Inhibiting tumor cell plasticity by targeting the epigenome in breast cancer

Projektbeschreibung

Neue epigenetische Ziele bei Brustkrebs

Eine der Eigenschaften von Krebs ist die Heterogenität, das Vorhandensein von Unterpopulationen von Zellen mit abgegrenzten morphologischen, phänotypischen und genotypischen Profilen. Obwohl dies Einfluss auf die Wirksamkeit von Krebstherapien hat, ist die Ätiologie dahinter nur schlecht umrissen. Das EU-finanzierte Projekt EPICAN konzentriert sich auf den Phosphoinositid-3-Kinase-Signalweg (PI3K-Signalweg), ein Signaltransduktionssystem, das bei vielen wichtigen Zellfunktionen und in der Onkogenese beteiligt ist. Die Arbeitshypothese besagt, dass onkogene Mutationen der PI3K die Pluripotenz in Säugetierzellen reaktivieren, was zu Tumorplastizität und Heterogenität führt. Die Bestimmung epigenetischer Regulierung, die nach dem PT3K-Signalweg stattfindet, könnte neue therapeutische Ziele ergeben.

Ziel

Breast cancer is a heterogeneous disease which is classified into different histological and molecular subgroups presenting different clinical outcomes. Also, the diversity of genetic/epigenetic alterations in cancer cells and their interactions with the microenvironment enhance cell plasticity and result in intra-tumor heterogeneity. While tumor heterogeneity is a major hurdle to anti-cancer therapy, its underlying molecular mechanisms remain ill-defined. The Phosphoinositide 3-kinase (PI3K) pathway, which is hyperactive in more than 70% of breast cancers mostly due to oncogenic activating mutations (PIK3CA-E545K & PIK3CA-H1047R), is a major driver of cell transformation. Using spatio-temporal conditional expression of the mutant PIK3CAH1047R combined with in situ lineage tracing in transgenic mice, recent studies demonstrated that the PIK3CA-H1047R oncogene reprograms lineage-committed mammary epithelial progenitors into a multipotent state, giving rise to heterogeneous mammary tumors. However, the mechanisms by which the PIK3CA-H1047R oncogene reactivates multipotency in breast cancer remain unknown. An increasing number of studies demonstrates that epigenetic regulators participate downstream of PI3K/AKT kinases to regulate the epigenome and contribute to tumor malignancy. Given the importance of epigenetic regulation for cell fate, I hypothesize that the effects of PIK3CA-H1047R signaling on tumor cell plasticity are mediated by epigenetic regulators. Because single inhibition of the PI3K pathway often results in resistance, it is of paramount interest to identify new targets whose inhibition can synergize with PI3K inhibitors to block tumor outgrowth, reduce tumor heterogeneity and prevent resistance. The overarching goal of this proposal is to identify epigenetic regulators downstream of oncogenic activation of the PI3K pathway leading to tumor cell plasticity, and to validate them as new targets in breast cancer.