Research Group Molecular Disease Mechanisms

Research at Molecular Disease Mechanisms Group

Understanding molecular mechanisms that govern cellular communication and signaling in the healthy organism as well as in pathological conditions, such as inflammation and cancer, is a prerequisite for the development of targeted therapeutic intervention. To this end, the MDM Group currently focuses on the molecular mechanisms that govern colorectal cancer and its resistance to therapies.

Molecular mechanisms involved in cancer development

Colorectal cancer (CRC) is one of the most frequent and deadly cancers in the western world with more than 1.2 million yearly diagnoses and approximately 600,000 deaths each year. Patient survival is largely dependent on early diagnosis and intervention. Accordingly, there is an urgent need for novel diagnostic parameters as well as molecular determinants of clinical outcome, which would allow for the targeted treatment of patients at risk of relapse. Especially in stage II patients, the identification of biomarkers predicting the recurrence of the disease is an unmet clinical need.

Understanding molecular mechanisms that govern cellular communication and signalling in the healthy organism as well as in pathological conditions, such as inflammation and cancer, is a prerequisite for the development of targeted therapeutic intervention. Currently, our group has a very profound interest in dissecting the different resistance mechanisms in CRC by focusing on metabolic changes in tumor cells and cell of the microenvironment (TME). We are especially interested in tumor-initiating cells (TICs), also called cancer stem cells as well as in the TME (stromal cells and microbiome). Over the last years, we have been successful in establishing primary TIC-enriched cultures as well as primary fibroblast cultures directly from patient tumor tissue. Furthermore, our group has recently established the so called “mini -guts” (or organoids) that represent a functional colon. These represent powerful tools to test for new CRC therapies.

Some of our projects

Current research activities conducted by the MDM group focus on the following research areas:

  • Role of microenvironment factors on colon cancer
  • Identification of biomarkers and therapeutic targets in colon cancer

  • Start date

    01/04/2021

  • Duration in months

    48

  • Funding

    FNR; The Vera Nijs and Jens Erik Rosborg Foundation (FVNJER) under the aegis of the Fondation de Luxembourg

  • Project Team

    MDM Group

  • Abstract

    This project investigates two different cancers in parallel: melanoma and colorectal cancer (CRC).
    The proposed project, which combines genetic analysis and personalized drug library screening, offers a unique setup where efficient but novel drugs or combinations can be found within weeks in a personalised way. Additionally, this project will lead to a better understanding of resistance mechanisms that occur in melanoma and CRC after standard and identified drug treatments. This knowledge may potentially help to select new drugs and drug combinations to overcome therapy resistance.
    Objective 1: Establishment of a semiautomated melanoma/CRC drug-testing pipeline for routine medium- to high-throughput drug testing (set up phase).
    Objective 2: Establishment of clinical reporting lines to benefit late stage melanoma and CRC patients (translational phase).
    Objective 3: Identification of deregulated transcriptional networks and molecular mechanisms involved in successful drug treatments and drug resistance (experimental phase).

  • Start date

    01/03/2022

  • Duration in months

    48

  • Funding

    FNR

  • Project Team

    MDM Group

  • Abstract

    As the third most common form of cancer, colorectal cancer (CRC) is a major healthcare challenge worldwide. While public colorectal cancer (CRC) screening campaigns have yielded great success by preventing disease development through removal of precancerous lesions, many patients are still left with few effective therapeutic options as they often present with an advanced disease stage at diagnosis. Indeed, over 50% of patients are diagnosed in stages III or IV. Immune checkpoint inhibitors are a class of drugs that has changed the way we treat many cancers, but unfortunately, they show little effectiveness for the majority of CRC patients. Indeed, CRC tumors are often described as immunologically cold, being unable to elicit and sustain effective immune responses.

    The complex interplay between the immune and stromal compartments of the tumor microenvironment (TME) play a key role in tumor development and the above-mentioned immune escape. Within the TME, a stromal cell type known as cancer associated fibroblasts (CAF) have been emerging as a key player in determining patient outcomes and therapeutic efficacy.

    There’s been a growing body of knowledge on the interactions between CAF and immune cells, with CAF being shown to have a profound effect on both the makeup and functional properties of the immune compartment in the TME.

    Type I interferons (IFN-I) are a family of cytokines that are known to have a multitude of immunomodulatory effects. In the tumour microenvironment, high levels of IFN-I are reported to favour the development of a tolerogenic niche, with IFN-I being reported to induce PD-L1 expression multiple TME cell types, as well as causing increased proliferation and maintenance of immunosuppressive regulatory T-cells. Sustained IFN-I signalling has been proposed as a resistance mechanism to PD-L1 blockade based immune checkpoint inhibition therapies. Recent in-vitro studies have further shown that blocking of IFN-I could eliminate CAF dependant chemoresistance in breast cancer, however in-vivo data and information on the impact of this pathway in CRC and immunotherapy are major unexplored areas with promising implications for future treatments.

    In single cell RNA sequencing datasets of patient-derived CRC tissue, we observed that cancer associated fibroblasts expressed significantly higher levels of IFN-I receptors and downstream targets then normal fibroblast from outside the cancer margin. Tumors expressing high levels of IFN-I showed significantly reduced overall survival and were associated with a tolerogenic immune signature. They presented elevated levels of M2 macrophage polarization, T-cell exhaustion and inhibitory checkpoint molecule PD-L1. Further in-vitro experiments showed that CAF increased their PD-L1 surface expression when treated with IFN-α. Based on the reported immunomodulatory functions of IFN-I in the TME and on the supporting preliminary findings discussed above, we would like to highlight IFN-I signalling in CAF as a major unexplored area with promising implications for improving treatment responses. By using a combination of innovative in-vitro an in-vivo techniques as well as our internal collection of patient CRC biospecimens, we will investigate how IFN-I sensitive CAF shape the tumor immune microenvironment and their effect on chemo- and immunotherapy resistance. First, we will further characterize IFN-I sensitive CAF through a combination of bioinformatic and molecular approaches, by identifying surface markers expression patterns and differentially expressed signalling pathways. Second, we will investigate the mechanisms by which IFN-I activated CAFs influence cancer and immune cells of the TME via a variety of advanced in-vitro proliferation, invasion and co-culture assays. Finally, we will validate our findings in in-vivo preclinical models of CRC using stromal specific knockouts of IFN-I receptors. Immune
    phenotyping and treatment response rates to common immuno- and chemotherapy treatment plans will give valuable insight as to the clinical potential of stromal directed therapies targeting IFN-I signalling.

  • Start date

    01/02/2023

  • Duration in months

    36

  • Funding

    FNR; Daiwa Pharmaceutical Co.

  • Project Team

    MDM Group

  • Abstract

    Immunotherapy, in particular immune checkpoint inhibitors (ICI), represent one of the major advances in oncology in the past decade. However, many cancer patients do not respond to ICI. Recently, the microbiome has been identified as a potential underlying cause for resistance to ICI. Thus, researchers are currently investigating different possibilities to harness the microbiome for the development of innovative strategies to improve the response rate to ICI.

    Diet is a known microbiome regulator and might therefore play a significant role in therapy efficiency, potentially via the modulation of the immune system. However, dietary guidelines are poorly implemented in today’s cancer treatment plans.

    Here we will test a dietary fiber compound, ImunoBran®, with the aim to better understand how dietary fiber modulates the microbiome and consequently immune cells during cancer progression. We will perform a clinical randomized cross-over study in cancer patients undergoing ICI, as well as use humanized mouse cancer models to study the effect of fiber supplementation on therapy efficacy and on the host-microbiome cross-talk, which might further drive immune cell activation.

    The integration of the omics data from the patients and mouse models will specifically identify bacterial species and metabolites driving the beneficial effects of dietary fiber. Additionally, these results might lead to the identification of novel microbiome-based regulators (probiotics) alone or in combination with food supplements including ImunoBran®, for the benefit of cancer patients.

    Altogether this project will identify new intervention points targeting the host-microbiome crosstalk and contribute to the establishment of dietary guidelines for patients undergoing anti-cancer treatments. Finally, as the first study of its kind in Luxembourg, this project will help establish important collaborations between researchers and clinicians to develop innovative microbiome-based strategies for the improvement of cancer treatments in the future.

  • Start date

    01/10/2022

  • Duration in months

    60

  • Funding

    Fondation Cancer;UL

  • Project Team

    MDM Group

  • Abstract

    Colorectal cancer (CRC) is one of the most common and lethal malignancies in Western countries. It is the most commonly diagnosed cancer in Europe and the second most common cause of cancer death. Estimates indicate that around 1.2 million European citizens currently are living with a diagnosis of CRC (Globocan). In Luxemburg, CRC has an incidence generally exceeding 500 cases per year (Publication Registre National Cancer 2013).

    The high incidence and mortality rates emphasize the need for prevention and early diagnosis. Biomedical research and precision medicine heavily rely on biospecimens to identify new therapeutic targets and biomarkers. Researchers need access to high-quality samples and consistent clinical and pathological information. In this context, the Molecular Disease Mechanisms Group at the University of Luxembourg has established an ongoing collection of tumor tissue samples from CRC patients, assembling over 160 high quality patient samples. This collection, initiated in 2010, has been achieved through the involvement of oncologists and surgeons from different hospitals in Luxembourg, nurses from the Clinical and Epidemiological Investigation Center (CIEC) at LIH, pathologists from the LNS as well as collection managers at the IBBL and researchers at the University of Luxembourg. This collection, which contains several sample types, such as serum, stool and tumor tissue and normal counterparts from the same patients, is available to all researchers and allows them to perform translational research. The will at the University of Luxembourg is to integrate this collection as a national CRC cohort in the PLAN CANCER. This collection is perfectly suited to represent a research cohort available for researchers in Luxembourg and abroad.

  • Start date

    01/06/2021

  • Duration in months

    36

  • Funding

    FNR

  • Project Team

    MDM Group

  • Abstract

    Globally, colorectal cancer (CRC) is the third leading cause of cancer-related death and incidence is still increasing (World Cancer Research Fund). Our gastrointestinal tract is home to hundreds of bacterial species, constituting the gut microbiome. Evidence suggests that a state of pathological imbalance in the microbiome is present in CRC patients. Several studies have identified specific species that are highly enriched in their tissues, stool and saliva.

    Thus, the gut microbiome may play an important role in CRC development and therapy resistance. However, regarding host-microbial interactions, few CRC-associated microbes have been studied, hence the role of bacteria in the etiology of the disease remains unknown. Treatments and diet are two main factors linked to microbial modulation in CRC. In this project, we will study tumor initiation and progression, host-microbiome interaction and the influence of diet on these processes both in vitro and in vivo. First, we will analyze microbiome composition and metabolites present in different sample types, such as stool, tumor tissue and paired control tissue samples from CRC patients in a Luxembourg cohort, in order to identify top CRC-associated bacteria and metabolites. This data will be integrated into in silico metabolic models, allowing us to understand the role of bacterial communities in CRC. We will then delve into the mechanisms by which the identified CRC-associated bacteria influence CRC development. We will use the HuMiX model as a controlled environment for our in vitro studies. We will further continue our investigations in vivo. Fecal samples from healthy individuals or CRC patients will be introduced into a mouse model of CRC. We will evaluate the influence of diet on the complex interplay between microbiome, metabolome and host in CRC. The results of this study will help in developing strategies to circumvent the harmful effects of CRC-associated bacteria, both on tumor initiation and development. Most importantly, we anticipate that this work will lead to the development of dietary guidelines for CRC patients during the progression of the disease.