Research areas & fellows

Name: Joana Castro

Nationality: Portuguese

Academic Background: MSc in Cellular and Molecular Biology and BSc in Biology, University of Porto

Project Title: Deciphering the molecular mechanisms of desmoplastic stromal reaction in solid tumours

Project Background: A Disintegrin And Metalloproteinase Domain 12 (ADAM12) is a member of the ADAM family, participating as both proteases and signaling mediators to control cell fate. This protein has been shown to be upregulated in a variety of solid tumours specifically in the cancer cells, in tumour tissue from breast cancer patients, and to be an indicator of disease stage. The mechanisms underlying ADAM12-mediated cancer progression are not fully understood. Previous results in our lab have shown a stimulatory effect of ADAM12 on both primary tumour growth and metastasis in breast cancer models in mice. Thus, we hypothesize that ADAM12, whether expressed on the cancer cell surface or released into the tumor microenvironment (TME), cleaves pro-tumorigenic molecules, such as the ECM remodelling protein Basigin, and mediates cancer-associated fibroblast (CAF) activation, thus increasing ECM deposition and aiding cancer progression. We hypothesize that the CAFs in the TME are activated by ADAM12 derived from cancer cells, resulting in excessive ECM deposition (desmoplasia) that can be addressed therapeutically to improve cancer therapy effectiveness.

Project Aim:   In this study we aim  to evaluate the therapeutic significance of ADAM12-associated ECM deposition in breast, pancreatic and colorectal cancer patients, as well as to unravel the molecular mechanism by which cancer cell-derived ADAM12 activates the tumor stroma and promotes ECM production. With the overall goal to identify new strategies to limit the desmoplastic response as a way to improve cancer treatments, we aim to investigate the clinical impact of ADAM12-associated ECM deposition in cancer patients, to reveal the causative link between ADAM12 expression and excessive ECM deposition, and to identify ADAM12-dependent paracrine mediators of CAF activation, using in vitro co-culture assays. The overarching objective is to find novel ways to inhibit the desmoplastic response and hence enhance cancer therapies.

Expected Outcome:  The expected outcome of this project is to further consolidate the finding of a strong correlation between ADAM12 and desmoplasia. Moreover, we predict that the ADAM12-associated ECM content will exhibit a significant correlation to the clinical outcome of breast and/or colorectal cancer patients. Furthermore, we expect to reveal specific ADAM12-dependent changes in ECM expression, spatial distribution and/or structure, as well as changes in the CAF population and infiltration of various immune cells. Lastly, we hope to determine the mechanism whereby cancer cell-derived ADAM12 activates fibroblasts in the TME, including identification of one or more soluble factors that mediate the paracrine activation signal.

 Contact: joana.castro@bric.ku.dk

Name: Sanasadat Pourtabatabaei

Nationality: Iranian

Academic Background: Direct M.Sc. degree in Medical Biotechnology, University of Tehran

Project Title: Identifying and investigating the role of ribosome heterogeneity in pancreatic cancer

Project Background: The crucial complex of ribosomal RNAs (rRNA) and ribosomal proteins known as ribosome is responsible for translating genetic material into proteins. Ribosomes were thought to be housekeeping structures incapable of differentiating between various mRNAs. However, recent research from the Lund lab and others revealed that ribosomes have distinct compositions and modifications both at the protein and rRNA modification level, leading to the creation of ribosome subtypes (ribosome heterogeneity). The idea that ribosome subtypes offer an extra level of regulation to precisely control gene expression was strongly reinforced by subsequent research from the Lund group. Ribosomes' functional specialization is still being studied, therefore there is still much to learn about their functions in many biological circumstances, diseases, and the specific mechanisms that underlie them.

Project Aim: In this project, I will focus on translation in pancreatic cancer as one of the deadliest malignancies and a significant unresolved health issue. The main goal would be identifying ribosome heterogeneity and observing its effects on pancreatic ductal adenocarcinoma (PDAC) by focusing on alterations in rRNAs and ribosomal proteins. My hypothesis is that specialized ribosomes, with specific compositions and modifications at the protein and RNA levels, are positively chosen for translating mRNAs which promote pancreatic cancer. The project aims to characterize ribosome heterogeneity in pancreatic cancer. Specifically:

• How do ribosomes change in pancreas cells during pancreatitis and pancreatic ductal adenocarcinoma (PDAC) progression?
• Do different rRNA 2’-O-Me patterns and ribosomal protein heterogeneity exist, and how do they impact inflammation and tumorigenesis in the pancreas?

Expected Outcome: Based on the starting hypothesis, the expected observation is to detect significant effects of 2’-O-methylation of rRNAs and differential association of proteins to the core ribosome in pancreas tumorigenesis. These expected results would add to the knowledge of cancer- specific ribosomes in pancreatic cancer. This knowledge could be helpful for the development of new cancer prognostics and therapies.

Contact: sana.pourtabatabaei@bric.ku.dk

Name: Phan Thu Han Le

Nationality: Vietnam

Academic Background: Pharmacist, M.Sc. of Pharmacy

Project Title: The role of N-WASP and its hotspot mutations in cancer

Project Background: N-WASP is a multi-domain molecule present both in the cytoplasm and in the nucleus which can promote actin polymerization, but probably also has actin-independent effects (Alekhina et al., 2017). Several published studies suggested a cancer-promoting role of N-WASP in intravasation, invasion, and metastasis (Gligorijevic et al., 2012; Hou et al., 2017). However, the loss of N-WASP in a mouse model for colon cancer led to complex responses (Morris et al., 2018). In mice with a keratinocyte-restricted knock-out of N-WASP, hardly any tumor formed and N-WASP deficient keratinocytes showed premature senescence in vitro. This effect correlated with the complex formation of nuclear N-WASP with the DNA methyltransferase DNMT1 and with the histone methyltransferases G9a and GLP, resulting in epigenetic suppression of the expression of the cell cycle inhibitor CDKN2A (Li et al., 2019; Li et al., 2018). These data indicated for the first time a cancer-relevant role for nuclear N-WASP.

Cancer is caused by copy number alterations and point mutations of driver genes resulting in cancer-promoting effects such as increased proliferation, impaired DNA repair, and evasion of anti-tumor immune surveillance. Based on earlier studies by our group and others and in silico analysis of more than 10 000 cancer genomes provided by the Cancer Genome Atlas (TCGA) we propose that hotspot mutations in N-WASP (gene name: WASL) have an oncogenic function in different malignancies

Project Aim:  The aim of my project is to validate the cancer-promoting role of N-WASP hotspot mutations, to identify corresponding effector molecules, and to test the anticancer effect of an N-WASP inhibitor.

Expected Outcome:  We expect to identify novel drug targets for personalized therapy of cancer patients carrying N-WASP hotspot mutations.

Contact: thu.lephan@bric.ku.dk

Name: Yen Thi Kim Nguyen

Nationality: Vietnamese

Academic Background: M.Sc. in Cancer Biology

Project Title: Phosphoproteome profiling for personalized leukemia therapy  

Project Background: More than 75% of patients with Acute Myeloid Leukemia (AML) die within 5 years of diagnosis, primarily due to relapse and primary resistance toward current standard ChemoTherapy (CT) regimens including anti-metabolic and DNA damaging drugs. AML emerges through accumulation of genetic mutations including a few drivers that confer aberrant “oncogenic” activity of signaling and DNA Damage Response (DDR) pathways causally involved in malignant transformation and resistance toward CT. Consistently, clinical studies have demonstrated that cancer and AML patients, can be re-sensitized to CT by targeted inhibition of aberrantly activated signaling and DDR pathways. Although comprehensive genomics studies of large AML cohorts have identified novel therapeutic targets, these rarely identify the complete spectrum of druggable signaling and DDR molecules in AML patients, and have only led to approval of very few targeted therapies for AML treatment during the last decade. Hence, there is an unmet need to implement novel complementary diagnostic tools in the clinic to advance personalized therapeutic targeting of pathognomonic signaling and DDR molecules alone or in combination with conventional therapeutic regimens.

Project Aim: We aim to change the paradigm of explicit genomics-based AML diagnostics to an in-depth functional approach of combined genomics and Mass Spectrometry-based PhosphoProteomics (MS-PP) diagnostics. This novel approach is predicted to identify a broad spectrum of relevant druggable key signaling and DDR molecules that can be targeted by small molecule inhibitors to enhance CT efficacy, and ultimately improve clinical outcome of AML patients.

Expected Outcome:  We will explore the potential of our existing MS-PP platform in a clinical setting for guided therapeutic targeting of oncogenic signaling and DNA damage response pathways in AML patients in combination with CT. This is expected to identify novel complementary drugs for personalized AML treatment, which can potentiate CT response, overcome CT resistance, and ultimately improve clinical outcome of AML patients as well as patients suffering from other cancer entities. Following the successful implementation and validation of the MS-PP platform, we plan to apply for additional funding to explore the full potential of our MS-PP platform to guide personalized combination therapies for relapsed/refractory AML patients in a future clinical trial at Rigshospitalet in collaboration with national and international AML centers.

Contact: yen.nguyen@bric.ku.dk

Name: Virág Gehl

Nationality: Hungarian

Academic Background: Bachelor of Science in Microbiology and Genetics (University of Vienna), Master of Science in Molecular Medicine (University of Vienna)

Project Title: Impact of IL-6 activation on tumour behaviour and therapeutic sensitivities in bile duct cancer

Project Background: Cholangiocarcinoma (CCA) is the second most common primary liver cancer arising from the hepatobiliary epithelia along the biliary tract. There is a tendency to increased incidence rates however, the reasons behind this are not clarified. Patients are often diagnosed at a late stage, as the tumour is already advanced or metastatic when surgical removal is not an option anymore. Palliative treatment is the standard-of-care for patients with unresectable tumours and some of the recurrent genomic alterations can be targeted specifically. However, resistance to chemotherapies and targeted therapies invariably arise.

There are different types of CCA tumours depending on their anatomical location; intrahepatic CCA (iCCA) and extrahepatic CCA (eCCA). iCCA is located inside the liver and it is associated with worse prognosis compared to the extrahepatic subtype. iCCA is driven by genetic and epigenetic alterations nevertheless, the liver provides a unique, often inflamed, milieu that further promotes the progression of the disease. In this dense desmoplastic tumor microenvironment the cytokine signalling networks are often deregulated and the interactions between the tumor and immune cells are altered. Elevated levels of the proinflammatory cytokine, interleukin-6 (IL-6) are associated with low overall survival, providing prognostic information. In addition, blocking IL-6 signalling increases the efficacy of chemotherapy in iCCA xenograft models.

Although, high inter- and intracellular IL-6 levels correspond to poor prognosis, it remains unresolved how exactly IL-6 activity impacts the biology of tumour cells, contributing to disease progression. I hypothesize that chronic IL-6 signalling results in transcriptional reprogramming in tumour cells, promotes resistance to chemotherapy but also leads to new vulnerabilities that can be therapeutically exploited. 

Project Aim: Firstly, I will characterize the biological consequences of constitutive IL-6 signalling in iCCA by generating cell line models using CRISPR/Cas9. Then, I aim to identify targetable vulnerabilities acquired following IL-6 activation in iCCA by performing high-throughput drug screens. Lastly, I will investigate the impact of IL-6 signalling on tumour immunity and treatment response in iCCA by looking at samples from patients that underwent chemotherapy.

Expected Outcome: This project will provide novel insights into the underlying molecular mechanisms of IL-6-mediated tumour progression. The clinical relevance is ensured through applying primary patient-derived cell lines, tissue and blood samples and large clinical patient data sets to investigate the molecular and cellular consequences of active IL-6 signalling. This combined approach of experimental laboratory techniques and computational analyses will advance our understanding of tissue and systemic immunity in iCCA and help to identify new therapeutic approaches for iCCA.

Contact: virag.gehl@bric.ku.dk

Name: Xian Xin

Nationality: Chinese

Academic Background: Bachelor of Science in Biological Science at Huazhong Agricultural University, China; Master of Science in Bioinformatics at Lund University, Sweden

Project Title: Investigation of mechanisms of epileptogenesis: integration of single cell omics from multiple animal models and human patients

Project Background: Neurodevelopmental brain disorders, such as schizophrenia (SZ), epilepsy (EP) and others, are one of the most frequent causes of patient disability and pose an enormous burden to the society. In most cases, the mechanisms how a neurodevelopmental disorder arises are unknown and furthermore current patient treatment procedures are very general affecting whole brain function and thus leading to a number of severe side effects. Substantial evidence shows that in many neurodevelopmental disorders certain types of neurons are more vulnerable than others, and that in a given brain disorder only particular neuronal subtypes exhibit signs of pathogenesis that might contribute to cognitive abnormalities. These data are supported by extensive research in animal disease models demonstrating that functional impairment of few neuronal subtypes can lead to disorganization of local neuronal circuits and underlie behavioral abnormalities, e.g. in SZ or developmental EP, including Khodosevich group’s own recent data showing that vulnerability of neuronal subtypes depends on the time of developmental insults.

In order to treat a disease, we need to understand what kind of cells become unhealthy, those cells that trigger the disease and how each cell type contributes to disease etiology and heterogeneity. Due to technology development last few years, all of these questions can be addressed by single cell omics approaches, including single cell transcriptomics, epigenomics, genomics and proteomics. Single cell technologies provide information in single (e.g. RNA) or multiple (e.g. RNA + open chromatin + protein) modalities for each cell in a complex tissue/organ. Thus, single cell technologies are powerful tools to study disease etiology and identify new targets for treatment and diagnostics.

Project Aim: The aim of this PhD project is to identify changes in gene expression and cell composition in cell-type- and region-specific transcriptomic and epigenetic data for mouse models and post-mortem human samples of SZ and EP, and to associate results with the physiological phenotypic data.

Expected Outcome:  We will determine differences in single-cell transcriptome, open chromatin, and/or proteome data that are associated with neurodevelopmental disorders. These data will be used to identify those type(s) of cells and gene(s)/pathway(s) that contribute to neurodevelopmental disorders, which will finally be translated into new intervention strategies.

Contact: (email) xian.xin@bric.ku.dk

Name: Zala Zebec

Nationality: Slovenian

Academic Background: MSci in Neuroscience at University of Glasgow, with research placement year at the Institute of Clinical Neuroimmunology, LMU Klinikum, Munich.

Project Title: The role of IFNb-IFNAR signalling in Neuromyelitis Optica

Project Background: The focus of our group is neuroinflammation and investigating the role of traditionally immune genes in neuronal cells both under physiological conditions and in the context of neurodegenerative and autoimmune disease. Autoimmune disease is characterized by a failure of the immune system to recognize its own constituents as “self”, which allows an immune response against its own cells and tissues. Autoimmune diseases affect around 10% of the population and due to its chronic nature present a huge socioeconomic burden. Understanding the molecular mechanisms that lead to the mounting of an immune attack against “self”, is essential for the development of effective and safe therapeutics.

Neuromyelitis Optica (NMO) or Devic’s Syndrome, is a debilitating demyelinating disease of autoimmune origin. It is characterized by the presence of an autoantibody against a water channel – AQP4, expressed by the support cells of the brain – astrocytes. Without treatment, within 5 years, over 50% of the patients become blind and wheelchair bound, while 30% die. NMO shares many clinical features with multiple sclerosis (MS), however MS treatments have been shown to be ineffective or in some cases detrimental in NMO. Currently, NMO is mainly treated by general immunosuppressive drugs and plasma transfer. In contrast to patients with MS, IFNβ treatment is ineffective in NMO patients, yet the molecular basis of the distinct response in these two related autoimmune demyelinating diseases, remains to be fully elucidated. Improved understanding of molecular mechanisms that drive the autoimmune response against AQP4 is thus crucial for development of safer and more effective treatment options for NMO.

Project Aim: The overreaching aim of the project is to characterize the role of IFNβ-IFNAR signalling in molecular pathology of NMO by establishing novel disease models. Specifically, we aim to elucidate the molecular pathways that link IFNβ-IFNAR signalling and astrocyte homeostasis. Thereby, we hope to improve our understanding of NMO pathogenesis and identify new, highly specific therapeutic targets.

Expected Outcome: We expect to define the molecular pathways that links IFNβ-IFNAR signalling and AQP4 autoimmunity. Furthermore, we expect to elucidate how, why, and where the autoimmune response against AQP4 is mounted. Finally, we hope to translate our findings to humans, by examining whether our newly identified pathways are of relevance in patients and could therefore be used as novel therapeutic targets.

Contact: zala.zebec@bric.ku.dk