Molecular and epigenetic control of CNS tumour and progenitor cells

Despite advances in diagnosis and treatment, CNS tumours continue to result in high mortality and morbidity. Glioblastoma mutliforme (GBM), the most common primary brain tumour, is a recurrent tumour that despite advances in treatment, continues to demonstrate a median time of survival of 14.6 months. While GBM has a higher incidence in adults, medulloblastoma (MB) is more frequent in children. In this pediatric tumour, more recent therapeutic advances have improved the survival rate, however current treatments result in long lasting effects on cognitive development, subsequently leading to a poor quality of life for the patient. This emphasizes the need to better understand tumour mechanisms in this disease in order to design better treatments that will not only lead to destruction of the tumour, but also will not impact patient quality of life in the long term.

The heterogeneity of GBM cells is a huge drawback in current treatment, and can be attributed to the existence of a population of cancer stem cells (CSC). CSC share similar features with stem cells in that they can self renew and proliferate. In paper I, we describe the design and use of a novel system for detection of cancer stem cells involving fluorescent probes called luminescent conjugated oligothiophenes (LCO). We show that pHTMI, an LCO, is an improved cancer stem cell marker compared to existing markers. The role of the cytoskeleton in tumour malignancy is being explored as the cytoskeleton governs physical cellular features such as size, shape and regulates migration and invasiveness. In paper II we explore the cytoskeletal regulators of GBM cells and the effect on these regulators after oncology drugs. We identify a strong correlation between the cytoskeletal regulators and tumour malignancy that can help improve current GBM therapy.

Besides regulators of the cytoskeleton in the cytoplasm, the shape of the cell nucleus is affected by chromatin modifiers such as histone deacetylases (HDACs) and histone demethylases (HDMs) In paper III we elucidate the role of histone deacetylases specifically HDAC2 and HDAC3 in controlling differentiation of progenitor cells and the role of transcriptional regulators in overseeing these pathways. Previous studies have also identified the role of histone demethylases in regulating differentiation in progenitor cells. Since medulloblastoma is a developmental tumour, we explored this approach in medulloblastoma cells. In paper IV, we demonstrate the role of retinoic acid (RA) in regulating the expression of the histone demethylase KDM6B/JMJD3 and neuronal genes. Further, we show that there is a cross-talk with KDM6B/JMJD3 and the TGFβ signaling mediator SMAD3 in medulloblastoma cells. A better molecular understanding of the mechanisms of these tumours could ensure improved diagnosis and treating molecular subtypes specifically.

List of scientific papers

I. Live detection of neural and glioma-derived stem cells by an oligothiophene derivative. Ilkhanizadeh S, Gracias A, Åslund A.K.O, Bäck M, Simon R, Rraklli V, Migliori B, Kavanagh E, Nelander S, Westermark B, Uhrbom L, Forsberg- Nilsson K, Texeira A. I, Konradsson P, Uhlén P, Holmberg J, Joseph B, Hermanson O, Nilsson K. P.R. [Submitted]

II. Understanding cytoskeleton regulators in glioblastoma multiforme for therapy design. Masoumi S, Harisankar A, Gracias A, Bachinger F, Fufa T, Chandrasekar G, Gaunitz F, Walfridsson J, Kitambi SS. Drug Design, Development and Therapy. 2016:10 2881-2897.
https://doi.org/10.2147/DDDT.S106196

III. Neural stem cell differentiation is dictated by distinct actions of nuclear receptor corepressors and histone deacetylases. Castelo-Branco G, Lilja T, Wallenborg K, Falcão AM, Marques SC, Gracias A, Solum D, Paap R, Walfridsson J, Texeira AI, Rosenfeld MG, Jepsen K, Hermanson O. Stem Cell Reports. 2014. 3:502-515.
https://doi.org/10.1016/j.stemcr.2014.07.008

IV. Genome wide analysis reveals cross-talk between the retinoic acid-regulated H3K27 demethylase KDM6B/JMJD3 and the TGFβ signaling mediator SMAD3 in human medulloblastoma cells. Gracias A, Hermanson O. [Manuscript]