Cancer Epigenomics

Recurrent deletions in cancer genomes overlap with the chromosomal locations of tumor-suppressor genes. Knudson's two-hit hypothesis has successfully guided cancer biologists for the past fifty years in the identification of such tumor-suppressor genes. However, in many cases monoallelic loss can only explain haploinsufficiency of tumor-suppressor genes. Preliminary work in the division indicates that altered chromosome topology and epigenetic gene regulation can also affected by deletions, resulting in the activation of oncogenes located outside of the deleted segment.

We aim to establish a novel paradigm in interpreting (epi)genomic data in cancer. We hypothesize that oncogene activation, in concert with haploinsufficient tumor-suppressor genes, deregulated because of a single genetic event, could lead to the discovery of novel intertwined oncogenic pathways.

Using acute myeloid leukemia as a model, we aim:

• to reveal oncogene activation through novel molecular pathways in cases carrying deletions of 5q and 7q by molecular sequencing-based profiling and to validate the requirement of the novel oncogene(s) for leukemic growth.
• to determine the molecular mechanisms resulting from oncogene overexpression and to test the accelerated tumorigenesis dependent on haploinsufficient tumor suppressor genes.
• to determine the contribution of oncogene activation through structural variation in combination with haploinsufficiency in a pan-cancer setting.

A significant clinical problem and unmet need in cancer therapy represents the fact that almost all cancer patients treated, develop resistance to current therapeutic drugs. Cancer therapy resistance is intimately linked to tumor heterogeneity, either preexisting or acquired. Resistance is characterized by transcriptomic and phenotypic changes in both tumor cells and their tumor microenvironment (TME) as well as growth of cells that tolerate the treatment. In this context, drug resistance could either be mediated by the outgrowth of preexisting-refractory tumor-cell subpopulations present in a heterogeneous tumor cell pool, or alternatively the consequence of acquired alterations in the neoplastic cells leading to the generation of resistant cells (Fig.1). Insights into genomic and transcriptomic data from tumor cells contributed partly to a mechanistic understanding of treatment failure. However, in over 35% of cases non-genetically determined resistance mechanisms were postulated.

Non-genetic mechanisms of drug resistance could either represent the outgrowth of preexisting-refractory tumor-cell subpopulations (persister-cells), which carry an epigenetic pattern mediating a resistant phenotype or alternatively resistance could be the consequence of acquired epigenetic, intra-tumor heterogeneity with the generation of resistant cells. The molecular pathways leading to non-genetic alteration driving cancer therapies are not understood. This is however, of upmost importance since an improved mechanistic understanding of therapy resistance could support the discovery of novel vulnerabilities providing directions for novel therapeutic avenues.

We will focus our work on acute myeloid leukemia (AML) and lung cancer.