The identity and unique capacity of cancer stem cells (CSC) to drive tumor growth and resistance have been challenged in brain tumors. Here we report that cells expressing CSC-associated cell ...membrane markers in Glioblastoma (GBM) do not represent a clonal entity defined by distinct functional properties and transcriptomic profiles, but rather a plastic state that most cancer cells can adopt. We show that phenotypic heterogeneity arises from non-hierarchical, reversible state transitions, instructed by the microenvironment and is predictable by mathematical modeling. Although functional stem cell properties were similar in vitro, accelerated reconstitution of heterogeneity provides a growth advantage in vivo, suggesting that tumorigenic potential is linked to intrinsic plasticity rather than CSC multipotency. The capacity of any given cancer cell to reconstitute tumor heterogeneity cautions against therapies targeting CSC-associated membrane epitopes. Instead inherent cancer cell plasticity emerges as a novel relevant target for treatment.
Glioblastoma is a very aggressive tumor and represents the most common primary brain malignancy. Key characteristics include its high resistance against conventional treatments, such as radio‐ and ...chemotherapy and its diffuse tissue infiltration, preventing complete surgical resection. The analysis of migration and invasion processes in a physiological microenvironment allows for enhanced understanding of these phenomena and can lead to improved therapeutic approaches. Here, we combine two state‐of‐the‐art techniques, adult organotypic brain tissue slice culture (OTC) and light‐sheet fluorescence microscopy (LSFM) of cleared tissues in a combined method termed OTCxLSFM. Using this methodology, we can show that glioblastoma tissue infiltration can be effectively blocked through treatment with arsenic trioxide or WP1066, as well as genetic depletion of the tetraspanin, transmembrane receptor CD9, or signal transducer and activator of transcription 3 (STAT3). With our analysis pipeline, we gain single‐cell level, three‐dimensional information, as well as insights into the morphological appearance of the tumor cells.
Synopsis
Glioblastoma, an aggressive brain tumor, is resistant to standard treatments and infiltrates brain tissue. OTCxLSFM reveals that blocking infiltration is possible through pharmacological and genetic interventions, providing insights into tumor cell behavior.
Glioblastoma is a primary brain malignancy known for its aggressiveness and resistance to conventional therapies.
A novel approach, OTCxLSFM, combines brain tissue culture and advanced microscopy to study glioblastoma infiltration.
Glioblastoma tissue infiltration is effectively blocked with arsenic trioxide and WP1066, or by targeting CD9 or STAT3.
OTCxLSFM provides detailed single‐cell level, three‐dimensional insights into tumor cell behavior and morphology.
Glioblastoma, an aggressive brain tumor, is resistant to standard treatments and infiltrates brain tissue. OTCxLSFM reveals that blocking infiltration is possible through pharmacological and genetic interventions, providing insights into tumor cell behavior.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Brain cancer, one of the most lethal diseases, urgently requires the discovery of novel theranostic agents. In this context, molecules based on six‐membered phosphorus heterocycles – ...phosphaphenalenes – are especially attractive; they possess unique characteristics that allow precise chemical engineering. Herein, we demonstrate that subtle structural modifications of the phosphaphenalene‐based gold(I) complexes lead to modify their electronic distribution, endow them with marked photophysical properties and enhance their efficacy against cancer. In particular, phosphaphenalene‐based gold(I) complexes containing a pyrrole ring show antiproliferative properties in 14 cell lines including glioblastomas, brain metastases, meningiomas, IDH‐mutant gliomas and head and neck cancers, reaching IC50 values as low as 0.73 μM. The bioactivity of this new family of drugs in combination with their photophysical properties thus offer new research possibilities for both the fundamental investigation and treatment of brain cancer.
A new gold standard: Pyrrole‐based phosphaphenalene gold(I) complexes are potent anticancer agents with high efficacy against 14 different brain cancer cell lines derived from glioblastomas, brain metastases, meningiomas, IDH‐mutant gliomas and head and neck cancers. The IC50 values reach concentrations as low as 730 nM. Furthermore, these versatile and tunable agents exhibit favorable optoelectronic properties giving rise to potential theranostic applications.
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Invited for the cover of this issue are the groups of Christel Herold‐Mende and Carlos Romero‐Nieto at the Universities of Heidelberg and Castilla–La Mancha. The image depicts the use of ...phosphaphenalene gold(I) complexes for the treatment of brain cancer. Read the full text of the article at 10.1002/chem.202104535.
“Two years after the discovery of the phosphaphenalene derivatives in 2015, Carlos Romero‐Nieto and Christel Herold‐Mende met for the first time at the University of Heidelberg with the aim of combining their respective knowledge on phosphaphenalene chemistry and cancer research to make important breakthroughs towards the treatment of brain cancer.” This and more about the story behind the front cover can be found in the article at 10.1002/chem.202104535).
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It is elusive whether clonal selection of tumor cells in response to ionizing radiation (IR) is a deterministic or stochastic process. With high resolution clonal barcoding and tracking of over 400 ...000 HNSCC patient‐derived tumor cells the clonal dynamics of tumor cells in response to IR was analyzed. Fractionated IR induced a strong selective pressure for clonal reduction which significantly exceeded uniform clonal survival probabilities indicative for a strong clone‐to‐clone difference within tumor cell lines. IR induced clonal reduction affected the majority of tumor cells ranging between 96% and 75% and correlated to the degree of radiation sensitivity. Survival to IR is driven by a deterministic clonal selection of a smaller population which commonly survives radiation, while increased clonogenic capacity is a result of clonal competition of cells which have been selected stochastically. A 2‐fold increase in radiation resistance results in a 4‐fold (P < .05) higher deterministic clonal selection showing that the ratio of these parameters is amenable to radiation sensitivity which correlates to prognostic biomarkers of HNSCC. Evidence for the existence of a rare subpopulation with an intrinsically radiation resistant phenotype commonly surviving IR was found at a frequency of 0.6% to 3.3% (P < .001, FDR 3%). With cellular barcoding we introduce a novel functional heterogeneity associated qualitative readout for tracking dynamics of clonogenic survival in response to radiation. This enables the quantification of intrinsically radiation resistant tumor cells from patient samples and reveals the contribution of stochastic and deterministic clonal selection processes in response to IR.
What's new?
To date, the clonal dynamics of patient‐derived tumour cells in response to irradiation have not been comprehensively analysed. Here, the authors reveal novel insights into these processes by using high‐resolution cellular barcoding and tracking over 400.000 head and neck squamous cell carcinoma patient‐derived tumour cells. They provide a functional heterogeneity‐associated qualitative readout for deciphering the clinically‐relevant contributions of stochastic and deterministic clonal selection processes in response to ionising radiation. The results highlight that clonal selection processes differ between patient‐derived cell lines, potentially explaining differences in tumour control rates between head and neck squamous cell carcinoma patients.
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As a substantial part of the brain tumor microenvironment (TME), glioma-associated microglia/macrophages (GAMs) have an emerging role in tumor progression and in controlling anti-tumor immune ...responses. We review challenges and improvements of cell models and highlight the contribution of this highly plastic cell population to an immunosuppressive TME, besides their well-known functional role regarding glioma cell invasion and angiogenesis. Finally, we summarize first therapeutic interventions to target GAMs and their effect on the immunobiology of gliomas, focusing on their interaction with T cells.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Tumor‐initiating cells are a subpopulation of cells that have self‐renewal capacity to regenerate a tumor. Here, we identify stem cell‐like chromatin features in human glioblastoma initiating cells ...(GICs) and link them to a loss of the repressive histone H3 lysine 9 trimethylation (H3K9me3) mark. Increasing H3K9me3 levels by histone demethylase inhibition led to cell death in GICs but not in their differentiated counterparts. The induction of apoptosis was accompanied by a loss of the activating H3 lysine 9 acetylation (H3K9ac) modification and accumulation of DNA damage and downregulation of DNA damage response genes. Upon knockdown of histone demethylases, KDM4C and KDM7A both differentiation and DNA damage were induced. Thus, the H3K9me3–H3K9ac equilibrium is crucial for GIC viability and represents a chromatin feature that can be exploited to specifically target this tumor subpopulation.
What's new?
Glioblastoma‐initiating cells (GICs) exhibit stem cell‐like properties, including the capacity for continuous self‐renewal. In this study, owing to the relevance of histone methylation and acetylation to DNA repair and self‐renewal in mouse and human embryonic stem cells, the authors investigated chromatin features in GICs. Analyses show that GICs possess an open chromatin structure, with enrichment of histone acetylation and reduced methylation. Inhibition of the histone demethylases KDM4C and KDM7A, leading to global restoration of H3K9me3 levels, reduced viability and induced differentiation in GICs. The findings suggest that selective targeting of histone demethylases is a promising strategy for eliminating GIC subpopulations.
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Glioblastoma is the most common and aggressive brain tumor, with a subpopulation of stem‐like cells thought to mediate its recurring behavior and therapeutic resistance. The epithelial–mesenchymal ...transition (EMT) inducing factor Zeb1 was linked to tumor initiation, invasion, and resistance to therapy in glioblastoma, but how Zeb1 functions at molecular level and what genes it regulates remain poorly understood. Contrary to the common view that EMT factors act as transcriptional repressors, here we show that genome‐wide binding of Zeb1 associates with both activation and repression of gene expression in glioblastoma stem‐like cells. Transcriptional repression requires direct DNA binding of Zeb1, while indirect recruitment to regulatory regions by the Wnt pathway effector Lef1 results in gene activation, independently of Wnt signaling. Amongst glioblastoma genes activated by Zeb1 are predicted mediators of tumor cell migration and invasion, including the guanine nucleotide exchange factor Prex1, whose elevated expression is predictive of shorter glioblastoma patient survival. Prex1 promotes invasiveness of glioblastoma cells in vivo highlighting the importance of Zeb1/Lef1 gene regulatory mechanisms in gliomagenesis.
Synopsis
Genome‐wide characterization of Zeb1 transcriptional targets in glioblastoma stem cells reveals how Zeb1 coordinately regulates an EMT‐like program, simultaneously promoting gene activation and repression via two different mechanisms.
ChIP‐seq mapping correlates transcriptional repression with direct Zeb1 binding to gene regulatory regions.
Indirect recruitment mediated by Lef/Tcf factors potentiates gene expression independent of Wnt signaling.
Activated genes include regulators of cell migration and invasion that correlate with Zeb1 expression in tumors.
Zeb1 activates Prex1 to promote glioblastoma cell invasion in vivo.
Genome‐wide binding reveals that the EMT‐inducer Zeb1, best‐known as a transcriptional repressor, can team up with a transcriptional activator to indirectly enhance gene expression.
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To determine the sensitivity and specificity of HPV16 serology as diagnostic marker for HPV16‐driven oropharyngeal squamous cell carcinoma (OPSCC), 214 HNSCC patients from Germany and Italy with ...fresh‐frozen tumor tissues and sera collected before treatment were included in this study. Hundred and twenty cancer cases were from the oropharynx and 94 were from head and neck cancer regions outside the oropharynx (45 oral cavity, 12 hypopharynx and 35 larynx). Serum antibodies to early (E1, E2, E6 and E7) and late (L1) HPV16 proteins were analyzed by multiplex serology and were compared to tumor HPV RNA status as the gold standard. A tumor was defined as HPV‐driven in the presence of HPV16 DNA and HPV16 transformation‐specific RNA transcript patterns (E6*I, E1∧E4 and E1C). Of 120 OPSCC, 66 (55%) were HPV16‐driven. HPV16 E6 seropositivity was the best predictor of HPV16‐driven OPSCC (diagnostic accuracy 97% 95%CI 92–99%, Cohen's kappa 0.93 95%CI 0.8–1.0). Of the 66 HPV‐driven OPSCC, 63 were HPV16 E6 seropositive, compared to only one (1.8%) among the 54 non‐HPV‐driven OPSCC, resulting in a sensitivity of 96% (95%CI 88–98) and a specificity of 98% (95%CI 90–100). Of 94 HNSCC outside the oropharynx, six (6%) were HPV16‐driven. In these patients, HPV16 E6 seropositivity had lower sensitivity (50%, 95%CI 19–81), but was highly specific (100%, 95%CI 96–100). In conclusion, HPV16 E6 seropositivity appears to be a highly reliable diagnostic marker for HPV16‐driven OPSCC with very high sensitivity and specificity, but might be less sensitive for HPV16‐driven HNSCC outside the oropharynx.
What's new?
Human papillomavirus (HPV) infection is associated with a subset of oropharyngeal squamous cell carcinomas (OPSCC). HPV‐driven OPSCC patients have an improved survival, but a reliable marker that is applicable in clinical operations is still needed. Here, the authors analyzed HPV16 antibody levels to the oncoproteins E6 and E7 and to the regulatory proteins E1 and E2 in the serum of patients with molecularly‐defined tumor HPV status. HPV16 serology could identify HPV‐driven OPSCC patients with very high sensitivity 96% (95%CI 88–98) and specificity 98% (95%CI 90–100). HPV16 serology may thus represent a powerful and accurate diagnostic marker for HPV‐driven OPSCC.
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Insight into the complex regulation of CD133 in glioma Campos, Benito; Herold‐Mende, Christel C.
International journal of cancer,
1 February 2011, 2011-Feb-01, 2011-02-00, 20110201, Volume:
128, Issue:
3
Journal Article
Peer reviewed
Open access
The transmembrane protein CD133 and its extracellular epitope AC133 are controversial cancer markers. In glioma, AC133 demarcates a subpopulation of stem‐like tumor cells, so‐called cancer stem cells ...(CSCs), which seem to drive tumor formation and are highly resistant to conventional chemo‐ and radiotherapy. Lately, experimental evidence for the existence of AC133‐independent CSCs has challenged the importance previously attributed to AC133‐positive glioma cells. These findings either imply that (i) AC133‐positive and AC133‐negative glioma cells comprise different, independent CSC populations, (ii) AC133‐positive glioma cells are derived from primordial AC133‐negative CSCs or (iii) AC133‐negative CSCs have lost AC133 expression, while retaining their stem‐like features and tumor initiation capacity, and can reacquire AC133 expression in vivo. In our article, we review evidence for and against each of the possible tumor models in glioma and will discuss technical hurdles in the AC133 detection process. In addition, we will outline new insights into CD133 regulation, which suggest certain degree of plasticity between some AC133‐positive and AC133‐negative CSC populations.
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