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Background Regorafenib is an inhibitor of multiple kinases with aberrant expression and activity in neuroblastoma tumours that have potential roles in neuroblastoma pathogenesis. Methods We evaluated neuroblastoma cells treated with regorafenib for cell viability and confluence, and analysed treated cells for apoptosis and cell cycle progression. We evaluated the efficacy of regorafenib in vivo using an orthotopic xenograft model. We evaluated regorafenib-mediated inhibition of kinase targets and performed reverse-phase protein array (RPPA) analysis of neuroblastoma cells treated with regorafenib. Lastly, we evaluated the efficacy and effects of the combination of regorafenib and 13- cis -retinoic acid on intracellular signalling. Results Regorafenib treatment resulted in reduced neuroblastoma cell viability and confluence, with both induction of apoptosis and of cell cycle arrest. Regorafenib treatment inhibits known receptor tyrosine kinase targets RET and PDGFRβ and intracellular signalling through the RAS/MAPK, PI3K/Akt/mTOR and Fos/Jun pathways. Regorafenib is effective against neuroblastoma tumours in vivo, and the combination of regorafenib and 13- cis -retinoic acid demonstrates enhanced efficacy compared with regorafenib alone. Conclusions The effects of regorafenib on multiple intracellular signalling pathways and the potential additional efficacy when combined with 13- cis -retinoic acid represent opportunities to develop treatment regimens incorporating regorafenib for children with neuroblastoma.

Chemoimmunotherapy has recently failed to demonstrate significant clinical benefit in advanced bladder cancer patients; and the mechanism(s) underlying such suboptimal response remain elusive. To date, most studies have focused on tumor-intrinsic properties that render them “immune-excluded”. Here, we explore an alternative, drug-induced mechanism that impedes therapeutic response via disrupting the onset of immunogenic cell death. Using two immune-excluded syngeneic mouse models of muscle-invasive bladder cancer (MIBC), we show that platinum-based chemotherapy diminishes CD8+ T cell tumor infiltration and constraines their antitumoral activity, despite expression of activation markers IFNγ and granzyme B. Mechanistically, chemotherapy induces the release of prostaglandin E 2 (PGE 2 ) from dying cancer cells, which is an inhibitory damage-associated molecular pattern (iDAMP) that hinderes dendritic cell maturation. Upon pharmaceutical blockade of PGE 2 release, CD8+ T cells become tumoricidal and display an intraepithelial-infiltrating (or inflamed) pattern. This “iDAMP blockade” approach synergizes with chemotherapy and sensitizes bladder tumors towards anti-PD1 immune checkpoint inhibitor therapy. These findings provide a compelling rationale to evaluate this drug combination in future clinical trials. Chemoimmunotherapy recently failed to improve objective response for patients with advanced muscle-invasive bladder cancer (MIBC). Here using two murine models of immune-excluded MIBC, the authors show that resistance to chemoimmunotherapy can be overcome by blocking the COX-2/prostaglandin E2 axis, reinvigorating anti-tumor immune responses.

Cancer-induced immune responses affect tumour progression and therapeutic response. In multiple murine models and clinical datasets, we identified large variations of neutrophils and macrophages that define ‘immune subtypes’ of triple-negative breast cancer (TNBC), including neutrophil-enriched (NES) and macrophage-enriched subtypes (MES). Different tumour-intrinsic pathways and mutual regulation between macrophages (or monocytes) and neutrophils contribute to the development of a dichotomous myeloid compartment. MES contains predominantly macrophages that are CCR2-dependent and exhibit variable responses to immune checkpoint blockade (ICB). NES exhibits systemic and local accumulation of immunosuppressive neutrophils (or granulocytic myeloid-derived suppressor cells), is resistant to ICB, and contains a minority of macrophages that seem to be unaffected by CCR2 knockout. A MES-to-NES conversion mediated acquired ICB resistance of initially sensitive MES models. Our results demonstrate diverse myeloid cell frequencies, functionality and potential roles in immunotherapies, and highlight the need to better understand the inter-patient heterogeneity of the myeloid compartment. Kim et al. demonstrate neutrophil- and macrophage-enriched subtypes in triple-negative breast cancer and how these immune profiles affect therapeutic responses to immune checkpoint blockade.

Large-scale integrated cancer genome characterization efforts including the cancer genome atlas and the cancer cell line encyclopedia have created unprecedented opportunities to study cancer biology in the context of knowing the entire catalog of genetic alterations. A clinically important challenge is to discover cancer subtypes and their molecular drivers in a comprehensive genetic context. Curtis et al. [ Nature (2012) 486(7403):346–352] has recently shown that integrative clustering of copy number and gene expression in 2,000 breast tumors reveals novel subgroups beyond the classic expression subtypes that show distinct clinical outcomes. To extend the scope of integrative analysis for the inclusion of somatic mutation data by massively parallel sequencing, we propose a framework for joint modeling of discrete and continuous variables that arise from integrated genomic, epigenomic, and transcriptomic profiling. The core idea is motivated by the hypothesis that diverse molecular phenotypes can be predicted by a set of orthogonal latent variables that represent distinct molecular drivers, and thus can reveal tumor subgroups of biological and clinical importance. Using the cancer cell line encyclopedia dataset, we demonstrate our method can accurately group cell lines by their cell-of-origin for several cancer types, and precisely pinpoint their known and potential cancer driver genes. Our integrative analysis also demonstrates the power for revealing subgroups that are not lineage-dependent, but consist of different cancer types driven by a common genetic alteration. Application of the cancer genome atlas colorectal cancer data reveals distinct integrated tumor subtypes, suggesting different genetic pathways in colon cancer progression.

Tissue injury induces changes in cellular identity, but the underlying molecular mechanisms remain obscure. Here, we show that upon damage in a mouse model, epidermal cells at the wound edge convert to an embryonic-like state, altering particularly the cytoskeletal/extracellular matrix (ECM) components and differentiation program. We show that SOX11 and its closest relative SOX4 dictate embryonic epidermal state, regulating genes involved in epidermal development as well as cytoskeletal/ECM organization. Correspondingly, postnatal induction of SOX11 represses epidermal terminal differentiation while deficiency of Sox11 and Sox4 accelerates differentiation and dramatically impairs cell motility and re-epithelialization. Amongst the embryonic genes reactivated at the wound edge, we identify fascin actin-bundling protein 1 (FSCN1) as a critical direct target of SOX11 and SOX4 regulating cell migration. Our study identifies the reactivated embryonic gene program during wound repair and demonstrates that SOX11 and SOX4 play a central role in this process. Wounding induces changes in cell identity but the mechanisms regulating this are unclear. Here, the authors show that Sox11/Sox4 expression in the leading edge of wounds converts murine epidermal cells to an embryonic-like state and facilitates repair.

Metastases account for the majority of cancer deaths. While certain steps of the metastatic cascade are well characterized, identification of targets to block this process remains a challenge. Host factors determining metastatic colonization to secondary organs are particularly important for exploration, as those might be shared among different cancer types. Here, we showed that bladder tumor cells expressing the collagen receptor, CD167a, responded to collagen I stimulation at the primary tumor to promote local invasion and utilized the same receptor to preferentially colonize at airway smooth muscle cells (ASMCs)—a rich source of collagen III in lung. Morphologically, COL3-CD167a-driven metastatic foci are uniquely distinct from typical lung alveolar metastatic lesions and exhibited activation of the CD167a-HSP90-Stat3 axis. Importantly, metastatic lung colonization could be abrogated using an investigational drug that attenuates Stat3 activity, implicating this seed-and-soil interaction as a therapeutic target for eliminating lung metastasis. Collagen is a dynamic component of both the tumor and metastatic niche. Here, the authors show that airway smooth muscle cells are a collagen III rich niche bladder cancer cells expressing CD167a, and Stat3 is a downstream target for abrogating  these collagen III/CD167a-driven metastatic foci.

Nutrient excess, a major driver of obesity, diminishes hypothalamic responses to exogenously administered leptin, a critical hormone of energy balance. Here, we aimed to identify a physiological signal that arises from excess caloric intake and negatively controls hypothalamic leptin action. We found that deficiency of the gastric inhibitory polypeptide receptor (Gipr) for the gut-derived incretin hormone GIP protected against diet-induced neural leptin resistance. Furthermore, a centrally administered antibody that neutralizes GIPR had remarkable antiobesity effects in diet-induced obese mice, including reduced body weight and adiposity, and a decreased hypothalamic level of SOCS3, an inhibitor of leptin actions. In contrast, centrally administered GIP diminished hypothalamic sensitivity to leptin and increased hypothalamic levels of Socs3. Finally, we show that GIP increased the active form of the small GTPase Rap1 in the brain and that its activation was required for the central actions of GIP. Altogether, our results identify GIPR/Rap1 signaling in the brain as a molecular pathway linking overnutrition to the control of neural leptin actions.

Successful embryo implantation requires a receptive endometrium. Poor uterine receptivity can account for implantation failure in women who experience recurrent pregnancy loss or multiple rounds of unsuccessful in vitro fertilization cycles. Here, we demonstrate that the transcription factor Forkhead Box O1 (FOXO1) is a critical regulator of endometrial receptivity in vivo. Uterine ablation of Foxo1 using the progesterone receptor Cre (PgrCre) mouse model resulted in infertility due to altered epithelial cell polarity and apoptosis, preventing the embryo from penetrating the luminal epithelium. Analysis of the uterine transcriptome after Foxo1 ablation identified alterations in gene expression for transcripts involved in the activation of cell invasion, molecular transport, apoptosis, β-catenin (CTNNB1) signaling pathway, and an increase in PGR signaling. The increase of PGR signaling was due to PGR expression being retained in the uterine epithelium during the window of receptivity. Constitutive expression of epithelial PGR during this receptive period inhibited expression of FOXO1 in the nucleus of the uterine epithelium. The reciprocal expression of PGR and FOXO1 was conserved in human endometrial samples during the proliferative and secretory phase. This demonstrates that expression of FOXO1 and the loss of PGR during the window of receptivity are interrelated and critical for embryo implantation.

PurposeTriple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with poor survival outcomes. Metformin has been shown to have antitumor effects by lowering serum levels of the mitogen insulin and having pleiotropic effects on cancer cell signaling pathways. BMS-754807 is a potent and reversible inhibitor of both insulin-like growth factor 1 receptor (IGF-1R) and insulin receptor (IR). Both drugs have been reported to have some efficacy in TNBC. However, it is unclear whether the combination of the two drugs is more effective than single drug treatment in TNBC.MethodsWe treated a panel of TNBC cell lines with metformin and BMS-754807 alone and in combination and tested cell viability using MTS assays. We used the CompuSyn software to analyze for additivity, synergism, or antagonism. We also examined the molecular mechanism by performing reverse phase protein assay (RPPA) to detect the candidate pathways altered by single drugs and the drug combination and used Western blotting to verify and expand the findings.ResultsThe combination of metformin and BMS-754807 showed synergy in 11 out of 13 TNBC cell lines tested (85%). RPPA analysis detected significant alterations by the drug combination of multiple proteins known to regulate cell cycle and tumor growth. In particular, the drug combination significantly increased levels of total and phosphorylated forms of the cell cycle inhibitor p27Kip1 and decreased the level of the p27Kip1 E3 ligase SCFSkp2.ConclusionsWe conclude that the combination of metformin and BMS-754807 is more effective than either drug alone in inhibiting cell proliferation in the majority of TNBC cell lines, and that one important mechanism may be suppression of SCFSkp2 and subsequent stabilization of the cell cycle inhibitor p27Kip1. This combination treatment may represent an effective targeted therapy for a significant subset of TNBC cases and should be further evaluated.

Large-scale cancer genome projects, such as the Cancer Genome Atlas (TCGA) project, are comprehensive molecular characterization efforts to accelerate our understanding of cancer biology and the discovery of new therapeutic targets. The accumulating wealth of multidimensional data provides a new paradigm for important research problems including cancer subtype discovery. The current standard approach relies on separate clustering analyses followed by manual integration. Results can be highly data type dependent, restricting the ability to discover new insights from multidimensional data. In this study, we present an integrative subtype analysis of the TCGA glioblastoma (GBM) data set. Our analysis revealed new insights through integrated subtype characterization. We found three distinct integrated tumor subtypes. Subtype 1 lacks the classical GBM events of chr 7 gain and chr 10 loss. This subclass is enriched for the G-CIMP phenotype and shows hypermethylation of genes involved in brain development and neuronal differentiation. The tumors in this subclass display a Proneural expression profile. Subtype 2 is characterized by a near complete association with EGFR amplification, overrepresentation of promoter methylation of homeobox and G-protein signaling genes, and a Classical expression profile. Subtype 3 is characterized by NF1 and PTEN alterations and exhibits a Mesenchymal-like expression profile. The data analysis workflow we propose provides a unified and computationally scalable framework to harness the full potential of large-scale integrated cancer genomic data for integrative subtype discovery.