Exploring cell competition between normal and transformed epithelial cells as a novel cancer preventive mechanism
Description: For all of us, oncogenic transformation of cells is unavoidable and the risk of cancerogenesis increases with age. And even though in basically every elderly person cells with oncogenic mutations can be detected, fortunately, most of us will not live long enough to suffer from clinically-manifested tumor formation. Several mechanisms have been suggested to explain this discrepancy between frequent transformation and rare cancer development. More than 80% of malignant tumors originate from epithelial tissues and we have now identified a new process thereby epithelia actively prevent cancerogenesis. When transformation occurs, the causative mutation often affects few or even just one cell which is initially surrounded by normal epithelial cells. We have described that these normal cells will activate a dedicated program which can lead to the elimination of the transformed cells by apoptosis induction. We are only beginning to understand the molecular mechanisms underlying these phenomena and only few cell intrinsic and extrinsic signaling pathways have already been implicated. Importantly, a number of well-known oncogenes such as Ras, Src, and ErbB2 and of tumor suppressor genes such as Scribble were shown by us to induce elimination of the transformed cells. This raises the exciting possibility that cancer could be prevented if this endogenous protection program can be further strengthened. We now want to better define the molecular mechanisms behind the elimination of transformed cells by normal cells and identify genes and small molecules which can enhance this self-protection mechanism of our body. Moreover, we will test our concept with newly developed cancer models which will provide first evidence whether cancer formation can indeed be significantly delayed by enforcing endogenous defense mechanisms. A strength of our collaborative effort is that core competences of both groups will be combined to answer to these questions. The Japanese partner has extensive expertise in molecular cell biology while the Swiss partner is an expert in signalling mechanisms which govern initiation and progression of epithelial cancers and has a track record in establishing and analysing innovative cancer models. Together, we will perform and functionally validate screens to identify candidate genes and small molecules that can directly modulate this activity of normal epithelia. Hits from these screens will be validated by the Swiss partner in 3D organoid ex vivo assays which can inform about the activity of these compounds in a complex setting which supports long-term expansion of epithelial structures containing stem and differentiated cell compartments. When successful, our scientific program may establish the foundation of a new approach to the cancer problem: preventing and as much as possible delaying disease progression before clinical symptoms become detectable.
Amount: CHF 249,900
Funding type: research
Funder scheme: Strategic Japanese-Swiss Science and Technology Programme
Start date: 2017-07-01
End date: 2020-06-30
Investigator: Huelsken, Joerg
Institution: EPF Lausanne – EPFL
Funded outputs count: 0
Funder award ID: 171082
OpenAlex ID: G1796600554