Molecular origins of metastatic cancer phenotypes

The spread of cancer to distant organs in a process termed metastasis is one of the most devastating aspects of cancer, being the cause of ~90% of cancer-related deaths. The vast majority of metastatic cancers are refractory to treatment and are therefore incurable. Thus, there is a pressing clinical need for further research on the molecular basis of metastatic cancer. Our approach combines state-of-the-art experimental cancer models, functional genetics and computer-based analysis of cancer data sets to identify genetic factors that are required for the growth and maintenance of metastatic cancer. The expected benefit from this work is a better understanding of the molecular mechanism that drive cancer metastasis. This knowledge will serve as a basis for the development of rational therapeutic strategies to combat metastatic cancer. Thus, the potential secondary benefits of this work will go beyond basic cancer research, possibly leading to the identification of (i) new molecular targets for metastatic cancer and (ii) novel predictive and/or prognostic biomarkers for metastatic cancer.

Metastatic dissemination remains one of the most devastating complications of cancer. In the clinic, metastases often present as the final step of disease progression, but the molecular origins of metastases may be rooted in the early steps of carcinogenesis. Several lines of evidence suggest that instead of specific mutations, metastatic phenotypes can emerge from optimized output of the oncogenic pathways that drive tumour initiation and early progression. The molecular mechanisms as well as phenotypic consequences of such optimization of pathway output remain elusive. Yet, understanding how metastatic cancer phenotypes arise and persist, to what extent this is dependent on the pathways that drive tumour initiation and early progression, and what genetic vulnerabilities advanced cancer clones have could profoundly affect our ability to fight metastatic cancer.
Using an integrative approach combining experimental cancer models, high-throughput genomics, functional genetics, bioinformatics and clinical association analysis, this programme aims at identifying genetic dependencies in metastatic cancer. With a focus on VHL mutant renal cancer, we will explore molecular mechanisms that modulate the phenotypic output of tumour-initiating mutations in support of metastasis, and test the hypothesis that this optimisation of oncogenic signalling results in molecular vulnerabilities in the most aggressive cancer clones. Understanding the origins of metastatic cancer phenotypes will provide insights into the fundamental requirements of cancer cell states and help identify functionally relevant biomarkers as well as therapeutic targets. Knowledge of the molecular networks that bolster the output of tumour-initiating genetic pathways in cancer progression may also have implications for early intervention strategies for cancer.