| 1. |
- Ilkhanizadeh, Shirin, et al.
(författare)
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Live Detection of Neural Progenitors and Glioblastoma Cells by an Oligothiophene Derivative
- 2023
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Ingår i: ACS Applied Bio Materials. - : American Chemical Society (ACS). - 2576-6422. ; 6:9, s. 3790-3797
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Tidskriftsartikel (refereegranskat)abstract
- There is an urgent need for simple and non-invasive identification of live neural stem/progenitor cells (NSPCs) in the developing and adult brain as well as in disease, such as in brain tumors, due to the potential clinical importance in prognosis, diagnosis, and treatment of diseases of the nervous system. Here, we report a luminescent conjugated oligothiophene (LCO), named p-HTMI, for non-invasive and non-amplified real-time detection of live human patient-derived glioblastoma (GBM) stem cell-like cells and NSPCs. While p-HTMI stained only a small fraction of other cell types investigated, the mere addition of p-HTMI to the cell culture resulted in efficient detection of NSPCs or GBM cells from rodents and humans within minutes. p-HTMI is functionalized with a methylated imidazole moiety resembling the side chain of histidine/histamine, and non-methylated analogues were not functional. Cell sorting experiments of human GBM cells demonstrated that p-HTMI labeled the same cell population as CD271, a proposed marker for stem cell-like cells and rapidly migrating cells in glioblastoma. Our results suggest that the LCO p-HTMI is a versatile tool for immediate and selective detection of neural and glioma stem and progenitor cells.
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| 2. |
- Krona, Cecilia, et al.
(författare)
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GLIOBLASTOMA GROWTH IS SHAPED BY INVASION ROUTE-SPECIFIC FUNCTIONAL SIGNATURES
- 2023
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Ingår i: Neuro-Oncology. - 1522-8517. ; 25:Supplement: 5, MODL-16
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- One of the defining features of glioblastomas (GBMs) is the capacity for invasive growth along multiple anatomical pathways in the brain. GBM is well-studied on a genetic and molecular level, but clinically relevant and experimentally tractable models of invasive growth are largely lacking. Here, we report an integrated study of patient-matched information, genomic- and molecular profiles with growth in mouse brains to expose treatments and biomarkers associated with glioblastoma invasion and recurrence. In total, 64 patient-derived cell lines (PDCLs) were injected into the striatum of n ≥ 4 mice each. The 45 tumor-forming PDCLs were each scored for 10 distinct growth characteristics (n = 182 mice). The repertoire of phenotypes was highly divergent, and our material included clear cases of perivascular route invasion, white matter route invasion, perineuronal satellitosis, and gliosarcoma. We explored if cellular pathways, monitored by RNA-sequencing, could account for these differences. GSEA highlighted a positive enrichment for highly proliferative proneural tumors characterized by Notch activation, neuronal signaling, and epigenetic gene regulatory programs in the tumor-initiating lines. Transcriptional signatures were also strongly predictive of route-specific invasion. Diffuse invasion was predominantly seen in classical-subtype PDCLs with astrocytic or outer radial glia-like signatures. Proneural PDCLs, in turn, grew as solid tumors with an invasive peripheral region around vasculature, and mesenchymal tumors were more demarcated. To explore the therapeutic implications of our findings, we used our data-driven method (TargetTranslator, Nat Comm 2020) to predict the drug vulnerabilities of different types of invasive glioblastoma. Defined GBM tumors with perivascular invasion are characterized by increased IGFR1, MAPK/ERK, PI3K/AKT/mTOR, and JAK2 signaling. Diffusively growing GBM tumors, on the other hand, depend more on Wnt/β-catenin signaling, neuronal signaling, and active inflammatory response. Using a sphere invasion assay, we confirm that targeting both PI3K- and Wnt signaling selectively reduces glioblastoma invasion, highlighting their therapeutic potential.
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| 3. |
- Larsson, Ida, 1993-
(författare)
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Integrative modeling of intratumoral heterogeneity, plasticity and regulation in nervous system cancers
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The adult brain tumor glioblastoma (GBM) is characterized by short survival and a lack of efficient treatments. Median survival is 15 months from time of diagnosis and the 5-year survival rate is only 7 %. There is an urgent need for more efficient treatment against GBM, but there are many challenges, including the high extent of heterogeneity of GBM. The tumoral heterogeneity of GBM ranges from interpatient to intratumoral. The aim of this thesis has been to address unanswered questions relating to the intratumoral heterogeneity of GBM, with three specific focuses; (1) the organization of GBM cell state transitions (paper I and III), (2) the regulation of cell states and cell state transitions (paper II), and (3) targeted interventions against cell states (paper II and IV).In paper I, we develop an experimental-computational method to measure and quantify cell state transitions. We find that GBM cell states organize hierarchically, with a clear “source state” feeding cells downwards in the hierarchy towards a “sink state” with negative growth rate, but with multi-directional transitions between intermediate states. In paper II, we address the lack of computational methods to identify regulators of intratumoral heterogeneity by developing an algorithm called scRegClust that uses scRNA-seq data to estimate regulatory programs. Through an integrative study of the regulatory landscape of neuro-oncology we find two potential regulators of the macrophage-induced mesenchymal transition in GBM.In paper III, we explore the energy-concept as a way of measuring differentiation potential of single cells, instead of relying on gene markers or gene signatures of stemness. We fit a model called the Ising model from statistical mechanics to scRNA-seq data and show both on synthetic and real data that the estimated Ising energy is a good measure of a cell’s differentiation potential, where high Ising energy indicate a high degree of stemness.Finally, in paper IV, another experimental-computational method is developed to investigate drug-induced effects on both inter- and intratumoral heterogeneity. In summary, the high extent of intratumoral heterogeneity in nervous system cancer is a major caveat for the development of more efficient treatments. In this thesis we have taken a systems biology approach to understand how this heterogeneity is structured and how we can exploit that knowledge for therapeutic purposes.
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| 4. |
- Rosén, Emil, et al.
(författare)
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Inference of glioblastoma migration and proliferation rates using single time-point images
- 2023
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Ingår i: Communications Biology. - : Springer Nature. - 2399-3642. ; 6:1
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Tidskriftsartikel (refereegranskat)abstract
- Cancer cell migration is a driving mechanism of invasion in solid malignant tumors. Anti-migratory treatments provide an alternative approach for managing disease progression. However, we currently lack scalable screening methods for identifying novel anti-migratory drugs. To this end, we develop a method that can estimate cell motility from single end-point images in vitro by estimating differences in the spatial distribution of cells and inferring proliferation and diffusion parameters using agent-based modeling and approximate Bayesian computation. To test the power of our method, we use it to investigate drug responses in a collection of 41 patient-derived glioblastoma cell cultures, identifying migration-associated pathways and drugs with potent anti-migratory effects. We validate our method and result in both in silico and in vitro using time-lapse imaging. Our proposed method applies to standard drug screen experiments, with no change needed, and emerges as a scalable approach to screen for anti-migratory drugs. The spatial positioning of cultured glioblastoma cells is used to estimate cell motility and drug effects from single end-point images in vitro.
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