Tumor suppressor gene 53 (TP53) is the most frequently altered gene in human cancer with approximately 50% of tumors carrying mutations or deletions in TP53. Unlike other tumor suppressors that typically undergo bi-allelic inactivation through frame-shift mutations or deletions, most mutations in TP53 are missense mutations.
It has recently been demonstrated that not neomorphic gain-of-function (GOF) activities but a dominant-negative effect (DNE) drives the selection of TP53 missense mutations in myeloid malignancies (Boettcher et al., Science 2019).
This finding has important implications: Is the DNE the major driver of TP53 missense mutations in tumors originating in other tissues? How exactly does missense mutant p53 exert a DNE on wild-type p53 in heterozygous cells? Why are the frequencies of TP53 missense mutations so variable in the different tumor types?
We are addressing these and other questions related to p53 pathobiology using state-of-the-art experimentation involving CRISPR-mediated genome editing, proteomics, and unbiased genetic screening approaches.
Tumorigenesis is a stepwise process characterized by the sequential acquisition of oncogenic mutations over years and decades. The existence of a pre-malignant phase – a state where nascent tumors have not yet acquired full oncogenicity – has long been postulated and exemplified by the classic adenoma-carcinoma sequence in colorectal cancer. However, only recently have we begun to gain a better insight into the prevalence and genetic landscape of pre-malignancies in other tissues and in the general human population (Jaiswal et al., NEJM 2014; Martincorena et al., Science 2015; Martincorena et al., Science 2018).
Therefore, our principal aims are: (1) To describe the epidemiology of pre-malignancies in various organ systems; (2) To dissect the mechanisms of clonal selection and clonal evolution of pre-malignant cells over time; (3) To devise pre-emptive therapeutic strategies in order to prevent neoplastic transformation in individuals with pre-malignancies.
In order to achieve these goals, we combine epidemiological and genetic studies with hypothesis-driven experimentation as well as discovery-driven high-throughput screening approaches.
Genetic and epigenetic mechanisms generate the phenotypic diversity upon which Darwinian evolutionary forces can act thereby selecting for the best-adapted tumor in any given environmental context. Intriguingly, the ultimate outcome of tumor evolution is not ‘survival of the fittest clone’ that would result in homogenization of tumors. Instead, increasing tumor heterogeneity is observed over time.
The simplest explanation for this somewhat counterintuitive finding is that phenotypic and functional diversity ensures tumor survival under constantly changing environmental selective pressures. However, accumulating evidence also suggests that tumors function as intricate ecosystems, in which the multiple subclonal tumor cell populations interact leading to overall more robust oncogenic phenotypes and enhanced fitness of the entire tumor – a concept that has been termed clonal cooperativity.
We employ novel experimental approaches to systemically assess the extent and role of clonal cooperativity in tumors.