The Signaling Group

Why invasion and metastasis?

Metastasis is responsible for about 90% of cancer deaths, thus novel and innovative strategies for its targeting are truly needed. Our current research is largely based on our recent, original discovery of an invasion-promoting ErbB2-downstream signaling network that has brought completely new insight and previously unexplored tools for this research field. Our experimental aim is to explore carefully this signaling network and the tools we have discovered in order to understand and find novel ways to control malignant invasion and metastasis and thus hopefully improve patient survival.

Background

Lysosomes are important intracellular degradation units that cells also use for other specific functions such as lysosomal secretion, also known as lysosomal exocytosis.

Lysosomal exocytosis is an important process for example for the normal cellular clearance that is needed for the daily maintenance of cellular homeostasis. Cancer cells are able to amplify and “'hijack'” this “'housekeeping'” lysosomal secretion and use it to modify the extracellular microenvironment to favor invasion and metastasis. The exact mechanism by which they do this is not known.

We have shown that the ErbB2 (HER2)-oncogene induced breast cancer cell invasiveness in cellular 3-dimensional invasion model is dependent on the expression and activity of lysosomal cysteine cathepsins B and L (CTSB and CTSL1) and have identified key components of the signaling network involved.

Cathepsin B and L are interesting lysosomal hydrolases since they are capable of cleaving extracellular matrix when secreted outside the cells. Increasing amount of independent studies have verified their importance in cancer invasion and metastasis in vivo. The short-term aim of our research is to identify the molecular events regulating the cancer-induced malignant lysosomal secretion in order to find ways to control it.
The research at the CDM is strongly focused on '“alternative death pathways”' and aims at discovering novel treatments that can specifically kill malignant cancer cells. Lysosomal membrane permeabilization (LMP) is an efficient way to induce death in cancer cells, most of which have acquired resistance to caspase activation and classical apoptosis. In LMP lysosomal contents leak into the cytosol inducing caspase-independent programmed cell death. LMP can be induced by anti-cancer drugs such as cisplatin, etoposide, and siramesine.

We recently showed that transforming oncogenes such as Ras, Src and ErbB2 can sensitize cells to drug-induced LMP. During this work we found out that activation of ErbB2 in breast cancer cells induces the expression of lysosomal cysteine cathepsins B and L leading to their increased activity. Furthermore, we discovered that CTSB and CTSL1 mRNA and protein levels correlate positively with increased ErbB2 status in breast cancer patients in a study of over 1000 independent primary tumors. Importantly, from our previous work we now know that the activation of the invasion promoting, ErbB2-inducible signaling pathway (Figure 2) correlates with the oncogene-induced sensitization of cells to LMP, meaning that when lysosomes get ready for exocytosis they have also got more sensitive for permeabilization. A therapeutically important question concerning the “'lysosomal leakage'” leading to LMP and lysosomal exocytosis facilitating invasion is how to safely induce LMP without inducing invasion? With our research we also aim at evaluating the possible risks involved and finding ways to eliminate them.

Additional information

Active Collaborations

Competitive Funding

Major Publications