Cancer-associated fibroblasts (CAFs) are a major cellular component of tumor microenvironment in most solid cancers. Altered cellular metabolism is a hallmark of cancer, and much of the published literature has focused on neoplastic cell-autonomous processes for these adaptations. We demonstrate that exosomes secreted by patient-derived CAFs can strikingly reprogram the metabolic machinery following their uptake by cancer cells. We find that CAF-derived exosomes (CDEs) inhibit mitochondrial oxidative phosphorylation, thereby increasing glycolysis and glutamine-dependent reductive carboxylation in cancer cells. Through 13C-labeled isotope labeling experiments we elucidate that exosomes supply amino acids to nutrient-deprived cancer cells in a mechanism similar to macropinocytosis, albeit without the previously described dependence on oncogenic-Kras signaling. Using intra-exosomal metabolomics, we provide compelling evidence that CDEs contain intact metabolites, including amino acids, lipids, and TCA-cycle intermediates that are avidly utilized by cancer cells for central carbon metabolism and promoting tumor growth under nutrient deprivation or nutrient stressed conditions.DOI: http://dx.doi.org/10.7554/eLife.10250.001

Exosomes are a distinct source of tumor DNA that may be complementary to other liquid biopsy DNA sources. A higher percentage of patients with localized PDAC exhibited detectable KRAS mutations in exoDNA than previously reported for cfDNA. A substantial minority of healthy samples demonstrated mutant KRAS in circulation, dictating careful consideration and application of liquid biopsy findings, which may limit its utility as a broad cancer-screening method.

Purpose: Early detection of pancreatic ductal adenocarcinoma (PDAC) remains elusive. Precursor lesions of PDAC, specifically intraductal papillary mucinous neoplasms (IPMNs), represent a bona fide pathway to invasive neoplasia, although the molecular correlates of progression remain to be fully elucidated. Single-cell transcriptomics provides a unique avenue for dissecting both the epithelial and microenvironmental heterogeneities that accompany multistep progression from noninvasive IPMNs to PDAC. Experimental Design: Single-cell RNA sequencing was performed through droplet-based sequencing on 5,403 cells from 2 low-grade IPMNs (LGD-IPMNs), 2 high-grade IPMNs (HGD-IPMN), and 2 PDACs (all surgically resected). Results: Analysis of single-cell transcriptomes revealed heterogeneous alterations within the epithelium and the tumor microenvironment during the progression of noninvasive dysplasia to invasive cancer. Although HGD-IPMNs expressed many core signaling pathways described in PDAC, LGD-IPMNs harbored subsets of single cells with a transcriptomic profile that overlapped with invasive cancer. Notably, a proinflammatory immune component was readily seen in low-grade IPMNs, composed of cytotoxic T cells, activated T-helper cells, and dendritic cells, which was progressively depleted during neoplastic progression, accompanied by infiltration of myeloid-derived suppressor cells. Finally, stromal myofibroblast populations were heterogeneous and acquired a previously described tumor-promoting and immune-evading phenotype during invasive carcinogenesis. Conclusions: This study demonstrates the ability to perform high-resolution profiling of the transcriptomic changes that occur during multistep progression of cystic PDAC precursors to cancer. Notably, single-cell analysis provides an unparalleled insight into both the epithelial and microenvironmental heterogeneities that accompany early cancer pathogenesis and might be a useful substrate to identify targets for cancer interception. See related commentary by Hernandez-Barco et al., p. 2027

OBJECTIVEBile acids (BA) participate in the maintenance of metabolic homeostasis acting through different signaling pathways. The nuclear BA receptor farnesoid X receptor (FXR) regulates pathways in BA, lipid, glucose, and energy metabolism, which become dysregulated in obesity. However, the role of FXR in obesity and associated complications, such as dyslipidemia and insulin resistance, has not been directly assessed.RESEARCH DESIGN AND METHODSHere, we evaluate the consequences of FXR deficiency on body weight development, lipid metabolism, and insulin resistance in murine models of genetic and diet-induced obesity.RESULTSFXR deficiency attenuated body weight gain and reduced adipose tissue mass in both models. Surprisingly, glucose homeostasis improved as a result of an enhanced glucose clearance and adipose tissue insulin sensitivity. In contrast, hepatic insulin sensitivity did not change, and liver steatosis aggravated as a result of the repression of β-oxidation genes. In agreement, liver-specific FXR deficiency did not protect from diet-induced obesity and insulin resistance, indicating a role for nonhepatic FXR in the control of glucose homeostasis in obesity. Decreasing elevated plasma BA concentrations in obese FXR-deficient mice by administration of the BA sequestrant colesevelam improved glucose homeostasis in a FXR-dependent manner, indicating that the observed improvements by FXR deficiency are not a result of indirect effects of altered BA metabolism.CONCLUSIONSOverall, FXR deficiency in obesity beneficially affects body weight development and glucose homeostasis.

Photographs are valuable aids in the estimation of food portion sizes and are easy to use in dietary surveys. As with other methods, employing photographs to estimate portion sizes consumed produces errors due to the method itself and errors from other sources such as poor recall of amounts actually eaten. This study was aimed at the first type of error and investigated errors due to the visual perception of food portions from food photographs in the absence of recall biases. Two hundred and seventy women were presented with various amounts of foods and asked to indicate the portion sizes using appropriate sets of photographs. The photographs showed three portion sizes (small, medium, large) for each of 45 foods commonly found in the French diet. The portions of real food estimated by subjects were prepared to the same weights as the portions photographed. Estimates of portion sizes were compared to the weighed amounts. They were found to be accurate within 25% in most cases. Except for three foods, errors on estimates were seen for one or more portions per food. Two patterns of errors were identified. For 22 foods, the small portion sizes were overestimated and the large portion sizes underestimated, but no error occurred with the medium portion. For 20 other foods, the three portion sizes were either all underestimated or all overestimated. The first pattern of error may be due to a general tendency to avoid extreme response categories, while the second pattern of error may be related to biased visual perception. In general, there was no obvious way to link the patterns of errors with the type or physical appearance of the foods. In conclusion, the photograph method is recommended for the assessment of portion sizes, provided that great care is taken to suggest the volume of the food portions in the photographs and in selecting a range of portions which encompasses the range of amounts of food actually consumed in the diet.

High-resolution profiling of the genomic and transcriptomic landscapes of visceral cancers using the DNA and RNA of tumor shed exosomes has the potential to be used as a clinical tool for cancer diagnosis, therapeutic stratification and treatment monitoring, precluding the need for direct tumor sampling.

Clinicopathologic characteristics, survival outcomes, functional impact, and gene expression profiling were similar between patients with KRAS 12/13 and those with NRAS or KRAS 61/146-mutated mCRC. These clinical and bioinformatic findings support the notion that colorectal tumors driven by these RAS mutations are phenotypically similar.

Summary The GI-101 human breast tumour xenograft line is unique in that it spontaneously metastasises to the lungs of athymic murine hosts from subcutaneous trochar implants. Both tumour and lung metastases are positive for normal human breast tissue markers. GI-101 also is positive for the p53 antigen but negative for the c-erbB-2 oncogene.