Bengt Westermark's research projects on human malignant glioma
Regulation of multitherapy resistance and creation of a road-map for sensitization of treatment resistant glioblastoma cells
Anna Segerman, Mia Niklasson
By studying single-cell-derived cultures (clones) from the same glioblastoma tumour sample (Segerman et al., Cell Reports, 2016), we find that the cancer cells naturally, but at low speed, can slide back and forth between more treatment-resistant (mesenchymal (MES)-like) and more treatment-sensitive (proneural-like) cell states. The project aims to identify regulatory mechanisms behind this spontaneous change in cell state and based on this knowledge find drugs/substances or combinations of these that induce the cell state linked to treatment sensitivity.
Multitherapy-resistant glioma cells exploit similarly high levels of drug resistance as normal reference cells (astrocytes and neural stem cells) to common chemotherapeutic drugs. Reversal of the plastic MES-like cell state, through epigenetic reprogramming, may thus be essential to make such clones responsive to (any) treatment.
Mesenchymal transition of cancer cells is a generally acknowledged resistance mechanism. The studies are concentrated on GBM but the concept might well be applicable on other tumour types.
Anna Segerman, Bo Segerman, Mia Niklasson, Tobias Bergström, Erika Dalmo, Ida Gustavsson, Bengt Westermark
Glioma cell lines are continuously established from fresh biopsies and characterized with regard to genotype (structural alterations in known oncogenes and suppressor genes), phenotype (e.g. expression of stem cells and differentiation markers and tumourigenicity in immunocompromized mice) and treatment response using the standard glioma regimen (radiation and temozolomide). Selected cell lines and clonal derivatives are subjected to transcriptomic, proteomic, and epigenomic analysis to define biomarker signatures.
Using growth inhibition as endpoint, we analyse the response of individual glioma cell lines to BMP4. Using CRISP-Cas9 knock out technology, we aim to define BMP4 signalling in growth inhibition. A few candidate genes have been identified and are currently functionally analysed. The role of the transcription factor SOX2 as a target for BMP4-induced growth retardation is studied.
Undifferentiated (anaplastic) tumours are highly malignant, rapidly growing and invasive, and constitute a major clinical problem. This project focuses on anaplastic thyroid carcinoma (ATC) and our aim is to elucidate the genetic events involved in generating the tumour.
Our laboratory has established several cell lines from human anaplastic thyroid cancer biopsies. Analyses of their karyotypes showed an abundance of double minute chromosomes (DMs) in two of the cell lines. DMs are known to harbour amplified gene sequences. With this in mind, we are currently using “next generation” sequencing technology to identify the amplified sequences.