Biology subjects

Santos, A.

Publications and source records attributed to Santos, A..

6 recordsLinked to original sources

bioRxiv2018

Integrative analysis of transcriptomic and clinical data uncovers the tumor suppressive activity of MITF in prostate cancer.

The dysregulation of gene expression is an enabling hallmark of cancer. Computational analysis of transcriptomics data from human cancer specimens, complemented with exhaustive clinical annotation, provides an opportunity to identify core regulators of the tumorigenic process. Here we exploit well-annotated clinical datasets of prostate cancer for the discovery of transcriptional regulators relevant to prostate cancer. Following this rationale, we identify Microphthalmia-associated transcription factor (MITF) as a prostate tumor suppressor among a subset of transcription factors. Importantly, we further interrogate transcriptomics and clinical data to refine MITF perturbation-based empirical assays and unveil Crystallin Alpha B (CRYAB) as an unprecedented direct target of the transcription factor that is, at least in part, responsible for its tumor suppressive activity in prostate cancer. This evidence was supported by the enhanced prognostic potential of a signature based on the concomitant alteration of MITF and CRYAB in prostate cancer patients. In sum, our study provides proof-of-concept evidence of the potential of the bioinformatics screen of publicly available cancer patient databases as discovery platforms, and demonstrates that the MITF-CRYAB axis controls prostate cancer biology.

cancer biology↗

bioRxiv2018

The association between 25(OH)D levels, frailty status and adiposity indices in older adults

BackgroundVitamin D deficiency is common in older adults and has been linked with frailty and obesity, but it remains to be studied whether frail obese older adults are at higher risk of vitamin D deficiency. Therefore, the aim of this study is to explore the association between frailty, adiposity indices and serum 25(OH)D concentrations.\n\nMethods1447 individuals with 65 years or older, participating in a cross-sectional study (Nutrition UP 65). Frailty, according to Fried et al., body mass index (BMI), waist circumference (WC), body roundness index (BRI) and body shape index (ABSI) were evaluated. A stepwise multinomial logistic regression was carried out to quantify the association between 25(OH)D quartiles and independent variables.\n\nResultsMedian 25(OH)D levels were lower in individuals presenting both frailty and obesity (p<0.001). In the multivariate analysis, pre-frailty (OR 2.65; 95% CI 1.63-4.32) and frailty (OR 3.76; 95% CI 2.08-6.81) were associated with increased odds of lower 25(OH)D serum levels (first quartile). Regarding adiposity indices, obesity (OR 1.75; 95% CI 1.07-2.87) and the highest categories of WC (OR 3.46; 95% CI 1.95-6.15), BRI (OR 4.35; 95% CI 2.60-7.29) and ABSI (OR 3.17 95% CI 1.86-5.38) were directly associated with lower 25(OH)D serum levels (first quartile).\n\nConclusionsA positive association between frailty or obesity and lower levels of vitamin D was found. Moreover, besides BMI and WC, other indicators of body adiposity, such as BRI and ABSI, were associated with lower 25(OH)D serum concentrations.

epidemiology↗

bioRxiv2018

Interfering with MIF-CD74 signalling on macrophages and dendritic cells with a peptide-based approach restores the immune response against metastatic melanoma.

Mounting an effective immune response against cancer requires the activation of innate and adaptive immune cells. Metastatic melanoma is the most aggressive form of skin cancer. Immunotherapies that boost the activity of effector T cells have shown a remarkable success in melanoma treatment. Patients, however, can develop resistance to such therapies by mechanisms that include the establishment of an immune suppressive tumour microenvironment. Understanding how metastatic melanoma cells suppress the immune system is vital to develop effective immunotherapies against this disease. In this study, we find that the innate immune cells, macrophages and dendritic cells are suppressed in metastatic melanoma. The Ig-CDR-based peptide C36L1 is able to restore macrophages and dendritic cells immunogenic functions and to inhibit metastatic growth in vivo. Mechanistically, we found that C36L1 interferes with the MIF-CD74 tumour-innate immune cells immunosuppressive signalling pathway and thereby restores an effective anti-tumour immune response. C36L1 directly binds to CD74 on macrophages and dendritic cells, disturbing CD74 structural dynamics and inhibiting MIF signalling through CD74. Our findings suggest that interfering with MIF-CD74 immunosuppressive signalling in macrophages and dendritic cells using peptide-based immunotherapy can restore the anti-tumour immune response in metastatic melanoma. Our study provides the rationale for further development of peptide-based therapies to restore the anti-tumour immune response.

cancer biology↗

bioRxiv2017

Blockade of insulin-like growth factors increases efficacy of paclitaxel in metastatic breast cancer.

Breast cancer remains the leading cause of cancer death in women due to metastasis and the development of resistance to established therapies. Macrophages are the most abundant immune cells in the breast tumor microenvironment and can both inhibit and support cancer progression. Thus, gaining a better understanding of how macrophages support cancer could lead to the development of more effective therapies. In this study, we find that breast cancer associated macrophages express high levels of insulin-like growth factors 1 and 2 (IGFs) and are the main source of IGFs within both primary and metastatic tumours. 75% of breast cancer patients show activation of Insulin/IGF-1 receptor signaling and this correlates with increased macrophage infiltration and advanced tumor stage. In patients with invasive breast cancer, activation of Insulin/IGF-1 receptors increased to 87%. Blocking IGF in combination with paclitaxel, a chemotherapeutic agent commonly used to treat breast cancer, showed a significant reduction in tumor cell proliferation and lung metastasis in a pre-clinical breast cancer model compared to paclitaxel monotherapy. Our findings provide the rationale for further developing the combination of paclitaxel with IGF blockers for the treatment of invasive breast cancer, and Insulin/IGF1R activation and IGF+ stroma cells as potential biomarker candidates for further evaluation.

cancer biology↗

bioRxiv2017

An integrative method to unravel the host-parasite interactome: An orthology-based approach

The study of molecular host-parasite interactions is essential to understand parasitic infection and adaptation within the host system. As well, prevention and treatment of infectious diseases require clear understanding of the molecular crosstalk between parasites and their hosts. As yet, experimental large-scale identification of host-parasite molecular interactions remains challenging and the use of in silico predictions becomes then necessary. Here, we propose a computational integrative approach to predict host-parasite protein-protein interaction (PPI) networks resulting from the infection of human by 12 different parasites. We used an orthology-based method to transfer high-confidence intra-species interactions obtained from the STRING database to the corresponding inter-species protein pairs in the host-parasite system. To reduce the number of spurious predictions, our approach uses either the parasites predicted secretome and membrane proteins or only the secretome depending on whether they are uni- or multicellular respectively. Besides, the host proteome is filtered for proteins expressed in selected cellular localizations and tissues supporting the parasites growth. We evaluated the inferred interactions by analyzing the enriched biological processes and pathways in the predicted networks and their association to known parasitic invasion and evasion mechanisms. The resulting PPI networks were compared across parasites to identify common mechanisms that may define a global pathogenic hallmark. The predicted PPI networks can be visualized and downloaded at http://orthohpi.jensenlab.org.\n\nAuthor SummaryA protein-protein interaction (PPI) network is a collection of interactions between proteins from one or more organisms. Host-parasite PPIs are key to understanding the biology of different parasitic diseases, since predicting PPIs enable to know more about the parasite invasion, infection and persist. Our understanding of PPIs between host and parasites is still very limited, as no many systematic experimental studies have so far been performed. Efficacy of treatments for parasitic diseases is limited and in many cases parasites evolve resistance. Thus, there is an urgent need to develop novel drugs or vaccines for these neglected diseases, and thus interest in the functions and interactions of proteins associated with parasitism processes. Here we developed an in silico method to shed light on the interactome in twelve human parasites by combining an orthology based strategy and integrating, domain-domain interaction data, sub-cellular localization and to give a spatial context, we only took in to account those human tissues that support the parasites tropism. Here we show that is possible to identify relevant interactions across different parasites and their human host and that these interactions are well supported based on the biology of the parasites.

systems biology↗

bioRxiv2016

Slow and steady wins the race: encounters of myosin-5 and myosin-6 on shared actin filaments

In the cellular environment multiple myosins use the same filamentous actin (F-actin) tracks, yet little is known about how this track sharing is achieved and maintained. To assess the influence that different myosin classes have on each other, we developed an assay that combines two dynamic elements: elongating actin filaments with identified barbed and pointed ends, and myosins moving along these filaments. We studied two different myosins, myosin-5 and myosin-6. These myosins have distinct functions in the cell and are known to travel in opposite directions along actin filaments. Myosin-5 walks towards the barbed end of F-actin and generally into dynamically rearranging actin at the cell periphery. Myosin-6 is a pointed-end directed myosin that generally walks towards the cell center. We successfully reconstituted simultaneous bidirectional motility of myosin-5 and myosin-6 on single polymerizing filaments of actin. We report and provide statistical analysis of encounters between myosin-5 and myosin-6 walking along the single filaments. When myosin-5 and myosin-6 collide, myosin-5 detaches more frequently than myosin-6. The experimental observations are consistent with a stochastic stepping model based upon known myosin kinetics, which suggests that faster motors are more likely to detach.

biophysics↗