Events

Title: Development and application of novel computational approaches for the
characterization of cancer subtypes

Autor: Camilla Pegoraro
Directors: María de la Iglesia-Vayá, Francisco García García

Abstract: Cancer remains a global health crisis, demanding further research to understand its molecular basis. Even within the same cancer type, inter-patient variability is an obstacle to disease understanding and therapy development. Cancer subtyping, therefore, becomes essential to address cancer heterogeneity. One promising approach to unravel this heterogeneity is through cancer subtyping based on the transcriptomic landscape of patients. Through gene expression profiling, researchers can identify groups of patients that may represent distinct cancer subtypes with unique biological characteristics, response to therapies and clinical outcomes. However, this approach has its major challenge in requiring large sample sizes, which are crucial for the identification of meaningful subtypes.
This is where transcriptomics data meta-analysis emerges as a powerful statistical tool. By systematically collecting and re-analyzing data from public repositories,
researchers can integrate sample sizes across multiple studies, overcoming the limitations of individual datasets. This approach allows for the identification of subtle
yet critical differences in gene expression patterns that might be missed in smaller cohorts. In this thesis, we explored cancer heterogeneity in two distinct contexts: lung adenocarcinoma and pancreatic ductal adenocarcinoma. We used an in-silico approach, leveraging published data through meta-analysis, overcoming limitations
of individual studies, and driving novel discoveries. We have identified sex-specific transcriptomic differences in lung adenocarcinoma, particularly in the immune system, purinergic signaling, and lipid metabolism pathways. We have also characterized the transcriptomic landscape of pancreatic ductal adenocarcinoma and its links to patient survival, revealing two prognostic gene signatures associated with the immune system and the extracellular matrix.

12:00 – 12:30 – Juan José Esteve
Smart Nanoparticles for Targeted Cancer Therapy: From Controlled Drug Release to Self-Propelled Nanomotors

Abstract: Nanomedicine has revolutionized cancer therapy by enabling precise drug delivery, minimizing side effects, and improving treatment efficacy. Advanced nanocarriers offer innovative strategies to overcome biological barriers and enhance therapeutic outcomes. Here we present a collection of “smart” and multifunctional nanoparticles to release cytotoxic drugs in a controlled manner (using molecular gates or magnetic field), improving the therapeutic effect of the drugs.

In recent years, near-infrared (NIR) light has gained significant interest as a strategy for localized tumor treatment due to its precise targeting capabilities. We have developed two systems based on gold nanostars to enable photoactivation of Doxorubicin prodrugs by NIR light. The results demosntrated that the chemotherapeutic agent is released exclusively at the irradiated site and significantly improved therapeutic effect in a melanoma tumor model.

On the other hand, we developed nanoparticles with autonomous movement (nanomotors) to enhanced drug delivery into deep areas of the tumors. In this case, Janus nanoparticles based on platinum and mesoporous silica nanoparticles (MSNs) faces were used as scaffold. Doxorubicin was loaded into the pores of MSNs and the enzyme lactate oxidase (Lox) was used as capping ensemble (to control drug release) and unit to start the movement. The movement is driven by catalytic elements (e.g., metals or enzymes) that convert surrounding chemical species into kinetic energy, enabling self-propulsion. The results demonstrated the remarkable advantages of the movement, including enhanced penetration in melanoma spheroids and improved therapeutic effect in a melanoma tumor model.

12:30 – 13:00 – Carla Perpiñà
Sex-Based Molecular Responses to Alcohol: Insights from Integrated Lipidomic and Transcriptomic Profiling from the Plasma Secretome

Abstract: Sex influences the biological response to alcohol at multiple molecular levels. In this talk, I will present findings from my PhD project, which integrates lipidomic and miRNA analyses of plasma extracellular vesicles to study the effects of binge drinking and alcohol use disorder (AUD) in both humans and mouse models (WT and TLR4-KO), with a particular focus on sex differences. Our principal findings in humans with AUD reveal sex-specific molecular signatures associated with neuroinflammation, hepatotoxicity, and cancer-related pathways. In females, we observed alterations in lysophosphatidylcholine/phosphatidylcholine ratios and increased phospholipase activity, suggesting enhanced neuroinflammatory and oncogenic signaling. In contrast, males exhibited disruptions in sphingomyelin metabolism, pointing to hepatotoxic effects. Functional miRNA analyses further highlight sex-divergent regulation of gene expression, protein turnover, vesicle trafficking, and neuronal structure. Additionally, integrative multi-omic analysis revealed that both alcohol exposure and sex significantly contribute to the observed molecular variance. This multi-omic approach uncovers novel sex-dependent biomarkers and mechanisms, offering new insights into the molecular basis of alcohol-related disorders.

Avances Preclínicos en Gotas Oculares para el Tratamiento de la Retinosis Pigmentaria

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Title: Study of molecular bases behind sex differences in non-alcoholic fatty liver disease and multiple sclerosis through transcriptomic meta-analysis

Autor: Francisco Català Senent
Directors: Francisco García García & Marta R. Hidalgo

Abstract: Sex differences in health are one of the primary biases in medicine today. Traditionally, males have been used as models in research and medicine, ignoring the fact that the development, symptoms, and response to a pathology are not necessarily the same in both sexes. Fortunately, in recent decades, researchers and institutions have made significant advances to reduce this bias, with the aim of providing more efficient treatment of diseases.

In this context, this doctoral thesis has contributed in reducing sex bias in medicine by studying the molecular basis of sex-related alterations in two diseases with a significant impact on the population: non-alcoholic fatty liver disease (NAFLD) and multiple sclerosis (MS). NAFLD comprises a range of liver disorders that begin with an accumulation of fat in the hepatocytes (NAFL) and progress to the development of inflammation (NASH), which can lead to loss of liver function and cancer. The latest studies estimate the overall prevalence of the disease at around 30% (with an upward trend), being higher in men (40%) than in women (26%). Among women, a lower prevalence is observed in premenopausal women, while after menopause, it is equal to that of men. This high prevalence of the pathology makes NAFLD a worldwide problem and the most common liver disease in developed countries.

On the other hand, MS is a chronic autoimmune, inflammatory, and degenerative disease of the central nervous system. This pathology presents different forms and stages and can, in the most severe cases, seriously affect the quality of life of those who suffer from it. As is usual in neurodegenerative diseases, MS is more prevalent in women than in men and is mainly diagnosed in young adults.

In the NAFLD work, 7 studies, including 323 patients, were selected from the 114 baseline work. Meta-analyses identified molecular mechanisms significantly overexpressed in premenopausal women versus men, including processes associated with DNA regulation, vinculin binding, responses to interleukin-2 (IL-2), negative regulation of neuronal death, and ion and cation transport. In males, we discovered an overrepresentation of genes associated with negative regulation of interleukin-6 (IL-6) and the establishment of planar polarity involved in neural tube closure. The differences in immune response observed between premenopausal men and women in the transition from NAFL to NASH suggest the role of IL-2 and IL-6 in the differential progression of NAFLD as a function of sex.

On the other hand, in the chapter on MS, 122 publications were reviewed, of which 9 met the defined criteria. These 9 studies (5 of blood samples and 4 of brain tissue samples) included 474 individuals. The blood and brain tissue meta-analyses identified, respectively, 1 and 13 MS-associated genes altered differently between men and women. In the case of functional analyses in the brain, sex-associated immune patterns were detected, among others. Women were more affected in the proinflammatory environment and innate immune responses related to the myeloid lineage, whereas adaptive responses were more affected in men.

Overall, the results of this dissertation reaffirm the usefulness of the systematic review and meta-analysis strategy as a tool for the reuse of openly published data. In this case, the application of this methodology has allowed us to detect a set of molecular alterations affected differently between women and men in both non-alcoholic fatty liver disease and multiple sclerosis. Particularly noteworthy is the presence of changes associated with interleukins 2 and 6 in both diseases, which highlights the role that the immune system plays in sex-associated alterations. The results of this work open the door to further research to translate these results into clinical practice.

12:30 – Konstantin Mineev

Institute for Organic Chemistry and Chemical Biology, Center for Biomolecular Magnetic Resonance (BMRZ), Johann Wolfgang Goethe University, Frankfurt/Main, Germ

Speaker: José Manuel García Aznar
Aragon Institute of Engineering Research (I3A)
Department of Mechanical Engineering
University of Zaragoza

Role of the mechanical microenvironment in tumor growth and immunotherapy: from microfluidic-based cultures to computational simulations

Abstract: Mechanobiology is a field of science that aims to understand how mechanics regulate biology. It focuses on how mechanical forces and alterations in mechanical properties of cell or tissues regulate biological processes in development, physiology and disease. In fact, all these processes occur in our body, which presents a clear structural and hierarchical organization that goes from the organism to the cellular level. To advance in the understanding of all these processes at different scales requires the use of simplified representations of our body, which is normally known as modelling or equivalently the creation of a model. Different types of models can be found in the literature: in-vitro, in-vivo and in-silico models.

Here, I will present our modelling strategy in which we integrate different mathematical models and in-vitro experiments in order to tackle relevant mechanical-based mechanisms in tumor growth and immunotherapy [1,2].

Due to the complexity of all these mechanisms, mathematical modelling is a relevant tool for providing deeper insight and quantitative predictions of the mechanical interplay between cells and extracellular matrix during cell migration and tumour growth. To assess the predictive capacity of these models, we will compare our numerical results with microfluidic-based experiments [2,3], which provide experimental information to test and refine the main assumptions of our models. Actually, we design and fabricate multi-channel 3D microfluidics cell culture chips, which allow recreating the tumour micro-environment by means of developing tumour organoids [4]. Therefore, this kind of organ-on-a-chip experiments constitutes a novel modelling strategy of in vitro multicellular human systems that in combination with mathematical simulations provide a relevant tool for research in mechanobiology.

In the presentation I will focus on showing our more recent findings about how matrix mechanics is regulating the size and organization of tumour organoids [5].

References

1. Hervas-Raluy, S., Wirthl, B., Guerrero, P. E., Rei, G. R., Nitzler, J., Coronado, E., … & Wall, W. A. (2023). Tumour growth: An approach to calibrate parameters of a multiphase porous media model based on in vitro observations of Neuroblastoma spheroid growth in a hydrogel microenvironment. Computers in Biology and Medicine, 159, 106895.
2. Gonçalves, I. G., & Garcia-Aznar, J. M. (2021). Extracellular matrix density regulates the formation of tumour spheroids through cell migration. PLoS computational biology, 17(2), e1008764.
3. Plou, J., Juste-Lanas, Y., Olivares, V., Del Amo, C., Borau, C., & García-Aznar, J. M. (2018). From individual to collective 3D cancer dissemination: roles of collagen concentration and TGF-β. Scientific reports, 8(1), 12723.
4. Hernández-Hatibi, S., Borau, C., Martínez-Bosch, N., Navarro, P., García-Aznar, J. M., & Guerrero, P. E. (2025). Quantitative characterization of the 3D self-organization of PDAC tumor spheroids reveals cell type and matrix dependence through advanced microscopy analysis. APL bioengineering, 9(1).
5. Camacho-Gomez, D., Sorzabal-Bellido, I., Ortiz-de-Solorzano, C., Garcia-Aznar, J. M., & Gomez-Benito, M. J. (2023). A hybrid physics-based and data-driven framework for cellular biological systems: Application to the morphogenesis of organoids. Iscience, 26(7).

Speaker: Dr. Mark Alkema
University of Massachusetts

The extended phenotype: Diet, Microbiome and Behavior

Abstract: