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Background Breast cancer studies frequently focus on the role of the tumor microenvironment in the promotion of cancer; however, the influence of the normal breast microenvironment on cancer cells remains relatively unknown. To investigate the role of the normal breast microenvironment on breast cancer cell tumorigenicity, we examined whether extracellular matrix molecules (ECM) derived from premenopausal African-American (AA) or Caucasian-American (CAU) breast tissue would affect the tumorigenicity of cancer cells in vitro and in vivo . We chose these two populations because of the well documented predisposition of AA women to develop aggressive, highly metastatic breast cancer compared to CAU women. Methods The effects of primary breast fibroblasts on tumorigenicity were analyzed via real-time PCR arrays and mouse xenograft models. Whole breast ECM was isolated, analyzed via zymography, and its effects on breast cancer cell aggressiveness were tested in vitro via soft agar and invasion assays, and in vivo via xenograft models. Breast ECM and hormone metabolites were analyzed via mass spectrometry. Results Mouse mammary glands humanized with premenopausal CAU fibroblasts and injected with primary breast cancer cells developed significantly larger tumors compared to AA humanized glands. Examination of 164 ECM molecules and cytokines from CAU-derived fibroblasts demonstrated a differentially regulated set of ECM proteins and increased cytokine expression. Whole breast ECM was isolated; invasion and soft agar assays demonstrated that estrogen receptor (ER) - , progesterone receptor (PR)/PR - cells were significantly more aggressive when in contact with AA ECM, as were ER + /PR + cells with CAU ECM. Using zymography, protease activity was comparatively upregulated in CAU ECM. In xenograft models, CAU ECM significantly increased the tumorigenicity of ER + /PR + cells and enhanced metastases. Mass spectrometry analysis of ECM proteins showed that only 1,759 of approximately 8,000 identified were in common. In the AA dataset, proteins associated with breast cancer were primarily related to tumorigenesis/neoplasia, while CAU unique proteins were involved with growth/metastasis. Using a novel mass spectrometry method, 17 biologically active hormones were measured; estradiol, estriol and 2-methoxyestrone were significantly higher in CAU breast tissue. Conclusions This study details normal premenopausal breast tissue composition, delineates potential mechanisms for breast cancer development, and provides data for further investigation into the role of the microenvironment in cancer disparities.

Objective The standard therapy for advanced hepatocellular carcinoma (HCC) is sorafenib, with most patients experiencing disease progression within 6 months. Label-retaining cancer cells (LRCC) represent a novel subpopulation of cancer stem cells (CSC). The objective was to test whether LRCC are resistant to sorafenib. Methods We tested human HCC derived LRCC and non-LRCC before and after treatment with sorafenib. Results LRCC derived from human HCC are relatively resistant to sorafenib. The proportion of LRCC in HCC cell lines is increased after sorafenib while the general population of cancer cells undergoes growth suppression. We show that LRCC demonstrate improved viability and toxicity profiles, and reduced apoptosis, over non-LRCC. We show that after treatment with sorafenib, LRCC upregulate the CSC marker aldehyde dehydrogenase 1 family, wingless-type MMTV-integration-site family, cell survival and proliferation genes, and downregulate apoptosis, cell cycle arrest, cell adhesion and stem cells differentiation genes. This phenomenon was accompanied by non-uniform activation of specific isoforms of the sorafenib target proteins extracellular-signal-regulated kinases and v-akt-murine-thymoma-viral-oncogene homologue (AKT) in LRCC but not in non-LRCC. A molecular pathway map for sorafenib treated LRCC is proposed. Conclusions Our results suggest that HCC derived LRCC are relatively resistant to sorafenib. Since LRCC can generate tumours with as few as 10 cells, our data suggest a potential role for these cells in disease recurrence. Further investigation of this phenomenon might provide novel insights into cancer biology, cancer recurrence and drug resistance with important implications for the development of novel cancer therapies based on targeting LRCC.

Empirical two-part models describe the relationship between conservation spending, human development pressures and biodiversity loss and can inform sustainable development strategies by predicting the effects of financing decisions on future biodiversity losses. Conservation costs Financial investments into conservation are often held back by a lack of certainty over the benefits of spending more. Anthony Waldron and colleagues assess the impact of conservation spending on biodiversity between 1996 and 2008 in 109 countries that signed up to the Convention on Biological Diversity. They find that conservation spending over this period reduced national-level biodiversity loss by 29%, on average. They also find that the funding needed to achieve specific conservation goals rises with socioeconomic pressures. The authors develop a predictive model of biodiversity decline, which takes into account the effects of human development pressures and conservation financing. They propose that this could help to predict the funding that each country needs to achieve specific biodiversity policy goals, including those laid out in the Convention on Biological Diversity and the broader United Nations Sustainable Development Goals. Halting global biodiversity loss is central to the Convention on Biological Diversity and United Nations Sustainable Development Goals 1 , 2 , but success to date has been very limited 3 , 4 , 5 . A critical determinant of success in achieving these goals is the financing that is committed to maintaining biodiversity 6 , 7 , 8 , 9 ; however, financing decisions are hindered by considerable uncertainty over the likely impact of any conservation investment 6 , 7 , 8 , 9 . For greater effectiveness, we need an evidence-based model 10 , 11 , 12 that shows how conservation spending quantitatively reduces the rate of biodiversity loss. Here we demonstrate such a model, and empirically quantify how conservation investment reduced biodiversity loss in 109 countries (signatories to the Convention on Biological Diversity and Sustainable Development Goals), by a median average of 29% per country between 1996 and 2008 We also show that biodiversity changes in signatory countries can be predicted with high accuracy, using a dual model that balances the effects of conservation investment against those of economic, agricultural and population growth (human development pressures) 13 , 14 , 15 , 16 , 17 , 18 . Decision-makers can use this model to forecast the improvement that any proposed biodiversity budget would achieve under various scenarios of human development pressure, and then compare these forecasts to any chosen policy target. We find that the impact of spending decreases as human development pressures grow, which implies that funding may need to increase over time. The model offers a flexible tool for balancing the Sustainable Development Goals of human development and maintaining biodiversity, by predicting the dynamic changes in conservation finance that will be needed as human development proceeds.

Brain tumors are dynamic complex ecosystems with multiple cell types. To model the brain tumor microenvironment in a reproducible and scalable system, we developed a rapid three-dimensional (3D) bioprinting method to construct clinically relevant biomimetic tissue models. In recurrent glioblastoma, macrophages/microglia prominently contribute to the tumor mass. To parse the function of macrophages in 3D, we compared the growth of glioblastoma stem cells (GSCs) alone or with astrocytes and neural precursor cells in a hyaluronic acid-rich hydrogel, with or without macrophage. Bioprinted constructs integrating macrophage recapitulate patient-derived transcriptional profiles predictive of patient survival, maintenance of stemness, invasion, and drug resistance. Whole-genome CRISPR screening with bioprinted complex systems identified unique molecular dependencies in GSCs, relative to sphere culture. Multicellular bioprinted models serve as a scalable and physiologic platform to interrogate drug sensitivity, cellular crosstalk, invasion, context-specific functional dependencies, as well as immunologic interactions in a species-matched neural environment.

Inadequate funding levels are a major impediment to effective global biodiversity conservation and are likely associated with recent failures to meet United Nations biodiversity targets. Some countries are more severely underfunded than others and therefore represent urgent financial priorities. However, attempts to identify these highly underfunded countries have been hampered for decades by poor and incomplete data on actual spending, coupled with uncertainty and lack of consensus over the relative size of spending gaps. Here, we assemble a global database of annual conservation spending. We then develop a statistical model that explains 86% of variation in conservation expenditures, and use this to identify countries where funding is robustly below expected levels. The 40 most severely underfunded countries contain 32% of all threatened mammalian diversity and include neighbors in some of the world’s most biodiversity-rich areas (Sundaland, Wallacea, and Near Oceania). However, very modest increases in international assistance would achieve a large improvement in the relative adequacy of global conservation finance. Our results could therefore be quickly applied to limit immediate biodiversity losses at relatively little cost.

Two drugs, miconazole and clobetasol, have functions that modulate differentiation of oligodendrocyte progenitor cells directly, enhance remyelination, and significantly reduce disease severity in mouse models of multiple sclerosis. Remyelination in multiple sclerosis Multiple sclerosis is characterized by an autoimmune response and failure of remyelination in the brain due to defects in differentiation of myelin-producing cells from oligodendrocyte progenitor cells. Most current treatments target the immune system. Paul Tesar and colleagues screened for compounds that can enhance oligodendrocyte maturation from mouse pluripotent epiblast stem-cell-derived oligodendrocyte progenitors. They found two drugs — miconazole (an antifungal) and clobetasol (a steroid) — that enhance myelin production in vivo in mouse models of multiple sclerosis and enhanced the differentiation of human oligodendrocytes progenitors in vitro . Mechanistically, these compounds appear to target both the immune response and oligodendrocyte progenitor cells. Multiple sclerosis involves an aberrant autoimmune response and progressive failure of remyelination in the central nervous system. Prevention of neural degeneration and subsequent disability requires remyelination through the generation of new oligodendrocytes, but current treatments exclusively target the immune system. Oligodendrocyte progenitor cells are stem cells in the central nervous system and the principal source of myelinating oligodendrocytes 1 . These cells are abundant in demyelinated regions of patients with multiple sclerosis, yet fail to differentiate, thereby representing a cellular target for pharmacological intervention 2 . To discover therapeutic compounds for enhancing myelination from endogenous oligodendrocyte progenitor cells, we screened a library of bioactive small molecules on mouse pluripotent epiblast stem-cell-derived oligodendrocyte progenitor cells 3 , 4 , 5 . Here we show seven drugs function at nanomolar doses selectively to enhance the generation of mature oligodendrocytes from progenitor cells in vitro . Two drugs, miconazole and clobetasol, are effective in promoting precocious myelination in organotypic cerebellar slice cultures, and in vivo in early postnatal mouse pups. Systemic delivery of each of the two drugs significantly increases the number of new oligodendrocytes and enhances remyelination in a lysolecithin-induced mouse model of focal demyelination. Administering each of the two drugs at the peak of disease in an experimental autoimmune encephalomyelitis mouse model of chronic progressive multiple sclerosis results in striking reversal of disease severity. Immune response assays show that miconazole functions directly as a remyelinating drug with no effect on the immune system, whereas clobetasol is a potent immunosuppressant as well as a remyelinating agent. Mechanistic studies show that miconazole and clobetasol function in oligodendrocyte progenitor cells through mitogen-activated protein kinase and glucocorticoid receptor signalling, respectively. Furthermore, both drugs enhance the generation of human oligodendrocytes from human oligodendrocyte progenitor cells in vitro . Collectively, our results provide a rationale for testing miconazole and clobetasol, or structurally modified derivatives, to enhance remyelination in patients.

An in vivo RNA interference screening strategy in glioblastoma enabled the identification of a host of epigenetic targets required for glioblastoma cell survival that were not identified by parallel standard screening in cell culture, including the transcription pause–release factor JMJD6, and could be a powerful tool to uncover new therapeutic targets in cancer. In vivo screening of brain tumour transcription factors Most high-throughput target discovery screens for glioblastoma have been limited to in vitro models with uncertain physiological relevance. Here, Jeremy Rich and colleagues perform two parallel RNA interference screens for transcriptional regulators, comparing an in vitro screen in cell lines to an in vivo screen that recapitulates the tumour microenvironment. They find several transcriptional elongation factors that are specifically required for glioblastoma cell survival in vivo , particularly the transcriptional pause release factor JMJD6 which is highly expressed in gliomas. This type of in vivo functional screen has the potential to uncover novel therapeutic targets for cancer that have not been identified in previous in vitro approaches. Glioblastoma is a universally lethal cancer with a median survival time of approximately 15 months 1 . Despite substantial efforts to define druggable targets, there are no therapeutic options that notably extend the lifespan of patients with glioblastoma. While previous work has largely focused on in vitro cellular models, here we demonstrate a more physiologically relevant approach to target discovery in glioblastoma. We adapted pooled RNA interference (RNAi) screening technology 2 , 3 , 4 for use in orthotopic patient-derived xenograft models, creating a high-throughput negative-selection screening platform in a functional in vivo tumour microenvironment. Using this approach, we performed parallel in vivo and in vitro screens and discovered that the chromatin and transcriptional regulators needed for cell survival in vivo are non-overlapping with those required in vitro . We identified transcription pause–release and elongation factors as one set of in vivo -specific cancer dependencies, and determined that these factors are necessary for enhancer-mediated transcriptional adaptations that enable cells to survive the tumour microenvironment. Our lead hit, JMJD6, mediates the upregulation of in vivo stress and stimulus response pathways through enhancer-mediated transcriptional pause–release, promoting cell survival specifically in vivo . Targeting JMJD6 or other identified elongation factors extends survival in orthotopic xenograft mouse models, suggesting that targeting transcription elongation machinery may be an effective therapeutic strategy for glioblastoma. More broadly, this study demonstrates the power of in vivo phenotypic screening to identify new classes of ‘cancer dependencies’ not identified by previous in vitro approaches, and could supply new opportunities for therapeutic intervention.

Despite evident regulatory roles of heparan sulfate (HS) saccharides in numerous biological processes, definitive information on the bioactive sequences of these polymers is lacking, with only a handful of natural structures sequenced to date. Here, we develop a “ S hotgun” I on M obility M ass S pectrometry S equencing (SIMMS 2 ) method in which intact HS saccharides are dissociated in an ion mobility mass spectrometer and collision cross section values of fragments measured. Matching of data for intact and fragment ions against known values for 36 fully defined HS saccharide structures (from di- to decasaccharides) permits unambiguous sequence determination of validated standards and unknown natural saccharides, notably including variants with 3 O -sulfate groups. SIMMS 2 analysis of two fibroblast growth factor-inhibiting hexasaccharides identified from a HS oligosaccharide library screen demonstrates that the approach allows elucidation of structure-activity relationships. SIMMS 2 thus overcomes the bottleneck for decoding the informational content of functional HS motifs which is crucial for their future biomedical exploitation. Heparan sulfates (HS) contain functionally relevant structural motifs, but determining their monosaccharide sequence remains challenging. Here, the authors develop an ion mobility mass spectrometry-based method that allows unambiguous characterization of HS sequences and structure-activity relationships.

Water temperature is critical for the ecology of lakes. However, the ability to predict its spatial and seasonal variation is constrained by the lack of a thermal classification system. Here we define lake thermal regions using objective analysis of seasonal surface temperature dynamics from satellite observations. Nine lake thermal regions are identified that mapped robustly and largely contiguously globally, even for small lakes. The regions differed from other global patterns, and so provide unique information. Using a lake model forced by 21 st century climate projections, we found that 12%, 27% and 66% of lakes will change to a lower latitude thermal region by 2080–2099 for low, medium and high greenhouse gas concentration trajectories (Representative Concentration Pathways 2.6, 6.0 and 8.5) respectively. Under the worst-case scenario, a 79% reduction in the number of lakes in the northernmost thermal region is projected. This thermal region framework can facilitate the global scaling of lake-research. Water temperature is a critical variable for lakes, but its spatial and temporal patterns are not well characterised globally. Here, the authors use surface temperature dynamics to define lake thermal regions that group lakes with similar patterns, and show how these regions shift under climate change.

Brain tumor initiating cells (BTICs) utilize high-affinity glucose uptake, which is normally active in neurons to maintain energy demands and self-renew. Leveraging metabolomic and genomic analyses, Wang et al . report that de novo purine biosynthesis reprograms BTIC metabolism, revealing a potential point of fragility amenable to targeted cancer therapy. Brain tumor initiating cells (BTICs), also known as cancer stem cells, hijack high-affinity glucose uptake active normally in neurons to maintain energy demands. Here we link metabolic dysregulation in human BTICs to a nexus between MYC and de novo purine synthesis, mediating glucose-sustained anabolic metabolism. Inhibiting purine synthesis abrogated BTIC growth, self-renewal and in vivo tumor formation by depleting intracellular pools of purine nucleotides, supporting purine synthesis as a potential therapeutic point of fragility. In contrast, differentiated glioma cells were unaffected by the targeting of purine biosynthetic enzymes, suggesting selective dependence of BTICs. MYC coordinated the control of purine synthetic enzymes, supporting its role in metabolic reprogramming. Elevated expression of purine synthetic enzymes correlated with poor prognosis in glioblastoma patients. Collectively, our results suggest that stem-like glioma cells reprogram their metabolism to self-renew and fuel the tumor hierarchy, revealing potential BTIC cancer dependencies amenable to targeted therapy.