Group members

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Femke Heindryckx

Ongoing projects:

Interaction between stellate cells and tumour cells

Platelets in hepatocellular carcinoma

The P2Y12 receptor in different hepatic cell populations

The effect of extracellular matrix on tumour stem cell properties



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Interaction between stellate cells and tumour cells

Every year 500.000 patients are diagnosed with hepatocellular carcinoma (HCC), making it one of the most common cancers worldwide. There are limited therapeutic options, resulting in an average survival of 4 months after diagnosis. HCC typically arises in the context of liver cirrhosis which is caused by chronic liver damage. One of the key players in the progression of cirrhosis to HCC is the hepatic stellate cell, which is activated during liver damage and differentiates towards a contractile myofibroblast-like cell. Activated stellate cells play an essential role in the onset and progression of HCC and blocking their activation has been proposed as a potential therapy for patients with HCC (Figure 1). We focus on the interaction between stellate cells and tumor cells, with the overall aim to find new therapeutic strategies for patients with HCC.

Figure 1: Activated stellate cells stimulate tumor cell proliferation, metastasis and drug resistance by secretion of growth factors, extracellular matrix and creating a hypoxic environment. Tumor cells contribute to the activation and recruitment of stellate cells by the secretion of growth factors such as TGF-beta and PDGF.

Figure 2: 3D tumor spheroids
consisting out of stellate cells (red)
and cancer cells (green).

Since our research focuses on the interaction between stellate cells and HCC-cells we have set up several co-culturing systems for studying cell interactions. There co-culturing systems enable us to study the phenotypic and genotypic changes in stellate cells and tumor cells; and specifically manipulate (e.g. transfection) one cell type within the co-culture, therefore allowing us to study the specific effects on one cell population in the context of a heterogenic tumor. One model includes the use of 3D cancer spheroids containing stellate cells and HCC cell lines (Figure 2). The spheroids have several physiological traits in common with in vivo tumors, such as the overall morphology, the formation of cell–cell and cell-ECM contacts, decreased proliferation rates, increased survival rates and the formation of a hypoxic core.


Platelets in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a primary liver cancer that usually develops in a background of chronic liver disease. It is characterized by a prolonged inflammatory process which induces a micro-environment that favours tumour growth and is a major factor in its complex molecular pathogenesis. This environment includes hepatic stellate cells, macrophages or Kupffer cells, endothelial cells, extracellular matrix (ECM) and a variety of immune cells. The dynamic cross-talk between these factors is believed to promote tumour initiation, proliferation and metastasis.

The liver plays a central role in coagulation and fibrinolysis but is also closely intertwined with the function and number of blood platelets. Platelets enter the injured liver and interact with hepatic sinusoidal endothelial cells, leading to platelet activation. This results in the release of a range of up to 300 bioactive proteins (including growth factors and chemokines). Platelets have been reported to interact with different cell types in the tumour micro-environment, including stellate cells, inflammatory cells, cancer cells and macrophages, thereby contributing to a more aggressive and metastatic tumour phenotype. We investigate the influence of platelets on different hepatic cell populations, including stellate cells, cancer cells and macrophages. Specifically, we look at how platelets alter the immune cell population and we study the functional effects on phagocytosis, tumor growth and metastasis.

Figure 1: phagocytosis of cancer cells (green) by macrophages (red)


The P2Y12 receptor in different hepatic cell populations

P2Y12 belongs to the G-protein coupled purinergic receptors and is a chemoreceptor for ADP. While the function of P2Y12 on platelets has been described extensively, we investigate the role of these receptors on different cell types in the liver. Hypoxia or inflammation, activates the release of extracellular nucleotides such as ATP and UTP which interact with cell surface P2Y-receptors to induce a broad range of physiological responses, which could be relevant in the pathogenesis of liver cirrhosis and hepatocellular carcinoma.

Figure 1: expression of P2Y12 in liver tissue


The effect of extracellular matrix on tumour stem cell properties

Activated hepatic stellate cells cause an excessive deposition of ECM in chronically damaged livers. ECM proteins as well as their proteolytic fragments play a crucial role in tumour growth, metastasis, and tumour neo-angiogenesis. While the effect of ECM on angiogenesis has been investigated extensively, less is known about the direct effects of ECM proteins and their degradation products on tumour growth. Interestingly, increasing evidence shows that the ECM is an essential component of the stem cell niche and that it can directly regulate stem cell differentiation, although the molecular details of how this is achieved have only just started to emerge. Liver progenitor cells (LPCs) reside in the canals of herring and are bipotential stem cells with the capacity to develop towards hepatocytes or cholangiocytes. HCC lesions often express LPC or cancer stem cell (CSC) markers and the LPC/CSC´s capacity to maintain uncontrolled proliferation and differentiation makes them specifically interesting since they could potentially give rise to several satellite tumour nodules after they acquire the potential to invade.

In our lab we study the direct effects of the deposition of ECM by activated stellate cells on tumour growth, mainly focusing on proliferation, migration and progenitor cell differentiation in HCC.


For further information about this research group please contact
Femke Heindryckx

Financial support

2018-2021

Cancerfonden project

2018-2020

Swedish
Society
for Medical Research
(SSMF)

2013-2014

Wenner-Gren Stiftelserna /
Wenner-Gren Foundations


Other funding

  • 2014-2018
    Cancerfonden postdoktortjänst

  • 2018


 



Collaborators

within the Department of Medical Cell Biology:

  • Johan Kreuger
  • Mia Phillipson
  • Peter Hansell
  • Olof Idevall

outside the Department of Medical Cell Biology:

  • Hans Lennernäs (Uppsala University)
  • Anna-Karin Ohlson (Uppsala University)
  • Jin-Ping Li (Uppsala University)
  • Hans Van Vlierberghe (Ghent University)
  • Krista Rombouts (UCL, London)
  • Markella Ponticos (UCL, London)