The fact that the identity of the cells that initiate metastasis in most human cancers is unknown hampers the development of antimetastatic therapies. Here we describe a subpopulation of CD44
cells ...in human oral carcinomas that do not overexpress mesenchymal genes, are slow-cycling, express high levels of the fatty acid receptor CD36 and lipid metabolism genes, and are unique in their ability to initiate metastasis. Palmitic acid or a high-fat diet specifically boosts the metastatic potential of CD36
metastasis-initiating cells in a CD36-dependent manner. The use of neutralizing antibodies to block CD36 causes almost complete inhibition of metastasis in immunodeficient or immunocompetent orthotopic mouse models of human oral cancer, with no side effects. Clinically, the presence of CD36
metastasis-initiating cells correlates with a poor prognosis for numerous types of carcinomas, and inhibition of CD36 also impairs metastasis, at least in human melanoma- and breast cancer-derived tumours. Together, our results indicate that metastasis-initiating cells particularly rely on dietary lipids to promote metastasis.
Polycomb group proteins are essential regulators of cell fate decisions during embryogenesis. In mammals, at least five different Cbx proteins (Cbx2, Cbx4, Cbx6, Cbx7, and Cbx8) are known to ...associate with the core Polycomb repressive complex 1 (PRC1). Here we show that pluripotency and differentiation of mouse embryonic stem cells (ESCs) is regulated by different Cbx-associated PRC1 complexes with unique functions. Maintenance of pluripotency primarily depends on Cbx7, while lineage commitment is orchestrated by Cbx2 and Cbx4. At the molecular level, we have uncovered a Polycomb autoregulatory loop in which Cbx7 represses the expression of prodifferentiation Cbx proteins, thereby maintaining the pluripotent state. We additionally show that the occupancy of Cbx7 on promoters is completely dependent on PRC2 activity but only partially dependent on a functional PRC1 complex. Thus, Cbx proteins confer distinct target selectivity to the PRC1 complex, achieving a balance between the self-renewal and the differentiation of ESCs.
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► PRC1 complexes assemble with different Cbx subunits during mouse ESC differentiation ► The subunit composition of PRC1 influences mESC fate decisions ► The H3K27me3 histone mark is required to recruit Cbx7 to its target genes in mESCs ► Cbx7-, Cbx2-, or Cbx4-depleted mESCs give rise to teratomas with varied phenotypes
Oncogene-induced senescence (OIS) is crucial for tumour suppression. Senescent cells implement a complex pro-inflammatory response termed the senescence-associated secretory phenotype (SASP). The ...SASP reinforces senescence, activates immune surveillance and paradoxically also has pro-tumorigenic properties. Here, we present evidence that the SASP can also induce paracrine senescence in normal cells both in culture and in human and mouse models of OIS in vivo. Coupling quantitative proteomics with small-molecule screens, we identified multiple SASP components mediating paracrine senescence, including TGF-β family ligands, VEGF, CCL2 and CCL20. Amongst them, TGF-β ligands play a major role by regulating p15(INK4b) and p21(CIP1). Expression of the SASP is controlled by inflammasome-mediated IL-1 signalling. The inflammasome and IL-1 signalling are activated in senescent cells and IL-1α expression can reproduce SASP activation, resulting in senescence. Our results demonstrate that the SASP can cause paracrine senescence and impact on tumour suppression and senescence in vivo.
Metastasis remains the leading cause of cancer-related deaths worldwide, and our inability to identify the tumour cells that colonize distant sites hampers the development of effective ...anti-metastatic therapies. However, with recent research advances we are beginning to distinguish metastasis-initiating cells from their non-metastatic counterparts. Importantly, advances in genome sequencing indicate that the acquisition of metastatic competency does not involve the progressive accumulation of driver mutations; moreover, in the early stages of tumorigenesis, cancer cells harbour combinations of driver mutations that endow them with metastatic competency. Novel findings highlight that cells can disseminate to distant sites early during primary tumour growth, remaining dormant and untreatable for long periods before metastasizing. Thus, metastatic cells must require local and systemic influences to generate metastases. This hypothesis suggests that factors derived from our lifestyle, such as our diet, exert a strong influence on tumour progression, and that such factors could be modulated if understood. Here, we summarize the recent findings on how specific metabolic cues modulate the behaviour of metastatic cells and how they influence the genome and epigenome of metastatic cells. We also discuss how crosstalk between metabolism and the epigenome can be harnessed to develop new anti-metastatic therapies.
Murine epidermal stem cells undergo alternate cycles of dormancy and activation, fuelling tissue renewal. However, only a subset of stem cells becomes active during each round of morphogenesis, ...indicating that stem cells coexist in heterogeneous responsive states. Using a circadian-clock reporter-mouse model, here we show that the dormant hair-follicle stem cell niche contains coexisting populations of cells at opposite phases of the clock, which are differentially predisposed to respond to homeostatic cues. The core clock protein Bmal1 modulates the expression of stem cell regulatory genes in an oscillatory manner, to create populations that are either predisposed, or less prone, to activation. Disrupting this clock equilibrium, through deletion of Bmal1 (also known as Arntl) or Per1/2, resulted in a progressive accumulation or depletion of dormant stem cells, respectively. Stem cell arrhythmia also led to premature epidermal ageing, and a reduction in the development of squamous tumours. Our results indicate that the circadian clock fine-tunes the temporal behaviour of epidermal stem cells, and that its perturbation affects homeostasis and the predisposition to tumorigenesis.
Human epidermal stem cells transit from a slow cycling to an actively proliferating state to contribute to homeostasis. Both stem cell states differ in their cell cycle profiles but must remain ...guarded from differentiation and senescence. Here we show that Cbx4, a Polycomb Repressive Complex 1 (PRC1)-associated protein, maintains human epidermal stem cells as slow-cycling and undifferentiated, while protecting them from senescence. Interestingly, abrogating the polycomb activity of Cbx4 impairs its antisenescent function without affecting stem cell differentiation, indicating that differentiation and senescence are independent processes in human epidermis. Conversely, Cbx4 inhibits stem cell activation and differentiation through its SUMO ligase activity. Global transcriptome and chromatin occupancy analyses indicate that Cbx4 regulates modulators of epidermal homeostasis and represses factors such as Ezh2, Dnmt1, and Bmi1 to prevent the active stem cell state. Our results suggest that distinct Polycomb complexes balance epidermal stem cell dormancy and activation, while continually preventing senescence and differentiation.
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► Cbx4 prevents human epSC proliferation, senescence, and differentiation ► Cbx4 regulates senescence solely via PRC1 and differentiation via its SUMO activity ► Cbx4 is the only PRC1-associated Cbx protein to promote hepSC quiescence ► Differentiation and senescence are two independent processes in human epidermis
► Sacha inchi (SI) oil has a unique fatty acid composition, similar in ω-3 but twice as much ω-6 levels compared to flax. ► Sacha inchi oil showed highest oxidative instability at 65°C when compared ...to corn, flax and high oleic sunflower oils. ► Portable handheld mid-infrared spectrometers provided fast and reliable tools to characterize and authenticate SI oils. ► Evaluation of commercial SI oils from Peruvian markets showed some prevalence of adulteration. ► Combining FT-IR spectroscopy with chemometrics has proven to be a great alternative to traditional testing methods.
Consumption of omega-3 fatty acids (ω-3’s), whether from fish oils, flax or supplements, can protect against cardiovascular disease. Finding plant-based sources of the essential ω-3’s could provide a sustainable, renewable and inexpensive source of ω-3’s, compared to fish oils. Our objective was to develop a rapid test to characterize and detect adulteration in sacha inchi oils, a Peruvian seed containing higher levels of ω-3’s in comparison to other oleaginous seeds. A temperature-controlled ZnSe ATR mid-infrared benchtop and diamond ATR mid-infrared portable handheld spectrometers were used to characterize sacha inchi oil and evaluate its oxidative stability compared to commercial oils. A soft independent model of class analogy (SIMCA) and partial least squares regression (PLSR) analyzed the spectral data. Fatty acid profiles showed that sacha inchi oil (44% linolenic acid) had levels of PUFA similar to those of flax oils. PLSR showed good correlation coefficients (R2>0.9) between reference tests and spectra from infrared devices, allowing for rapid determination of fatty acid composition and prediction of oxidative stability. Oils formed distinct clusters, allowing the evaluation of commercial sacha inchi oils from Peruvian markets and showed some prevalence of adulteration. Determining oil adulteration and quality parameters, by using the ATR-MIR portable handheld spectrometer, allowed for portability and ease-of-use, making it a great alternative to traditional testing methods.
This study investigated the impact of controlled germination on colour, carotenoids and tocopherols of Andean lupin (Lupinus mutabilis Sweet) seeds. Two Andean lupin ecotypes, Cholo fuerte and ...Altagracia, were germinated in the dark for two, four and six days; colour coordinates (L*, a*, b*) were determined by colorimeter, while carotenoids and tocopherols were quantified by HPLC. The germination significantly modified the characteristics examined. The luminosity decreased with increasing germination time, while only minor changes were recorded for a* and b* . The sum of all carotenoids increased up to 12-fold during germination, with lutein always being the most abundant compound. The predominant tocol was γ-tocopherol; although total tocol content was almost unchanged, α-tocopherol increased from not-quantifiable up to 74.8 mg/kg dry matter, improving the vitamin E activity, while γ-tocopherol decreased progressively. Our results demonstrate that germination promises to be a cost-effective approach to improve the nutritional properties of lupin seeds.
•Seeds of two Andean lupins were germinated in the dark for two, four and six days.•The content of carotenoids (mainly lutein) augmented during germination.•The α-tocopherol increased while the γ-tocopherol decreased during the germination.•The carotenoids and α-tocopherol increase improved the biological activity of lupins.•Germination is a cost-effective way to improve the nutritional value of Andean lupin.
•The effect of tomato lycopene extract (TLE) on linseed oil shelf life was evaluated.•80 mg lycopene/kg oil showed the same induction time at 110 °C of 200 mg BHT/kg oil.•TLE addition slowed oil ...degradation without changing the mechanism.•Rancidity followed first order kinetics during storage at 40–60 °C until 90 days.•TLE increased oil shelf-life at 25 °C by 31% (Rancimat) and 42% (kinetics).
The effect of tomato lycopene-rich extract (TLE) addition on shelf-life of linseed oil was evaluated. Linseed oil was extracted by cold pressing and TLE by supercritical CO2. Linseed oils with and without TLE addition were characterized for moisture, color, refractive index, fatty acid composition and antioxidants. Adding TLE to 80 mg lycopene/kg oil improved linseed oil stability, showing the same induction time at 110 °C (by Rancimat) of control linseed oil with 200 mg/kg butylhydroxytoluene. The increase of free fatty acid, peroxide value, p-anisidine value, K232 and K268 at 40, 50, and 60 °C until 90 days followed first-order kinetics. Rancidity rate augmented with temperature. TLE addition slowed oil degradation without changing the mechanism since the Arrhenius lines were parallel. Mean Ea were respectively 38.2, 24.7, 38.0, 38.2, 41.5 kJ/mol. TLE addition increased linseed oil shelf-life by 31% (Rancimat) and by 42% (stability kinetics during storage).
Background. The characterization and evaluation of the nutritional composition of lupine (Lupinus mutabilis) seeds has a long history. However, the determination of the fatty acid profile has only ...been carried out in a few varieties. Objective. This study determined the fatty acid profile and chemical composition of the oil of six varieties of lupine consumed in Peru. Methods. The extraction of oil from each lupine variety was carried out using the Soxhlet method. Fatty acids, moisture, acidity index, free fatty acids, peroxide value, iodine value, saponification value, and density were determined using official AOAC methods. Results. In general, the average values of saturated fatty acids are lower than those of unsaturated fatty acids. Among the monounsaturated fatty acids (MUFA), oleic acid (C18:1) was the most representative, with values ranging from 41.83% to 54.33%. The “Andenes” variety showed an average oleic acid value of 54.60% compared to the other varieties. The composition of polyunsaturated fatty acids (PUFA) was dominated by linoleic acid (C18:2), and the variety “Cholo fuerte” reported higher values (34.70%) compared to the other varieties. Likewise, the highest average PUFA was 36% and was observed in the “Cholo fuerte” variety. The concentration of linolenic fatty acid (C18:3) ranges from 2.1% for the “Andenes” variety to 2.9% for the common lupine. Additionally, the mean content of linolenic (ω-6) and linoleic (ω-3) acids was 2.33 and 30.89% (13 : 1 ratio), respectively, with the consequent ratio of ω-6/ω-3 fatty acids at the mean level of 0.08. All physicochemical characteristics of lupine seed oil are in accordance with the requirements for edible oils. Conclusion. These findings make the six lupine varieties a new source of promising food components of high nutritional value.
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