Cancer stem cells (CSCs) are critical for cancer progression and chemoresistance. How lipid metabolism regulates CSCs and chemoresistance remains elusive. Here, we demonstrate that JAK/STAT3 regulates lipid metabolism, which promotes breast CSCs (BCSCs) and cancer chemoresistance. Inhibiting JAK/STAT3 blocks BCSC self-renewal and expression of diverse lipid metabolic genes, including carnitine palmitoyltransferase 1B (CPT1B), which encodes the critical enzyme for fatty acid β-oxidation (FAO). Moreover, mammary-adipocyte-derived leptin upregulates STAT3-induced CPT1B expression and FAO activity in BCSCs. Human breast-cancer-derived data suggest that the STAT3-CPT1B-FAO pathway promotes cancer cell stemness and chemoresistance. Blocking FAO and/or leptin re-sensitizes them to chemotherapy and inhibits BCSCs in mouse breast tumors in vivo. We identify a critical pathway for BCSC maintenance and breast cancer chemoresistance.

The novel multitargeted tyrosine kinase inhibitor sunitinib is used as an anti-angiogenic agent for the treatment of several types of cancer, including metastatic renal cell carcinoma (RCC). Sunitinib was shown to positively change the immunosuppressive phenotype in RCC patients. In order to improve its antitumor efficacy, and offer strategies for its combination with other approaches, it is critical to fully elucidate its mechanisms of action. We show that sunitinib induces tumor cell apoptosis and growth arrest in RCC tumor cells, which correlates with Stat3 activity inhibition. Sunitinib-mediated direct effects on tumor cells occur regardless of von Hippel-Lindau tumor suppressor gene status and hypoxia-inducible transcription factor-2α levels. Reduction of Stat3 activity enhances sunitinib's antitumor effects, whereas expression of a constitutively-activated Stat3 mutant rescues tumor cell death. Intravital multi-photon microscopy data show that sunitinib induces mouse Renca tumor cell apoptosis in vivo before tumor vasculature collapse. Sunitinib also inhibits Stat3 in Renca tumor-associated myeloid derived suppressor cells (MDSCs), downregulates angiogenic gene expression, and reduces MDSCs and tumor T regulatory cells. These results suggest that Stat3 activity is important for RCC response to sunitinib, and Stat3 inhibition permits sunitinib's direct proapoptotic activity on tumor cells and positive effects on tumor immunologic microenvironment.

Background The symbiotic rumen microbiota is essential for the digestion of plant fibers and contributes to the variation of production and health traits in ruminants. However, to date, the heritability of rumen microbial features and host genetic components associated with the rumen microbiota, as well as whether such genetic components are animal performance relevant, are largely unknown. Results In the present study, we assessed rumen microbiota from a cohort of 709 beef cattle and showed that multiple factors including breed, sex, and diet drove the variation of rumen microbiota among animals. The diversity indices, the relative abundance of ~ 34% of microbial taxa (59 out of 174), and the copy number of total bacteria had a heritability estimate ( h 2 ) ≥ 0.15, suggesting that they are heritable elements affected by host additive genetics. These moderately heritable rumen microbial features were also found to be associated with host feed efficiency traits and rumen metabolic measures (volatile fatty acids). Moreover, 19 single nucleotide polymorphisms (SNPs) located on 12 bovine chromosomes were found to be associated with 14 (12 of them had h 2 ≥ 0.15) rumen microbial taxa, and five of these SNPs were known quantitative trait loci for feed efficiency in cattle. Conclusions These findings suggest that some rumen microbial features are heritable and could be influenced by host genetics, highlighting a potential to manipulate and obtain a desirable and efficient rumen microbiota using genetic selection and breeding. It could be a useful strategy to further improve feed efficiency and optimize rumen fermentation through targeting both cattle and their rumen microbiota. Electronic supplementary material The online version of this article (10.1186/s40168-019-0699-1) contains supplementary material, which is available to authorized users.

SUMMARY Recent studies underscore the importance of myeloid cells in rendering distant organs hospitable for disseminating tumor cells to colonize. However, what enables myeloid cells to have an apparently superior capacity to colonize distant organs is unclear. Here we show that S1PR1-STAT3 upregulation in tumor cells induces factors that activate S1PR1-STAT3 in various cells in pre-metastatic sites, leading to pre-metastatic niche formation. Targeting either S1PR1 or STAT3 in myeloid cells disrupts existing pre-metastatic niches. S1PR1-STAT3 pathway enables myeloid cells to intravasate, prime the distant organ microenvironment and mediate sustained proliferation and survival of their own and other stromal cells at future metastatic sites. Analyzing tumor-free lymph nodes from cancer patients shows elevated myeloid infiltrates, STAT3 activity and increased survival signal.

BackgroundMicroRNAs (MiRNAs) are short non-coding RNAs that control protein expression through various mechanisms. Their altered expression has been shown to be associated with various cancers. The aim of this study was to profile miRNA expression in colorectal cancer (CRC) and to analyze the function of specific miRNAs in CRC cells. MirVana miRNA Bioarrays were used to determine the miRNA expression profile in eight CRC cell line models, 45 human CRC samples of different stages, and four matched normal colon tissue samples. SW620 CRC cells were stably transduced with miR-143 or miR-145 expression vectors and analyzed in vitro for cell proliferation, cell differentiation and anchorage-independent growth. Signalling pathways associated with differentially expressed miRNAs were identified using a gene set enrichment analysis.ResultsThe expression analysis of clinical CRC samples identified 37 miRNAs that were differentially expressed between CRC and normal tissue. Furthermore, several of these miRNAs were associated with CRC tumor progression including loss of miR-133a and gain of miR-224. We identified 11 common miRNAs that were differentially expressed between normal colon and CRC in both the cell line models and clinical samples. In vitro functional studies indicated that miR-143 and miR-145 appear to function in opposing manners to either inhibit or augment cell proliferation in a metastatic CRC model. The pathways targeted by miR-143 and miR-145 showed no significant overlap. Furthermore, gene expression analysis of metastatic versus non-metastatic isogenic cell lines indicated that miR-145 targets involved in cell cycle and neuregulin pathways were significantly down-regulated in the metastatic context.ConclusionMiRNAs showing altered expression at different stages of CRC could be targets for CRC therapies and be further developed as potential diagnostic and prognostic analytes. The identified biological processes and signalling pathways collectively targeted by co-expressed miRNAs in CRC provide a basis for understanding the functional role of miRNAs in cancer.

Th17 is a newly identified T-cell lineage IntroductionAcute graft-versus-host disease (GVHD), the leading cause of morbidity and mortality of allogeneic hematopoietic cell transplantation (HCT), is a complex process involving dysregulation of inflammatory cytokine cascades and distorted donor cellular response against host alloantigens. 1 Activation of alloreactive donor T cells is initiated by host antigen-presenting cells (APCs), especially dendritic cells (DCs). [2][3][4][5] Much effort has been devoted to understand how the polarization of donor T cells to the Th1 or Th2 phenotype contributes to acute GVHD. In some experimental models, it has been shown that Th1 cells augment and Th2 cells ameliorate acute GVHD. 1,[6][7][8] However, it was also reported that the absence of Th1 cytokine interferon (IFN)-␥ augments acute GVHD, but loss of the Th2 cytokine interleukin (IL)-4 reduces acute GVHD. 9,10 Furthermore, donor T cells deficient in either Th1 or Th2 differentiation were shown to be able to mediate acute GVHD. 11 Therefore, the role of donor T-cell subsets in GVHD pathogenesis is still controversial. It is likely that T-cell subsets other than Th1 or Th2 play a role in mediating acute GVHD.Th17 is a newly identified T-cell lineage that secretes the proinflammatory cytokine IL-17. 12 Naive CD4 ϩ T cells differentiate into Th17 cells in the presence of IL-6 and transforming growth factor (TGF)-␤. [13][14][15] Th17 cells express IL-23 receptor, and IL-23, an IL-12 family member, is critical for their survival and proliferation. [16][17][18] Orphan nuclear receptor ROR␥t is the key transcription factor that orchestrates differentiation of the Th17 lineage. 19 Interestingly, it has been shown that naive CD8 ϩ T cells can also differentiate into IL-17-producing T cells in the same culture condition as CD4 ϩ T cells. 20 One of the important functions of IL-17 is to coordinate local tissue inflammation through the up-regulation of proinflammatory cytokines and chemokines. 21 Thus, IL-17 has been implicated in a critical role in the host defense against a series of extracellular pathogens, such as Klebsiella pneumoniae and Candida albicans. 22,23 However, uncontrolled Th17 cells have been reported to be involved in autoimmune diseases such as rheumatoid arthritis, inflammatory bowel disease, and experimental autoimmune encephalomyelitis (EAE). [24][25][26][27] In contrast, IL-17 has also been shown to have some regulatory effect in mediating tissue inflammation. It was reported that IL-17 inhibited CD4 ϩ T-cell activation, 28 suppressed the tissue expression of chemokines (eg, CCL5 and CCL27), 29,30 and down-regulated VCAM-1 expression on epithelial cells. 31 Moreover, neutralization of IL-17 was reported to aggravate dextran sulfate sodium-induced colitis in mice, 32 and absence of IL-17 augmented allergic asthma. 33 The role of Th17 cells in GVHD pathogenesis is still unknown. In the current study, we demonstrated that IL-17 Ϫ/Ϫ donor T cells showed an augmented Th1 differentiation and IFN-␥ production and induc...

Chronic graft-vs-host disease (GVHD) is a major cause of morbidity and mortality of long-term survivors of allogeneic hematopoietic cell transplantation (HCT). Chronic GVHD can have features of an autoimmune collagen vascular disease with clinical manifestations similar to autoimmune scleroderma and systemic lupus erythematosus (SLE). However, the pathogenesis of chronic GVHD is poorly understood. It is unclear how autoreactive T and B cells are generated in chronic GVHD recipients. We IntroductionChronic graft-versus-host disease (GVHD) is a serious and common long-term complication of allogeneic hematopoietic cell transplantation (HCT) occurring in 20% to 70% of patients surviving more than 100 days after HCT. [1][2][3][4] Despite improvements in the practice of allogeneic HCT over the last 25 years, there has been little change in the incidence, morbidity, and mortality of this complication. 3 One of the difficulties in combating chronic GVHD is the poor understanding of its pathogenesis.Chronic GVHD differs from acute GVHD in many aspects. First, the onset of acute GVHD is usually at 1 to 2 months following transplantation but the onset of chronic GVHD is usually delayed until 4 to 6 months after transplantation. 3 Second, although the target organ tissues of chronic GVHD are significantly overlapped with that of acute GVHD (ie, skin, gut, liver, and lung), the histopathology is distinguishably different. 3 While acute GVHD shows donor lymphocyte infiltration and host tissue-cell apoptosis and necrosis in target organs, chronic GVHD is featured by a marked increase in collagen deposition and a lack of T-lymphocyte infiltration in the target organ tissues. 3,4 Third, up to 70% of chronic GVHD patients have elevated levels of serum autoantibodies (eg, antinuclear, anti-dsDNA, and anti-smooth-muscle antibodies), 1,5,6 and depletion of B cells ameliorates refractory chronic GVHD in some patients. 3,7,8 Therefore, chronic GVHD has features similar to autoimmune collagen vascular disease such as scleroderma and systemic lupus erythematosus (SLE). 1,9 However, it is unclear how the autoimmune responses develop in chronic GVHD.Several murine HCT models have been used to study the pathogenesis of chronic GVHD. The first type of model is transplantation of parental lymphocytes into nonirradiated major histocompatibility complex (MHC)-mismatched F1 recipients. 10,11 In those models, the F1 recipients developed high levels of serum anti-dsDNA and glomerulonephritis, and the production of autoantibodies is a result of a cognate interaction between donor CD4 ϩ T cells and host B cells. [10][11][12][13][14][15] However, it is not clear whether the mechanisms revealed in those models reflect the pathogenesis of chronic GVHD in the irradiated HC transplant recipients.The second type of model is transplantation of donor lymphocytes into MHC-matched but minor antigen-mismatched irradiated recipients. In one model, donor LP/J (H-2 b ) bone marrow and spleen cells were transplanted into lethally irradiated C57BL/6 (H-2 b ) re...

Tuberculosis remains one of the world’s deadliest communicable diseases, novel anti-tuberculosis agents are urgently needed due to severe drug resistance and the co-epidemic of tuberculosis/human immunodeficiency virus. Here, we show the isolation of six anti-mycobacterial ilamycin congeners (1–6) bearing rare L-3-nitro-tyrosine and L-2-amino-4-hexenoic acid structural units from the deep sea-derived Streptomyces atratus SCSIO ZH16. The biosynthesis of the rare L-3-nitrotyrosine and L-2-amino-4-hexenoic acid units as well as three pre-tailoring and two post-tailoring steps are probed in the ilamycin biosynthetic machinery through a series of gene inactivation, precursor chemical complementation, isotope-labeled precursor feeding experiments, as well as structural elucidation of three intermediates (6–8) from the respective mutants. Most impressively, ilamycins E1/E2, which are produced in high titers by a genetically engineered mutant strain, show very potent anti-tuberculosis activity with an minimum inhibitory concentration value ≈9.8 nM to Mycobacterium tuberculosis H37Rv constituting extremely potent and exciting anti-tuberculosis drug leads.