The PP2A regulator IER5L supports prostate cancer progression.

Prostate cancer exhibits high prevalence and accounts for a high number of cancer-related deaths. The discovery and characterization of molecular determinants of aggressive prostate cancer represents an active area of research. The Immediate Early Response (IER) family of genes, which regulate Protein Phosphatase 2A (PP2A) activity, has emerged among the factors that influence cancer biology.

MAF amplification licenses ERα through epigenetic remodelling to drive breast cancer metastasis.

MAF amplification increases the risk of breast cancer (BCa) metastasis through mechanisms that are still poorly understood yet have important clinical implications. Oestrogen-receptor-positive (ER) BCa requires oestrogen for both growth and metastasis, albeit by ill-known mechanisms. Here we integrate proteomics, transcriptomics, epigenomics, chromatin accessibility and functional assays from human and syngeneic mouse BCa models to show that MAF directly interacts with oestrogen receptor alpha (ERα), thereby promoting a unique chromatin landscape that favours metastatic spread.

Direct reprogramming of human fibroblasts into insulin-producing cells using transcription factors.

Direct lineage reprogramming of one somatic cell into another without transitioning through a progenitor stage has emerged as a strategy to generate clinically relevant cell types. One cell type of interest is the pancreatic insulin-producing β cell whose loss and/or dysfunction leads to diabetes. To date it has been possible to create β-like cells from related endodermal cell types by forcing the expression of developmental transcription factors, but not from more distant cell lineages like fibroblasts.

Long-term platinum-based drug accumulation in cancer-associated fibroblasts promotes colorectal cancer progression and resistance to therapy.

A substantial proportion of cancer patients do not benefit from platinum-based chemotherapy (CT) due to the emergence of drug resistance. Here, we apply elemental imaging to the mapping of CT biodistribution after therapy in residual colorectal cancer and achieve a comprehensive analysis of the genetic program induced by oxaliplatin-based CT in the tumor microenvironment. We show that oxaliplatin is largely retained by cancer-associated fibroblasts (CAFs) long time after the treatment ceased.

Paradoxical suboptimal vitamin D levels in a Mediterranean area: a population-based study.

Policies in sunny countries, such as those in the Mediterranean area, do not promote vitamin D supplementation despite some studies might suggest the high prevalence of sub-optimal levels. The objective was to determine the vitamin D levels by 25-hydroxyvitamin D (25(OH)D) of a Mediterranean population and their characteristics. This population-based study included a database of public health system from all individuals living in Catalonia > 18 years who had some measure of 25(OH)D between January 2018 and April 2021.

Design and optimization of oestrogen receptor PROTACs based on 4-hydroxytamoxifen.

In the last four decades, treatment of oestrogen receptor positive (ER+) breast cancer (BCa), has focused on targeting the estrogenic receptor signaling pathway. This signaling function is pivotal to sustain cell proliferation. Tamoxifen, a competitive inhibitor of oestrogen, has played a major role in therapeutics.

Targeted immunotherapy against distinct cancer-associated fibroblasts overcomes treatment resistance in refractory HER2+ breast tumors.

About 50% of human epidermal growth factor receptor 2 (HER2)+ breast cancer patients do not benefit from HER2-targeted therapy and almost 20% of them relapse after treatment. Here, we conduct a detailed analysis of two independent cohorts of HER2+ breast cancer patients treated with trastuzumab to elucidate the mechanisms of resistance to anti-HER2 monoclonal antibodies. In addition, we develop a fully humanized immunocompetent model of HER2+ breast cancer recapitulating ex vivo the biological processes that associate with patients' response to treatment.

Remission of obesity and insulin resistance is not sufficient to restore mitochondrial homeostasis in visceral adipose tissue.

Metabolic plasticity is the ability of a biological system to adapt its metabolic phenotype to different environmental stressors. We used a whole-body and tissue-specific phenotypic, functional, proteomic, metabolomic and transcriptomic approach to systematically assess metabolic plasticity in diet-induced obese mice after a combined nutritional and exercise intervention. Although most obesity and overnutrition-related pathological features were successfully reverted, we observed a high degree of metabolic dysfunction in visceral white adipose tissue, characterized by abnormal mitochondrial morphology and functionality.

Glycaemia Fluctuations Improvement in Old-Age Prediabetic Subjects Consuming a Quinoa-Based Diet: A Pilot Study.

This study aimed to observe if quinoa could produce a benefit on postprandial glycemia that would result in less progression to type 2 diabetes (T2D). A cross-over design pilot clinical study with a nutritional intervention for 8 weeks was performed: 4 weeks on a regular diet (RD) and 4 weeks on a quinoa diet (QD). Nine subjects aged ≥65 years with prediabetes were monitored during the first 4 weeks of RD with daily dietary records and FreeStyle Libre®.

Low Percentage of Vegetable Fat in Red Blood Cells Is Associated with Worse Glucose Metabolism and Incidence of Type 2 Diabetes.

The identification of nutritional patterns associated with the development of type 2 diabetes (T2D) might help lead the way to a more efficient and personalized nutritional intervention. Our study is aimed at evaluating the association between fatty acids (FA) in red blood cell (RBC) membranes, as a quantitative biomarker of regular dietary fat intake, and incident type 2 diabetes in a Spanish population. We included 1032 adult Spaniards (57% women, age 49 ± 15 years, 18% prediabetes), without diabetes at study entry, from the Di@bet.

Ecology and evolution of dormant metastasis.

Genetic studies suggest that sequential dissemination from a primary metastasis, usually at the bone, is a major route of metastatic progression in early, radically resected cancer. Disseminated tumor cells (DTCs) can likely infiltrate but not grow, and may remain dormant once disseminated for extended intervals (from months to decades). The stationary nature of DTCs prevents them from being successfully treated as an asymptomatic residual disease in the adjuvant setting; critically, they can eventually relapse, adapt, and develop therapy resistance, causing incurable overt metastasis.

LCOR mediates interferon-independent tumor immunogenicity and responsiveness to immune-checkpoint blockade in triple-negative breast cancer.

Ligand-dependent corepressor (LCOR) mediates normal and malignant breast stem cell differentiation. Cancer stem cells (CSCs) generate phenotypic heterogeneity and drive therapy resistance, yet their role in immunotherapy is poorly understood. Here we show that immune-checkpoint blockade (ICB) therapy selects for LCOR CSCs with reduced antigen processing/presentation machinery (APM) driving immune escape and ICB resistance in triple-negative breast cancer (TNBC).

Loss of microRNA-135b Enhances Bone Metastasis in Prostate Cancer and Predicts Aggressiveness in Human Prostate Samples.

About 70% of advanced-stage prostate cancer (PCa) patients will experience bone metastasis, which severely affects patients' quality of life and progresses to lethal PCa in most cases. Hence, understanding the molecular heterogeneity of PCa cell populations and the signaling pathways associated with bone tropism is crucial. For this purpose, we generated an animal model with high penetrance to metastasize to bone using an intracardiac percutaneous injection of PC3 cells to identify PCa metastasis-promoting factors.

Fatty liver index as a predictor for type 2 diabetes in subjects with normoglycemia in a nationwide cohort study.

Our aim was to evaluate whether fatty liver index (FLI) is associated with the risk of type 2 diabetes (T2DM) development within the Spanish adult population and according to their prediabetes status; additionally, to examine its incremental predictive value regarding traditional risk factors. A total of 2260 subjects (Prediabetes: 641 subjects, normoglycemia: 1619 subjects) from the Di@bet.es cohort study were studied.

Amplification and Adjuvant Clodronate Outcomes in Early-Stage Breast Cancer in NSABP B-34 and Potential Impact on Clinical Practice.

Background: The Adjuvant Zoledronic Acid (ZA) study in early breast cancer (AZURE) showed correlation between a nonamplified gene in the primary tumor and benefit from adjuvant ZA. Adverse ZA outcomes occurred in MAF-amplified patients. NSABP B-34 is a validation study.

Mitochondrial cristae-remodeling protein OPA1 in POMC neurons couples Ca homeostasis with adipose tissue lipolysis.

Appropriate cristae remodeling is a determinant of mitochondrial function and bioenergetics and thus represents a crucial process for cellular metabolic adaptations. Here, we show that mitochondrial cristae architecture and expression of the master cristae-remodeling protein OPA1 in proopiomelanocortin (POMC) neurons, which are key metabolic sensors implicated in energy balance control, is affected by fluctuations in nutrient availability. Genetic inactivation of OPA1 in POMC neurons causes dramatic alterations in cristae topology, mitochondrial Ca handling, reduction in alpha-melanocyte stimulating hormone (α-MSH) in target areas, hyperphagia, and attenuated white adipose tissue (WAT) lipolysis resulting in obesity.

Gsα-dependent signaling is required for postnatal establishment of a functional β-cell mass.

Objective: Early postnatal life is a critical period for the establishment of the functional β-cell mass that will sustain whole-body glucose homeostasis during the lifetime. β cells are formed from progenitors during embryonic development but undergo significant expansion in quantity and attain functional maturity after birth. The signals and pathways involved in these processes are not fully elucidated.

Type 2 diabetes preventive effects with a 12-months sardine-enriched diet in elderly population with prediabetes: An interventional, randomized and controlled trial.

Background: Fish could play a role in preventing type 2 diabetes (T2D) but there has been little specification about the type of fish and the preventive mechanism involved in its health claim. The sardine is a source of omega-3 and taurine that, in isolation or in synergy, would produce T2D-delaying through different molecular mechanism.

Hypothesis: The consumption of twice a week of sardine, during one year would reduce T2D-developing risk in a population with prediabetes (preDM) and old age.

Endogenous cortisol excess confers a unique lipid signature and metabolic network.

Chronic cortisol excess induces several alterations on protein, lipid and carbohydrate metabolism resembling those found in the metabolic syndrome. However, patients exposed to prolonged high levels of cortisol in Cushing syndrome (CS) present exceeding cardiometabolic alterations not reflected by conventional biomarkers. Using 3 ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS) platforms, we aimed to characterise the serum metabolome of 25 patients with active endogenous CS and 25 control subjects matched by propensity score (sex, BMI, diabetes mellitus type 2 (T2D), high blood pressure (HBP) and dyslipidaemia) to search for potential disease-specific biomarkers and pathways associated to the clinical comorbidities.

In Vivo Assessment of Metastatic Cell Potential in Prostate Cancer.

Metastasis is the main cause of death for cancer patients, but our ability to improve clinical outcome first requires a better understanding of the dynamics, cellular mechanisms, and kinetics of metastasis. In prostate cancer (PCa), metastatic tumor cells preferentially colonize to bone. However, a lack of applicable mouse models has limited our ability to study this process accurately.

Cysteine and Folate Metabolism Are Targetable Vulnerabilities of Metastatic Colorectal Cancer.

With most cancer-related deaths resulting from metastasis, the development of new therapeutic approaches against metastatic colorectal cancer (mCRC) is essential to increasing patient survival. The metabolic adaptations that support mCRC remain undefined and their elucidation is crucial to identify potential therapeutic targets. Here, we employed a strategy for the rational identification of targetable metabolic vulnerabilities.

Wisp1 is a circulating factor that stimulates proliferation of adult mouse and human beta cells.

Expanding the mass of pancreatic insulin-producing beta cells through re-activation of beta cell replication has been proposed as a therapy to prevent or delay the appearance of diabetes. Pancreatic beta cells exhibit an age-dependent decrease in their proliferative activity, partly related to changes in the systemic environment. Here we report the identification of CCN4/Wisp1 as a circulating factor more abundant in pre-weaning than in adult mice.

Incidence and regression of metabolic syndrome in a representative sample of the Spanish population: results of the cohort di@bet.es study.

Introduction: Metabolic syndrome (MetS) is an important predictor of cardiovascular mortality. Identification of occurrence and regression trends of MetS could permit elaboration of preventive strategies with new targets. The objective of this study was to analyze the occurrence and regression rates of MetS and its associated factors in the representative cohort of Spain of the di@bet.