These data suggest that TLR signaling is a key determinant of the pro-metastatic niche. Preliminary data also show that, in the absence of a pro-metastatic niche, DTCs encountering the liver enter a dormant state. This finding suggests the need for a secondary cue to “awaken” dormant cancer cells and to trigger metastatic outgrowth. Consistent with this, recent studies have shown a role for migratory myeloid cells in reversing tumor cell dormancy in the lung. Similarly, my preliminary data show an accumulation of inflammatory monocytes within the niche that forms in the liver. Thus, the central hypothesis of this proposal is that SAA released by hepatocytes activates resident liver macrophages via TLR signaling to direct the formation of a pro-metastatic niche and ultimately direct the fate (i.e. dormancy versus outgrowth) of DTCs in the liver. In Aim one, I will determine the mechanisms by which SAA directs formation of the pro-metastatic niche. In Aim two, I will elucidate the impact of the pro-metastatic niche on DTC fate in the liver. Altogether, studies in this proposal will advance our understanding of the metastatic process with the potential to identify novel therapeutic approaches for intervening on cancer metastasis. In addition, this project will be sponsored by an established mentor with expertise in immunology and cancer biology. This sponsorship involves a commitment to mentorship and will occur at one of the foremost institutions in cancer immunology and cancer biology. This project also encompasses a graduate training plan which complements training in scientific research and includes didactics in cancer biology and immunology as well as training in scientific communication and teaching.