Research Steven Van Laere

Abstract

Metastasis is the process by which cancer cells from a primary tumour can travel through the blood to other organs and form a second tumor. About one in four patients with colon cancer will experience metastases in the liver. All too often, patients die as a result of liver metastases. We do not yet know enough about how cancer cells form a metastasis in the liver. By looking at liver metastases with a microscope, we have observed that there are two patterns of tumour growth in the liver. We can determine these growth patterns when the metastatic lesion in the liver is removed by a surgeon and have found that one growth pattern is assocoated with a more favourable outcome for the patient when compred to the other. Although a colon cancer develops as a result of gene mutations, the behaviour of a tumour afterwards is controlled by additional changes within cancer cells that control how genes are turned on and off. We call these 'epigenetic' changes. We think the epigenetic characteristics of cancer cells that form the two distinct growth patterns of liver metastases are different. We will investigate this in liver metastases from patients with colorectal cancer. This will give us a better understanding of how the cancer cells are able to form a metastasis and thus allow us to think about treatments that are better adapted to each of the two growth patterns. This will eventually lead to a more effective treatment for patients with liver metastases.

Researcher(s)

• Promoter: Van Laere Steven

Research team(s)

• Center for Oncological Research (CORE)

Project website

Project type(s)

• Research Project

Abstract

Heart failure (HF) and cancer are the two most common causes of death. An increasing number of patients suffer from both diseases. In the past, their occurrence in the same patients was exclusively attributed to shared risk factors, e.g. smoking. Recent studies have demonstrated that HF directly stimulates cancer growth in different mouse models of HF and cancer, but the underlying mechanisms are incompletely understood. An important unanswered question is whether treating HF with available therapy affect cancer progression. First, I will test the effects of currently used HF treatments in a mouse model of HF and solid cancer. I expect that specific HF therapies will slow HF-enhanced cancer growth. Second, I will test the same treatments in a mouse model of HF and spontaneously metastatic cancer. The comparison of the effects of HF treatments on solid and metastatic tumors will help to test the central hypothesis; it will provide clinicians with useful insights to select therapies for their patients, but will also be relevant to individuate the pathways involved in HF-enhanced cancer growth. Third, I will perform single-nuclei RNA sequencing of both tumors and myocardium. These experiments will reveal the underlying mechanisms linking HF to cancer thanks to the identification of receptors present on both tissues. The ultimate goal would be the identification of novel therapeutic targets, potentially helping millions of patients.

Researcher(s)

• Promoter: Segers Vincent
• Co-promoter: De Keulenaer Gilles
• Co-promoter: Van Laere Steven
• Fellow: Civati Celine

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

Breast cancer is one of the deadliest cancers in women and especially the aggressive subtypes such as triple-negative breast cancer (TNBC) are difficult to treat. Although the immune system provides a natural barrier against invading and metastasizing breast tumor cells, it often fails to halt the disease progression due to immunosuppressive activity orchestrated by breast tumor cells and surrounding stromal cells. The protein chitinase 3-like 1 (CHI3L1) has been highlighted as a potential immunotherapeutic target in cancer due to its stimulation of immunosuppression and metastasis, but its role in breast cancer and more specifically TNBC, remains to be unraveled. This project will investigate the involvement of CHI3L1 signaling in TNBC progression, lymphatic development and dissemination as well as inflammation of triple-negative breast tumors using an in-house characterized immunocompetent intraductal mouse model and clinical samples from TNBC patients. We will also examine the therapeutic effect of CHI3L1 blockade and assess whether such inhibition synergistically enhances the clinical efficacy of immunotherapeutic treatments in TNBC. The results of this project will unequivocally demonstrate if CHI3L1 blockade can be used as an effective TNBC treatment strategy, potentially in combination with other immunotherapies, providing a response to the high clinical demand for better TNBC therapeutics.

Researcher(s)

• Promoter: Van Laere Steven
• Fellow: Steenbrugge Jonas

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Protein phosphorylation is a reversible post-translational modification playing a crucial role in controlling the functional state of proteins in health and disease. Profiling protein kinase activity has become a critical component in molecular clinical biology precision medicine and constitutes a promising tool for drug discovery. However, current strategies can monitor only single kinases or imply complex procedures and infrastructure difficulting their assessment. The PPES platform performs parallel measurement(s) of kinase activities by recording phosphorylation changes in real time, revealing a more realistic view of the cellular signalling states and molecular mechanisms operating in disease and drugs mode of action. The PPES service facility for Global Kinase Activity profiling (https://www.kinases-epigenetics-ppes.com/) uses the Pamstation-12 (PamGene NVA, Netherlands), a fully automated instrument designed to process peptide microarrays (pamchips). This technology allows simultaneous measurement of multiple kinase activities (either activation or inhibition) through highly sensitive monitoring of the phosphorylation dynamics of 144 peptide substrates by Serine/ Threonine or 196 for Tyrosine kinases, present in (clinical) biosamples of interest (cells, tissues, organoids, ipscs, patients biopts). Our group has gained unique expertise in the profiling of kinase activity in a wide range of biological samples, including cell lines (glioblastoma, pancreatic cancer, neuroblastoma, multiple myeloma, T-cell acute lymphoblastic leukaemia, breast cancer), cells and patient-derived xenografts, patient-derived organoids, mouse, and human tissue samples (brain and colon), and patients' liquid biopsies. Moreover, the platform allows the "pharmacology on-chip" evaluation of kinase inhibitors that, together with the new systems biology core integrating kinome data with other omics techniques (e.g. transcriptome, phospho-proteome and epigenome data), will narrow the bridge between disease and drug discovery strategies. Our technology can be applied in a wide spectrum of fundamental, translational, diagnostic, and clinical research: a) Find novel targets, determine activities of kinase inhibitor drugs or novel food ingredients, and elucidate their mechanisms of action, b) to determine the mode of action of pharmacological compounds, c) to perform target interaction/ engagement studies, d) for Enzymatic characterization of novel or mutated kinases. e) for the identification of substrates for novel, mutated or post-translationally modified kinases, f) for prognosis and resistance Biomarker discovery and g) or evaluation of pharmacological drug dosage or combination therapy. In the frame of the IOF-service platform, we will setup a collaborative service with synergistic Biotech and ICT services to boost the knowledge gain from the initial (already running) platform. We will offer the service to academic research groups, clinical research labs as well as, drug screening, pharma, and biotech companies.

Researcher(s)

• Promoter: Vanden Berghe Wim
• Co-promoter: Van Laere Steven

Research team(s)

• Proteinscience, proteomics and epigenetic signaling (PPES)

Project website

Project type(s)

• Research Project

Abstract

Cancer metastases is responsible for 90% of the cancer related deaths. Due to an increased knowledge of the biology of cancer, more patients are referred to targeted therapy. The efficacy of these drugs depends on the molecular characteristics of the cancer cells. In addition, recent research has shown that molecular characteristics of cancer cells can change during cancer progression and metastasis. Since it is practically difficult to sample metastatic tissue repeatedly, investigating alternative matrices is imperative, paving the way for liquid biopsies. One possibility is to evaluate the molecular characteristics of circulating tumor cells, obtained from peripheral blood. However, before these cells can be used as matrix for molecular diagnostics, is should be evaluated if these CTCs have the same characteristics as the primary or metastatic tumor cells. In addition, due to heterogeneity in the primary tumor/metastases, is should be evaluated how many CTCs need to be analyzed in order to capture the dominant driving clones. In order to evaluate this, genomic changes from CTCs will be compared to the genomic composition of the primary tumor and the metastases. If successful, this project will allow a translation of liquid biopsies from the bench to the bedside, sparing patients from difficult and painful treatments.

Researcher(s)

• Promoter: Van Laere Steven
• Co-promoter: Peeters Marc
• Fellow: Brouwer Aaltje

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

IBC is characterized by a rapid onset, redness and swelling of the breast. Despite an aggressive therapy with chemotherapeutics, radiation and surgery the survival rate is the worst among all breast cancers with less than 40 % survival after 5 years. Therefore, further research is necessary. Although IBC and non-IBC (nIBC) tumours are different diseases in many ways, our lab showed that genetically an IBC tumour and a nIBC tumour are not so different after all. Based on these findings we think that the non-cancerous cells that are part of the tumour or the patient's response to the tumour can explain the difference. Thus we are interested in how the surrounding tissue and especially the immune cells respond to IBC and how this is different from nIBC. To examine this we will start our research by determining what types of cells are present in both tumour types and whether they are functioning as they should be. By correlating the presence of certain cell types or functional markers with response to treatment, survival information and properties of the tumour we can see what type of cells or functional markers could predict prognosis or response to therapy and can be called biomarkers. Furthermore, the combination of this information with data about which genes in a tumour sample are over- or underexpressed could lead to a better understanding of the genetic pathways that are important in IBC growth. If we can alter these pathways, we might find new targets for therapy.

Researcher(s)

• Promoter: Van Dam Peter
• Co-promoter: Colpaert Cecile
• Co-promoter: Trinh Xuan Bich
• Co-promoter: Van Laere Steven
• Fellow: Van Berckelaer Christophe

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

A recent analysis of gene expression microarray data revealed that IBC is characterized by altered TGFbeta and immune signaling. In an independent analysis, we observed that IBC cell motility induced by TGFbeta is remarkably decreased as compared to subtype-matched non-IBC cells. RNA-sequencing demonstrated a particular role for SMAD3, MYC and YY1. Moreover, the roles of SMAD3 and MYC in IBC were confirmed on patient samples using an integrated analysis of gene and protein expression data. YY1 is a powerful transcriptional regulator that is able to repress SMAD3 and activate MYC. In addition, YY1 activity is associated with a type 2 polarized immune response that is characteristic for IBC. Therefore, we hypothesize that the immune response that characterizes IBC leads to YY1 activity, which in turn antagonizes SMAD3 signaling, blunting the TGFbeta response. In turn, a blunted TGFbeta response, leads to patterns of collective migration and formation of tumor emboli, which are typical for IBC. This hypothesis is central to the current research proposal.

Researcher(s)

• Promoter: Van Laere Steven
• Fellow: Rypens Charlotte

Research team(s)

Project type(s)

• Research Project

Abstract

Cancer metastases is responsible for 90% of the cancer related deaths. Due to an increased knowledge of the biology of cancer, more patients are referred to targeted therapy. The efficacy of these drugs depends on the molecular characteristics of the cancer cells. In addition, recent research has shown that molecular characteristics of cancer cells can change during cancer progression and metastasis. Since it is practically difficult to sample metastatic tissue repeatedly, investigating alternative matrices is imperative, paving the way for liquid biopsies. One possibility is to evaluate the molecular characteristics of circulating tumor cells, obtained from peripheral blood. However, before these cells can be used as matrix for molecular diagnostics, is should be evaluated if these CTCs have the same characteristics as the primary or metastatic tumor cells. In addition, due to heterogeneity in the primary tumor/metastases, is should be evaluated how many CTCs need to be analyzed in order to capture the dominant driving clones. In order to evaluate this, genomic changes from CTCs will be compared to the genomic composition of the primary tumor and the metastases. If successful, this project will allow a translation of liquid biopsies from the bench to the bedside, sparing patients from difficult and painful treatments.

Researcher(s)

• Promoter: Van Laere Steven
• Co-promoter: Peeters Marc
• Fellow: Brouwer Aaltje

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

IBC is characterized by a rapid onset, redness and swelling of the breast. Despite an aggressive therapy with chemotherapeutics, radiation and surgery the survival rate is the worst among all breast cancers with less than 40 % survival after 5 years. Therefore, further research is necessary. Although IBC and non-IBC (nIBC) tumours are different diseases in many ways, our lab showed that genetically an IBC tumour and a nIBC tumour are not so different after all. Based on these findings we think that the non-cancerous cells that are part of the tumour or the patient's response to the tumour can explain the difference. Thus we are interested in how the surrounding tissue and especially the immune cells respond to IBC and how this is different from nIBC. To examine this we will start our research by determining what types of cells are present in both tumour types and whether they are functioning as they should be. By correlating the presence of certain cell types or functional markers with response to treatment, survival information and properties of the tumour we can see what type of cells or functional markers could predict prognosis or response to therapy and can be called biomarkers. Furthermore, the combination of this information with data about which genes in a tumour sample are over- or underexpressed could lead to a better understanding of the genetic pathways that are important in IBC growth. If we can alter these pathways, we might find new targets for therapy.

Researcher(s)

• Promoter: Van Dam Peter
• Co-promoter: Van Laere Steven
• Fellow: Van Berckelaer Christophe

Research team(s)

Project type(s)

• Research Project

Abstract

Despite the discovery of promising targets for breast cancer treatment in preclinical models, the majority of new (immunomodulatory) drugs face inefficiencies and failures in clinical trials. The characterization of more relevant preclinical mouse models for the study of breast cancer growth and metastasis could alleviate this costly problem. Our research group has recently developed and characterized an innovative intraductal mouse model for breast cancer metastasis by injecting luminescent E-cadherin-positive triple-negative 4T1 cells intraductally in the mammary gland of lactating, immunocompetent and syngeneic mice. In the current project we aim to validate this model by comparing it with the classical fat pad model for breast cancer through elegant in vivo imaging techniques that allow visualization of tumor growth, metastasis and lymphatic dissemination. We will also study the immune response and tumor microenvironment in both preclinical models by investigating inflammatory immune cell influx (especially macrophages and neutrophils), analyzing cytokine and chemokine profiles, and performing immunohistochemical evaluation of immune response profiles. This approach will allow the identification of targets for immunotherapy in the biologically relevant intraductal model. The translation to the clinical setting will eventually be established through RNA-sequencing of mastectomized primary tumors from both mouse models and comparing the gene expression profiles with data from samples of breast cancer patients.

Researcher(s)

• Promoter: Van Laere Steven

Research team(s)

Project type(s)

• Research Project

Abstract

Cancer metastases is responsible for 90% of the cancer related deaths. Due to an increased knowledge of the biology of cancer, more patients are referred to targeted therapy. The efficacy of these drugs depends on the molecular characteristics of the cancer cells. In addition, recent research has shown that molecular characteristics of cancer cells can change during cancer progression and metastasis. Since it is practically difficult to sample metastatic tissue repeatedly, investigating alternative matrices is imperative, paving the way for liquid biopsies. One possibility is to evaluate the molecular characteristics of circulating tumor cells, obtained from peripheral blood. However, before these cells can be used as matrix for molecular diagnostics, is should be evaluated if these CTCs have the same characteristics as the primary or metastatic tumor cells. In addition, due to heterogeneity in the primary tumor/metastases, is should be evaluated how many CTCs need to be analyzed in order to capture the dominant driving clones. In order to evaluate this, genomic changes from CTCs will be compared to the genomic composition of the primary tumor and the metastases. If successful, this project will allow a translation of liquid biopsies from the bench to the bedside, sparing patients from difficult and painful treatments.

Researcher(s)

• Promoter: Van Laere Steven
• Co-promoter: Peeters Marc
• Co-promoter: Van Camp Guy
• Fellow: Brouwer Aaltje

Research team(s)

Project type(s)

• Research Project

Abstract

The objective of this study is a multi-center clinical validation of a sensitive assay to detect the presence of wild-type (so-called 'full-length') and alternatively spliced variants (ARV) of the androgen receptor (AR) in enriched circulating tumour cells (CTC) of patients with castration-resistant prostate cancer (CRPC). This approach forms an important tool to predict whether or not a patient with CRPC is likely to benefit from a new line hormonal treatment (including but not restricted to e.g. abiraterone acetate and enzalutamide) and thereby contributes to a more personalized treatment approach for this rapidly increasing patient group.

Researcher(s)

• Promoter: Van Laere Steven
• Co-promoter: Dirix Luc

Research team(s)

Project type(s)

• Research Project

Abstract

This project aims to characterize liver metastases with a different growth pattern at the molecular level. In a recent study, we showed that these growth patterns are clinically relevant (Frentzas et al, Nat Med, in press). The replacement growth pattern, in which cancer cells replace the normal hepatocytes without disturbing the normal liver architecture, is associated with a more aggressive natural history in addition to a reduced sensitivity to anti-angiogenic drugs. This observation can be explained by the fact that cancer cells that replace normal hepatocytes usurp the sinusoidal vlood vessels in the liver and thus are not dependent of the formation of new blood vessels, which is typical for liver metastases with a desmoplastic growth pattern that are characterized by a tumor nodule surrounded by fibrous tissue. By performing RNA-sequencing, we aim at understanding the biological basis of the different histological growth patterns.

Researcher(s)

• Promoter: Van Laere Steven

Research team(s)

Project type(s)

• Research Project

Abstract

The objective of this POC study is the assessment of the clinical feasibility and validation of a potential new predictive assay for resistance against androgen receptor (AR)-directed therapies in the treatment of castration-resistant prostate cancer.

Researcher(s)

• Promoter: Van Laere Steven

Research team(s)

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand the client. UA provides the client research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Van Laere Steven

Research team(s)

Project type(s)

• Research Project

Abstract

Histological and biological characteristics of 'non-angiogenic' liver metastases of carcinomas in humans will be studied, also comparing the growth pattern of the primary tumour with that of the metastasis in individual patients. The influence of the growth pattern of liver metastases (angiogenic or non-angiogenic), on the clinical course of the disease will be assessed. A comparison will be made between the medical imaging data (CT and/or MRI) and the different growth patterns. The techniques that will be employed are tissue-micro-arrays in order to determine angiogenic tissue parameters, expression of adhesion molecules and of VEGF, electron microscopy for the study of the ultrastructure of incorporated vessels, RNA-isolation after laser-microdissection and determination of the expression of angiogenesis related genes using real-time RT-PCR. Preparation of a cDNA micorarray experiment.

Researcher(s)

• Promoter: Van Marck Eric
• Fellow: Van Laere Steven

Research team(s)

Project type(s)

• Research Project