Pancreatic cancer outcomes remain dismal, even for the ~15-20% of patients that present with early-stage, surgically-resectable disease. Most patients that undergo months of neoadjuvant chemotherapy followed by radical pancreaticoduodenectomy will recur with metastases within a few years. These clinical challenges illustrate the fact that pancreatic tumor cells spread to distant organs early in disease, and to mitigate metastasis progression, there is a profound need for therapies that target disseminated tumor cells (DTCs). Although standard-of-care chemotherapy aids in tumor control and can be highly effective in some patients, our previous studies demonstrated that systemic chemotherapy accelerates liver metastasis outgrowth and reduces overall survival in a mouse model of pancreatic cancer liver metastasis. We have several ongoing studies aimed to define and target the pro-metastatic liver signals generated by chemotherapy that supports the survival and outgrowth of liver-resident disseminated tumor cells. Our major goal is to identify novel therapeutic approaches for reducing risk of disease recurrence.

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1. Liver endothelial and fibroblast secretion of the tissue inhibitor of matrix mellatoproteinases-1, Timp1.

Our previous studies demonstrated that oxaliplatin treatment, a chemotherapy included in the standard-of-care therapy FOLFIRINOX, accelerates liver metastasis outgrowth and reduces overall survival in a mouse model of pancreatic cancer liver metastasis. Proteomic analysis revealed that oxaliplatin triggers increased expression of Timp1 in liver interstitial fluid. Pharmacologic blockade of Timp1 significantly reduces liver metastasis progression in mice, virtually reversing the accelerated metastasis phenotype caused by oxaliplatin treatment. Further, surgically-resected pancreatic cancer patients that recur early with metastases have higher serum TIMP1 protein levels than patients that recur late or don’t recur, suggesting that high TIMP1 may functionally contribute to metastasis in patients. Timp1 is an extracellular protein that can both modulate the extracellular matrix (ECM) by inhibiting matrix metalloproteinase (MMP) function or act as a cytokine that binds and activates transmembrane receptors such as CD63. The overall objective of this project is to define the mechanisms by which oxaliplatin triggers Timp1 secretion from liver cell populations, and determine how Timp1 acts to accelerate metastasis.

 

This project is led by Omar Cortez-Toledo and Kai Liptow. We are grateful for funding support from American Gastroenterological Association (AGA), Vince Lombardi Cancer Foundation (VLCF), Sky Foundation, the MCW Research Affairs Committee, and support for Omar Cortez-Toledo by the MCW Cancer Center graduate student fellowship.

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2. Hepatocyte-derived secretion of the pleiotropic growth factor, Midkine.

We further performed single-cell RNA sequencing analysis of livers from mice treated with oxaliplatin or vehicle control. This revealed that oxaliplatin triggers increased expression of Midkine (MDK) in midlobular hepatocytes. MDK is a pleiotropic growth factor that mediates signaling through interaction with cell-surface proteoglycan and non-proteoglycan receptors. Our preliminary studies demonstrate that MDK is significantly higher in the serum of early-stage pancreatic cancer patients as compared to healthy adults, and increased in patients that recur with liver metastasis following surgery. Exogenous MDK increases the migratory behavior of pancreatic cancer cells suggesting that MDK may drive metastatic behavior. Further, bioinformatic analysis of publicly-available single-cell RNA-sequencing datasets revealed MDK expression is not restricted to liver, but also expressed in cancer cells. MDK is significantly enriched in cancer cells of the more aggressive basal subtype, and enriched in cancer cells from liver metastasis. Taken together, these findings suggest that high MDK may contribute to metastasis possibly through both paracrine (metastatic niche) and autocrine (cell-autonomous) signaling. The overall objective of this project is to determine the functional impact of microenvironmental- and cancer cell-derived MDK in pancreatic cancer liver metastasis and therapy response.

 

This project is led by Dr. Priyanga Jayakrishnan with the support of Parnian Vakili. We are grateful for funding support from We Care Fund for Medical Innovation and Research, and support for Parnian Vakili by the MCW Cancer Center – UW Milwaukee Undergraduate Research Grant.

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3. Chemotherapy-driven depletion of Kupffer cells.

Our recent studies reveal that FOLFIRINOX, a chemotherapy regimen used to treat pancreatic cancer, can also accelerate liver metastasis in mouse models. To investigate the impact of FOLFIRINOX on the metastatic liver microenvironment, we established a mouse model of pancreatic cancer liver metastasis in which the tumor cells label adjacent niche cells with a red fluorescent protein, enabling isolation of cells in the adjacent metastatic niche. Single cell RNA sequencing analysis revealed a profound shift in macrophage composition at the metastatic site following FOLFIRINOX treatment, including depletion of Kupffer cells, liver tissue-resident macrophages, and expansion of alternatively activated (M2-like) macrophages. Furthermore, remaining Kupffer cells had reduced expression of formyl protein receptor 1 (Fpr1) following FOLFIRINOX, a GPCR that responds to damage-associated molecular patterns and promotes anti-tumor immunity. Our ongoing studies are aimed to determine if Kupffer cell therapy can be leveraged to prevent metastatic recurrence to the liver following chemotherapy. Further, we are investigating the role of Fpr1 in Kupffer cell-mediated anti-tumor immunity. The overall objective of this project is to attenuate the shift towards immunosuppressive macrophage populations triggered by chemotherapy.

 

This project is led by Isabella Facchine.