Deciphering the tumor progression-dependent changes in mitotic bookmarking of triple-negative breast cancer cells
General Genetics and Functional Genome Biology
Final Report Abstract
During cancer progression, cancer cells show alterations in their phenotypes, gene expression patterns and epigenetic landscape. These differences have to be remembered during mitosis and successfully transmitted to the progeny to maintain the transformed cellular state. As cell identity maintenance is challenged at every cell division, these mechanisms have to be tightly controlled in a cell type-specific manner. However, the mechanism behind is not yet fully understood. With the proposed research project, I aimed to shed light on the role of transcription factors (TF) being important for mitotic bookmarking in metastatic triple negative breast cancer (TNBC) and how they exert their function. In the first part of the project, I analyzed how chromatin accessibility at distal cis-regulatory regions (CRE) is altered during the early stages of mitosis at different cancer stages and whether I can identify differences within. I could show that chromatin is globally compacted at the beginning of mitosis and then rapidly regaining accessibility. Based on these findings, I investigated whether different TF footprints on the DNA could be identified, which highlight an important function of the associated TF during the early timepoints of mitosis. In combination with analyzing the newly transcribed (nascent) RNA during mitosis, I could identify a subset of TFs showing increased footprints at the early stages of mitosis as well as ongoing transcription during mitosis. Among the TFs found, several are described to be upregulated in patients with TNBC and linked to metastasis. In the second part I then focused on one of the identified TFs, SOX9, to study its function during mitosis and its potential role as a metastasis-specific bookmarking factor. By using a PROteolysis TArgeting Chimera (PROTAC) I could deplete SOX9 in a timely manner prior to mitosis and highlight the changes in chromatin accessibility at CREs during mitosis. I could show that SOX9 has a role in maintaining CREs linked to genes associated with quiescence, a characteristic of the metastatic phenotype. Interference with SOX9 prior to mitosis in metastatic cells altered the quiescent phenotype of the progeny. Taken together, with the performed study I provide evidence that the action of single TFs during mitosis can be linked to the maintenance of a cellular phenotype in the progeny. Interference with these mechanisms might be a promising tool for the development of new therapeutic approaches targeting mitotic bookmarking factors and interfering with memory propagation.
Publications
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An Epigenetic Perspective on Intra-Tumour Heterogeneity: Novel Insights and New Challenges from Multiple Fields. Cancers, 13(19), 4969.
Beyes, Sven; Bediaga, Naiara Garcia & Zippo, Alessio
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Effective targeting of breast cancer stem cells by combined inhibition of Sam68 and Rad51. Oncogene, 41(15), 2196-2209.
Turdo, Alice; Gaggianesi, Miriam; Di Franco, Simone; Veschi, Veronica; D.’Accardo, Caterina; Porcelli, Gaetana; Lo, Iacono Melania; Pillitteri, Irene; Verona, Francesco; Militello, Gabriella; Zippo, Alessio; Poli, Vittoria; Fagnocchi, Luca; Beyes, Sven; Stella, Stefania; Lattanzio, Rossano; Faldetta, Naida; Lentini, Vincenzo L.; Porcasi, Rossana ... & Todaro, Matilde
