The first project involves the discovery of cath-D partners and substrates by the yeast two-hybrid and the proteomic approaches as well, and of its target genes by microarray analysis.
We recently identified two cath-D partners by yeast two-hybrid using a normal breast cDNA library:
(1) The first cath-D partner is a receptor. We have shown that this receptor mediates the paracrine action of cath-D secreted by cancer cells on fibroblasts. Our current project involves the studies of this receptor in relation to cath-D in cancer. We will currently work on the following:
- Elucidation of the biological roles of the cath-D/receptor interaction in breast cancer cell and in adipocyte, a key component of the breast tumor micro-environment;
- Study of the effect of cath-D/receptor interaction on transcription and analysis of cath-D target genes by microarray analysis in cancer;
- Characterisation of the cath-D/receptor interacting domains to prevent this interaction in pathologies.
(2) The second cath-D partner is an inhibitor of protease. We will study the mechanism and the relevance of this interaction in the proteolytic cascades in breast cancer.
Our future project will be focused on the identification of new cath-D partners by yeast two-hybrid using a breast cancer library. In parallel, we will determine cath-D substrates by analysis of its degradomic by a proteomic approach.

In addition to these mechanistic studies, we will search for drugs that depend on cath-D overexpression to induce apoptosis in chemo-resistant breast cancer in an integrated European project. Because of its pro-apoptotic function in induced-apoptosis, cath-D might sensitize cancer cells to a new class of apoptotic drugs.

This project will bring new molecules regulating cath-D action as leads for the development of potential anticancer chemotherapeutics.

The second project of our team concerns the role of cath-D and its receptor in the regulation of autophagy. Macroautophagy, or autophagy, is a bulk degradative process that ends in the lysosome. A basal level, autophagy acts a s a quality control process. It is also a stimulable process that permits cell survival after stress such as starvation. However, when deregulated, autophagy may be deleterious for the cell that dies through autodigestion (autophagic cell death).
A close link exists between autophagy and cancer. Depending on the conditions, autophagy may be an oncogenic process (cancer cell survival, inhibition of apoptosis for example) or a tumor suppressor mechanism (inhibition of proliferation degradation of damaged mitochondria, cell death).
ATG genes (AuTophaGy), specific of autophagy, are conserved among evolution. It is important to notice that atg6 gene, called also beclin1, is a haploinsufficient tumor suppressor gene. Beclin 1 is frequently deleted in breast and ovarian cancer. The interaction between Beclin 1 and the oncogene Bcl-2 determines the future of the cell. If they both interact, autophagy is inhibited. On the contrary, the inhibition of their interaction through JNK activity stimulates autophagy. Indeed, a deregulation of this interaction leads to autophagic cell death. The comprehension of the mechanism that regulates autophagy in cancer cell is essential to conclude on its role 1) as an oncogenic or a tumor suppressor process and 2) on cell death. In this context, we propose to focus on the role of cath-D, a lysosomal protease that has oncogenic and pro-apoptotic properties.

International Patent : E Liaudet-Coopman, C Prébois, D Derocq, M Beaujouin. WO 2009/043858 “Methods for treating and diagnosing a cancer secreting cathepsin D or Alzheimer’s disease”.