Speaker: Prof. Jochen Prehn
Institution: Centre for Systems Medicine Dublin, Ireland
Place: Salón de Actos Jerónimo Forteza CIPF

TITLE: Bugs, Fungi and Cells in Cells – the weird side of colorectal cancer and tumour progression

Abstract: My talk will focus on two new aspects of cancer biology and tumour progression in the setting of colorectal cancer: the role of the microbiome and the role of cell dynamics and formation of cell-in-cell structures.

Entosis is a form of non-phagocytic cell-in-cell (CIC) interaction where a living cell enters into another. Tumours show evidence of entosis, however factors controlling entosis remain to be elucidated.  I will present data showing that death receptor activation is a potent induces of entosis in colon cancer cells.  Induction of entosis and apoptosis by an activation of death receptors by ligands such as TRAIL occurred simultaneously and required the presence of caspase-8. Analysis of colorectal cancer tumours showed a significant association between expression levels of TRAIL and CICs. Notably, the presence of CICs in the invasive front regions of colorectal tumors was significantly correlated with adverse patient prognosis.

Dysbiosis of the microbiome has also been implicated in colorectal cancer (CRC) development, progression and response to therapy. Fusobacterium nucleatum (Fn), a commensal Gram-negative anaerobe from the Fusobacteriales order, is an onco-bacterium in CRC as a causal relationship between Fn prevalence and CRC pathogenesis, progression and treatment response has been reported in vivo. We showed that Fn/Fusobacteriales prevalence is associated with immune involvement (decrease in macrophages M1 and increase in macrophages M2) and activation of specific signalling programs (inflammation, DNA damage, WNT, metastasis, proliferation, cell cycle) in the host tumours, and is prognostic in particular in mesenchymal CRC tumors. We also systematically investigated alterations in the bacteriome and mycobiome of CRC patients in tumours and matched adjacent mucosa resulting in the identification of microbiome-based subtypes associated with host clinico-pathological and molecular characteristics. Tumours and adjacent mucosa samples were classified into 4 microbial subtypes, termed C1 to C4, based on the bacteriome and mycobiome composition. Microbial subtypes were associated with distinct tumour and patient phenotypes including T stage, tumour location, history of colon polyps and other malignancies, age, lymphovascular invasion and p53 status and disease-free survival.

Myelin regeneration: from gene therapy to energy metabolism

Speaker: Dr. Vanja Tepavcevic
Institution: Departamento de Neurociencias, Facultad de Medicina y Enfermería, Universidad del País Vasco. Leioa, Spain
Place: CIPF conference room

Abstract: Multiple sclerosis (MS), a chronic demyelinating disease of the central nervous system (CNS), is the leading cause of acquired neurological disability in young adults. Current treatments are immunomodulatory and provide temporary relief during relapses, but mostly lack an effect on disability progression, caused by axonal degeneration. Remyelination (myelin repair) of demyelinated axons reduces axonal degeneration in mice and patients, but this process eventually fails with disease progression. Thus, promoting remyelination in MS is a potential therapeutic strategy to prevent irreversible neurological deficits. So far, the search for pro-remyelinating agents has focused primarily on compounds that promote differentiation of oligodendrocyte progenitor cells (OPCs), the remyelinating cells of the CNS, thus generation of new oligodendrocytes. Yet, clinical trials performed have shown modest functional benefits and scarce impact on the clinical outcome. In this talk, I will we argue that achieving clinical benefits in patients with MS will likely require complementary/alternative approaches to stimulate remyelination. I will present our recently published data on gene therapy as a therapeutically relevant strategy for stimulating OPC repopulation of demyelinating lesions that, as I will show, fails in the disease. Then, I will present our ongoing work based on the hypothesis that remyelination in MS fails due to metabolic deficit that prevents OPCs from synthesizing new myelin.

12:00 – 12:30 Gergana Mincheva

Extracellular vesicles from mesenchymal stem cells reverse neuroinflammation and cognitive and motor impairment in rats with mild liver damage

Cirrhotic patients may develop minimal hepatic encephalopathy (MHE), with mild cognitive impairment, psychomotor slowing and motor incoordination. Human mesenchymal stem cells derived extracellular vesicles (MSC-EVs) have been proposed as therapy for different diseases due to their immunomodulatory, anti-inflammatory and regenerative properties. The aim of this study was to assess if MSC-EVs reverse cognitive and motor impairment in rats with mild liver damage and identifying the underlying mechanisms. Mild liver damage was induced by intraperitoneal injection of CCl4 during four weeks. MSC-EVs were isolated from human adipose tissue-derived stem and were injected intravenously. We assessed cognitive and motor impairment with different behavioral tests, neuroinflammation and neurotransmission alterations were assessed by immunohistochemistry and Western Blot. MSC-EVs injected intravenously reduce neuroinflammation in hippocampus and cerebellum and reverse cognitive and motor impairment in rats with mid liver damage. This suggests that MSC-EVs are a promising therapy which could be used to improve MHE and the quality of life in cirrhotic patients.

12:30 – 13:00 Irene Soler

Unveiling transcriptomic sex differences of multiple sclerosis: an in silico atlas across cell types analysing scRNA-seq and snRNA-seq data

 Multiple sclerosis (MS) is the leading cause of nontraumatic disability in young adults. Its major hallmark is myelin damage in the central nervous system, resulting in chronic neuroinflammation and neurodegeneration. Sex differences in the incidence, prevalence, disease progression, symptom variability, and response to treatment of MS have been reported. However, the molecular mechanisms underlying these differences remain poorly understood. The aim of this work is to exhaustively characterize sex bias in MS by cell type. To this end, we performed an in silico analysis of scRNA-seq and snRNA-seq data using the R programming language. First, we performed a systematic review in public repositories following the PRISMA guidelines. Three datasets were identified, each representing a different MS subtype. Then, we processed each selected dataset independently. After the annotation of the different cell types, all of them were fully characterized with the following analyses: differential gene expression, functional profiling, signaling pathways and cell-cell communication. In this seminar, we will focus on the secondary progressive MS subtype in nervous tissue, where the results obtained for astrocytes, microglia, neurons, oligodendrocytes, and oligodendrocyte precursor cells will be addressed

Thesis Title: Development of analytical procedures for the characterization of polypeptide-based nanoconjugates

Author: Snežana Đorđević

Supervisor: Prof. María J. Vicent

Tutor: Prof. Ramon Martínez-Máñez

Abstract: 

Due to the (poly)ionic and proteinic nature of polypeptide-drug conjugates (PDCs), their translation “from bench to bedside” represents a complex and expensive undertaking, requiring reproducible and scalable polymerization techniques, the implementation of sophisticated analytical tools, exhaustive characterization steps, and the collection of detailed safety and efficacy data.

Classical techniques, such as liquid chromatography (LC) – UV/Vis and size exclusion chromatography (SEC) implemented in the quality control of PDCs during and after synthesis, cannot always support a qualitative and quantitative analysis of degradation products and metabolites. As an alternative, mass spectrometry (MS) and asymmetric flow field flow fractionation (AF4) have grown in influence on polypeptide and PDC characterization. The analysis of drug and degradation products/metabolites can take advantage of LC when coupled to MS. Meanwhile, AF4-mediated separation does not suffer from problems related to the interaction of the analyte with the column like in SEC; instead, AF4 applies a cross flow in an empty channel, which supports the “tailor-made” separation of molecules according to size and molecular weight.

The research included in this Ph.D. thesis focuses on developing new analytical procedures that will aid the selection of PDC candidates for further preclinical studies. We implemented an artificial intelligence tool (design of experiments) to develop analytical methods and optimize the synthesis of genipin-crosslinked PDCs. Moreover, we explored relatively new techniques, such as AF4 and mass spectrometry imaging, in developing novel single and combination PDCs and studying their biological fate in the search for efficient therapies for a range of diseases (advanced solid tumors, including triple negative breast, prostate, and pancreatic cancer, as well as spinal cord injury).

12:00 – 12:30 Milagros Buffa

Targeting MCL-1 and BOK Interaction: Hit Compound Optimization and Mechanistic Insights for Cancer Therapy

Finding new cancer therapies is critical to improve treatment options and increasing patient survival. Dr. Mar Orzaez’s laboratory has discovered a hit compound for a new therapeutic target. In the outer mitochondrial membrane, induced myeloid leukemia cell differentiation protein (MCL1) and BCL2-related ovarian killer (BOK) interact through their transmembrane domains. Our hit compound, MBoIN 179, disrupts this interaction and releases BOK to induce cell death. To optimize the structure of our compound and learn more about its mechanism of action, we are performing several structural studies. Additionally, as a high overexpression of MCL-1 has been observed in lung tumours, we are performing functional experiments on 2D and 3D lung cancer models with our hit compound, to highlight the potential cell death effect of MBoIN 179.