The liver is the most common site of metastatic disease1. While this metastatic tropism may reflect mechanical trapping of circulating tumor cells, liver metastasis is also dependent, at least in part, on formation of a “pro-metastatic” niche that supports tumor cell spread to the liver2,3. Mechanisms that direct formation of this niche, though, are poorly understood. Here, we show that hepatocytes coordinate myeloid cell accumulation and fibrosis within the liver, and in doing so, increase the susceptibility of the liver to metastatic seeding and outgrowth. Early during pancreatic tumorigenesis, hepatocytes demonstrate activation of Signal Transducer and Activator of Transcription 3 (STAT3) signaling and increased production of serum amyloid A1 and A2 (SAA). Overexpression of SAA by hepatocytes also occurs in pancreatic and colorectal cancer patients with liver metastases, and many patients with locally advanced and metastatic disease display elevated levels of circulating SAA. STAT3 activation in hepatocytes and the subsequent production of SAA are dependent on interleukin 6 (IL-6) that is released into the circulation by non-malignant cells. Genetic ablation or blockade of components of IL-6/STAT3/SAA signaling prevents establishment of a pro-metastatic niche and inhibits liver metastasis. Our data reveal an intercellular network underpinned by hepatocytes that forms the basis for a pro-metastatic niche in the liver and identify new therapeutic targets.

Dense fibrosis and a robust macrophage infiltrate are key therapeutic barriers in pancreatic ductal adenocarcinoma (PDAC). CD40 activation can circumvent these barriers by inducing macrophages, originating from peripheral blood monocytes, to deplete fibrosis. The precise mechanism and therapeutic implications of this anti-fibrotic activity, though, remain unclear. Here, we report that IFN-γ and CCL2 released systemically in response to a CD40 agonist cooperate to redirect a subset of Ly6C+CCR2+ monocytes/macrophages to infiltrate tumors and deplete fibrosis. Whereas CCL2 is required for Ly6C+ monocyte/macrophage infiltration, IFN-γ is necessary for tumor-infiltrating monocytes/macrophages to shift the profile of matrix metalloproteinases (MMPs) in tumors leading to MMP-dependent fibrosis degradation. In addition, MMP13-dependent loss of extracellular matrix components induced by a CD40 agonist increased PDAC sensitivity to chemotherapy. Our findings demonstrate that fibrosis in PDAC is a bidirectional process that can be rapidly altered by manipulating a subset of tumor-infiltrating monocytes leading to enhanced chemotherapy efficacy.

Macrophages enforce anti-tumor immunity by engulfing and killing tumor cells. Although these functions are determined by a balance of stimulatory and inhibitory signals, the role of macrophage metabolism is unknown. Here, we study the capacity of macrophages to circumvent inhibitory activity mediated by CD47 on cancer cells. We show that stimulation with CpG, a TLR9 agonist, evokes changes in the central carbon metabolism of macrophages that enable anti-tumor activity, including engulfment of CD47 + cancer cells. CpG activation engenders a metabolic state, that requires fatty acid oxidation and shunting of tricarboxylic acid cycle intermediates for de novo lipid biosynthesis. This integration of metabolic inputs is underpinned by carnitine palmitoyltransferase 1A and ATP citrate lyase, which together, impart macrophages with anti-tumor potential capable of overcoming inhibitory CD47 on cancer cells. Our findings identify central carbon metabolism to be a novel determinant and potential therapeutic target for stimulating anti-tumor activity by macrophages.

Pancreatic ductal adenocarcinoma (PDAC) ranks fourth among cancer-related deaths in the United States and for patients with unresectable disease, treatment options are currently limited and lack curative potential. Preclinical mouse models of PDAC that recapitulate the biology of human pancreatic cancer offer an opportunity for the rational development of novel treatment approaches that may improve patient outcomes. With the recent success of immunotherapy for subsets of patients with solid malignancies, interest is mounting regarding how to utilize immunotherapy for the treatment of PDAC. Here, we discuss the value of genetic mouse models for informing the immunobiology of PDAC and describe their application for investigating novel immunotherapeutics. In addition, we present several variants of these models, which may be used in drug development and to inform unique aspects of disease biology and therapeutic responsiveness.

Our study identified β-hemolytic Streptococcus and Pseudomonas spp. as the most common bacterial pathogens in canine bacterial keratitis presenting for referral. Many cases exhibited clinical factors known to influence corneal integrity that may predispose them to ulceration and infection. Based on in vitro antimicrobial susceptibility patterns and clinical outcomes, monotherapy with a fluoroquinolone may be ineffective in ulcers caused by β-hemolytic Streptococcus spp.