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Increased levels of intestinal bile acids (BAs) are a risk factor for colorectal cancer (CRC). Here we show that the convergence of dietary factors (high-fat diet) and dysregulated WNT signaling (APC mutation) alters BA profiles to drive malignant transformations in Lgr5-expressing (Lgr5(+)) cancer stem cells and promote an adenoma-to-adenocarcinoma progression. Mechanistically, we show that BAs that antagonize intestinal Farnesoid X receptor (FXR) function, including tauro-β-muricholic acid (T-βMCA) and deoxycholic acid (DCA), induce proliferation and DNA damage in Lgr5(+) cells. Conversely, selective activation of intestinal FXR can restrict abnormal Lgr5(+) cell growth and curtail CRC progression. This unexpected role for FXR in coordinating intestinal self-renewal with BA levels implicates FXR as a potential therapeutic target for CRC.

Summary: PGC1α is a pleiotropic co-factor that affects angiogenesis, mitochondrial biogenesis, and oxidative muscle remodeling via its association with multiple transcription factors, including the master oxidative nuclear receptor ERRγ. To decipher their epistatic relationship, we explored ERRγ gain of function in muscle-specific PGC1α/β double-knockout (PKO) mice. ERRγ-driven transcriptional reprogramming largely rescues muscle damage and improves muscle function in PKO mice, inducing mitochondrial biogenesis, antioxidant defense, angiogenesis, and a glycolytic-to-oxidative fiber-type transformation independent of PGC1α/β. Furthermore, in combination with voluntary exercise, ERRγ gain of function largely restores mitochondrial energetic deficits in PKO muscle, resulting in a 5-fold increase in running performance. Thus, while PGC1s can interact with multiple transcription factors, these findings implicate ERRs as the major molecular target through which PGC1α/β regulates both innate and adaptive energy metabolism. : Fan et al. demonstrate that ERRγ improves mitochondrial energy metabolism in PGC1α/β-deficient muscle through its direct activation of target genes. Such ERRγ-induced effects are further boosted in combination with exercise training, suggesting ERRs are the major transcriptional modulator through which PGC1α/β regulates both innate and adaptive energy metabolism. Keywords: ERR, estrogen related receptor, PGC1, mitochondria, muscle, exercise, vasculature, fatty acid oxidation, glycolysis, muscle damage

Management of energy stores is critical during endurance exercise, with a shift in substrate utilization from glucose towards fat being a hallmark of trained muscle. Here we show that this key metabolic adaptation is both dependent on muscle PPARδ and stimulated by PPARδ ligand. Furthermore, we find that muscle PPARδ expression positively correlates with endurance performance in BXD mouse reference populations. In addition to stimulating fatty acid metabolism in sedentary mice, PPARδ activation potently suppresses glucose catabolism and does so without affecting either muscle fiber type or mitochondrial content. By preserving systemic glucose levels PPARδ acts to delay the onset of hypoglycemia and extends running time by ~100 minutes in treated mice. Collectively, these results identify a bifurcated PPARδ program that underlies glucose sparing and highlight the potential of PPARδ-targeted exercise mimetics in the treatment of metabolic disease, dystrophies and unavoidably, the enhancement of athletic performance.

Although feast and famine cycles illustrate that remodelling of adipose tissue in response to fluctuations in nutrient availability is essential for maintaining metabolic homeostasis, the underlying mechanisms remain poorly understood(1,2). Here we identify fibroblast growth factor 1 (FGF1) as a critical transducer in this process in mice, and link its regulation to the nuclear receptor PPAR gamma (peroxisome proliferator activated receptor gamma), which is the adipocyte master regulator and the target of the thiazolidinedione class of insulin sensitizing drugs(3-5). FGF1 is the prototype of the 22-member FGF family of proteins and has been implicated in a range of physiological processes, including development, wound healing and cardiovascular changes(6). Surprisingly, FGF1 knockout mice display no significant phenotype under standard laboratory conditions(7-9). We show that FGF1 is highly induced in adipose tissue in response to a high-fat diet and that mice lacking FGF1 develop an aggressive diabetic phenotype coupled to aberrant adipose expansion when challenged with a high-fat diet. Further analysis of adipose depots in FGF1-deficient mice revealed multiple histopathologies in the vasculature network, an accentuated inflammatory response, aberrant adipocyte size distribution and ectopic expression of pancreatic lipases. On withdrawal of the high-fat diet, this inflamed adipose tissue fails to properly resolve, resulting in extensive fat necrosis. In terms of mechanisms, we show that adipose induction of FGF1 in the fed state is regulated by PPAR gamma acting through an evolutionarily conserved promoter proximal PPAR response element within the FGF1 gene. The discovery of a phenotype for the FGF1 knockout mouse establishes the PPAR gamma-FGF1 axis as critical for maintaining metabolic homeostasis and insulin sensitization.

Recent clinical successes with immune checkpoint blockades have provided promising immune-based therapeutic approaches for controlling malignancy. While therapeutic antibodies against CTLA-4 and PD-1/PD-L1 have resulted in potent and durable clinical responses in many patients, there still remains an urgent need to develop biomarker based assays to identify patients who may benefit from these approaches while avoiding toxicity and without compromising efficacy. While gene and protein expression of immune cell and checkpoint markers can be obtained through traditional techniques, insight regarding spatial and cell-specific expression within the tumor microenvironment is lacking, particularly in regards to secreted proteins with key immune functions. RNAscope® is an advanced in situ hybridization assay that allows for the visualization of single-cell gene expression, targeting mRNA sequences directly in tissues. The probes designed for this approach permit the detection of secreted markers, including cytokines and chemokines. In our investigation of 60 archived formalin-fixed paraffin embedded non-small cell lung cancer biopsies, expression profiles of immune checkpoint markers and immune functional molecules were evaluated in the tissue environment by RNAscope®. Each of the tumors displayed distinct co-expression patterns of immune checkpoint markers as well as varying levels of cytokines (TGFβ, IFNγ, and TNFα) and chemokines, which were measured in respect to their relative location in the tumor or stromal regions. Additionally, the detection of immune cell markers were used to pinpoint the location of infiltrating lymphocytes. The methods and findings in this study provide a valuable glimpse into the understanding of key immune functional markers in the tumor microenvironment to potentially advance treatment opportunities in this era of immuno-oncology therapies. Citation Format: Jeffrey Kim, Na Li, Mingxiao He, Bingqing Zhang, Nan Su, Xiao-Jun Ma, Emily Park. Evaluation of the expression of immune functional markers in the tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A24.