Jechlinger Group
Mechanisms of oncogene dependence and tumour relapse
Previous and current research
Extensive evidence now supports the concept of oncogene addiction (the dependence of tumour cells on their initiating lesion for survival). In patients and mouse models interference with the activity of cancerinitiating oncogenes can result in tumor regression. However, novel therapies that target the products of mutant alleles in human cancers are only partly successful, since maintenance of remission requires longterm treatment and relapse oft en occurs in the presence of therapeutic agents. Hence, a better understanding of drug resistance and tumour recurrence is needed for the design of more successful anti-cancer strategies.
Transgenic mice carrying regulatable transgenes represent tractable systems for studying the mechanisms of oncogene dependence, the response and resistance to targeted drugs and tumour recurrence. In a complementary approach, we have developed a 3D culture system of primary mouse mammary epithelial cells to study detailed responses to the induction and de-induction of oncogenes (mimicking treatment with an ideally targeted drug). This 3D system produced phenotypic changes similar to those observed in the mammary glands of the transgenic mice from which the cultures were derived. In addition, this new approach identified and isolated cells that had survived oncogene withdrawal, exhibited characteristics of mammary gland progenitors and could efficiently re-populate the mammary fat pads of immundeficient mice. The successful isolation of a pure population of surviving cells after oncogene withdrawal will allow us to characterise these residual ‘dormant’ tumour cells in detail.
Future projects and goals
- Determine at which point during tumorigenesis cells acquire the ability to survive oncogene withdrawal.
- Identify the molecular properties that distinguish surviving-residual cells, from naïve cells.
- Interfere with the mechanisms important for survival of residual ‘dormant’ cells.