Project Funding Details

Perturbations of DNA replication also referred to as DNA replication stress (RS) occur under stressful conditions and lead to the accumulation of mutations and the progression of cancers. However, although the mechanisms by which RS leads to genome instability are well documented, the contribution of RS to cancer hallmarks such as cell migration, tissue invasion, angiogenesis and immuno-evasion are less clear. Remarkably, similar to cancer embryonic and placenta cells such as trophoblasts are able to evade the immune system and invade surrounding tissues by promoting angiogenesis to establish pregnancy. The Costanzo's lab has recently shown that activation of RS surveillance pathway ATR-CHK1 in mouse embryonic cells (mESCs) promotes the activation of genes involved in trophoblast and placenta formation. This pathway is in part coordinated by DUX, the master regulator of zygotic genome activation. Significantly, a number of placenta genes have been found to be highly expressed in aggressive tumors and DUX4, the human ortholog of DUX often re-arranged in several tumors has been shown to be one of most specific human cancer genes promoting cancer aggressive features shared with placental cells. I propose to study the role of RS and ATR-CHK1 induced DUX activation in promoting the emergence of cancer cell aggressive features linked to the reactivation of embryonic placental pathways in adult cells. To verify this hypothesis, I will: 1) Study the molecular mechanisms leading to RS dependent activation of DUX 2) Explore the effects of RS dependent activation of placental genes in cancer To reach these goals: a) I will investigate the molecular mechanisms leading to DUX activation in response to RS by exploring the role of double strand break induced transcription at repetitive DUX locus. In particular I will follow up on preliminary evidence I recently obtained indicating a role of fork reversal enzymes in promoting DUX activation following RS; b) I will then study the links between ATR dependent DUX/DUX4 activation and the ability of cancer cells to acquire migratory and invasive features in relation to RS and DUX induced trophoblast master regulator genes TEAD4 and AP2, which I showed to be strongly expressed in invasive breast cancer cells. My experimental plan aims to reveal the link between DNA damage response/repair genes and the reactivation of pathways typically associated trophoblast and placenta development. The identification of RS and ATR-CHK1 dependent mechanisms leading to trophoblast gene reactivation in cancer cells cancers will set the stage to identify novel targets to suppress cancer aggressive features and metastasis.