Detection of disseminated tumor cells (DTCs) in bone marrow (BM) aspirates in patients with different cancers predicts for high risk of recurrences and reduced survival. DTCs enter a long-termed dormancy phase and are the sources of metastasis. Immediate goals: 1- to understand how DTCs enter dormancy; 2- to identify therapeutic alternatives to treat patients in remission. Current work: We have recently published a study showing that dormancy of DTCs is achieved by re-expression of a retinoid-responsive gene named NR2F1. We are exploring the epigenomic landscape regulated by NR2F1 during dormancy and how it regulates pluripotency programs (NANOG and SOX2) in dormant cancer cells. Long-term goal is to apply the knowledge gathered from understanding metastatic dormancy to reduce or prevent tumor relapses by finding strategies that stops residual disease from becoming a life-threatening metastasis. Description of the K22 project (3 years): We published that NR2F1 while lost in primary tumors is re-expressed upon surgical removal of the primary tumor in local and distant DTCs and allows them to undergo dormancy by regulating pluripotency gene transcription and histone-H3 post-translational modifications (H3-PTMs). The objective is to understand the mechanisms by which dormant DTCs hijack stem cell programs and to explore potential therapeutic treatments for minimal residual diseases. In this proposal we plan to use head and neck carcinoma models. The central hypothesis is that NR2F1 via NANOG and SOX2 supports tumor cell dormancy. The rationale is that characterization of the mechanisms responsible for DTC dormancy would provide molecular markers to identify dormant disease in human samples (e.g. BM aspirates) and this could be used to identify patients at risk of metastasis and monitoring response to therapies.
Specific aims : 1) Determine the role of NANOG and SOX2 downstream of NR2F1 in regulating tumor cell dormancy. To test this aim we will use gain of function (cDNA overexpression) and loss of function experiments (TET-ON-shmirRNA constructs) to uncover the role of NANOG and SOX2 in combination with immunofluorescence and immunochemistry methods. We will also use our published mouse model for dormancy. 2) Investigate the epigenomic landscape governed by NR2F1 and H3-PTMs in dormant cells by using ChIP-sequencing and computational approaches. 3) Determine the effectiveness of combining two therapeutic drugs (DNA methylation inhibitors + retinoids) currently in clinical trials in reprogramming residual disease into dormancy and thus reducing metastasis formation in mouse models. The approach is innovative because it proposes for the first time that pluripotency programs are responsible for dormancy of DTCs. The research is significant because it is expected to vertically advance the understanding of how dormant DTCs utilize stem cell genes to preserve their dormancy phenotype and the later tumor initiating capacity. Ultimately, this finding will contribute to the development of therapies that aim to preserve DTCs as chronic asymptomatic residual disease and/or eradicate them.
This proposed research is relevant to public health because the discovery of the mechanisms responsible to maintain disseminated tumor cells in a dormant state and those that awake them up is crucial to avoid tumor relapses. Thus, this project is relevant to the part of NHI's mission that seeks to develop necessary tools to avoid or reduce metastatic recurrences and prolong patients survival rates.
|Linde, Nina; Casanova-Acebes, Maria; Sosa, Maria Soledad et al. (2018) Macrophages orchestrate breast cancer early dissemination and metastasis. Nat Commun 9:21|