Migration pattern, actin cytoskeleton organization and response to PI3K-, mTOR-, and Hsp90-inhibition of glioblastoma cells with different invasive capacities

Memmel, Simon; Sisario, Dmitri; Zöller, Caren; Fiedler, V.; Katzer, Astrid; Heiden, Robin; Becker, Nicholas; Eing, Lorenz; Ferreira, Fábio L.R.; Zimmermann, Heiko; Sauer, Markus; Flentje, Michael; Sukhorukov, Vladimir L.; Djuzenova, Cholpon S.

doi:10.18632/oncotarget.16847

Cited by 29 publications

(44 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent studies indicate that the HSP90 inhibitors 17-AAG and AUY922 also can affect cancer cell motility and migration (31)(32)(33)(34). To investigate whether these effects translate to onalespib, the effects of cisplatin and/or onalespib on migration and wound healing were investigated in two separate migration assays (Figure 4).…”

Section: Discussionmentioning

confidence: 99%

Overcoming Limitations of Cisplatin Therapy by Additional Treatment With the HSP90 Inhibitor Onalespib

et al. 2020

View full text Add to dashboard Cite

Rational: Cisplatin based cancer therapy is an affordable and effective standard therapy for several solid cancers, including lung, ovarian and head and neck cancers. However, the clinical use of cisplatin is routinely limited by the development of drug resistance and subsequent therapeutic failure. Therefore, methods of circumventing cisplatin resistance have the potential to increase therapeutic efficiency and dramatically increase overall survival. Cisplatin resistance can be mediated by alterations to the DNA damage response, where multiple components of the repair machinery have been described to be client proteins of HSP90. In the present study, we have investigated whether therapy with the novel HSP90 inhibitor onalespib can potentiate the efficacy of cisplatin and potentially reverse cisplatin resistance in ovarian and head and neck cancer cells. Methods: Cell viability, cancer cell proliferation and migration capacity were evaluated in vitro on models of ovarian and head and neck cancer cells. Western blotting was used to assess the downregulation of HSP90 client proteins and alterations in downstream signaling proteins after exposure to cisplatin and/or onalespib. Induction of apoptosis and DNA damage response were evaluated in both monotherapy and combination therapy groups. Results: Results demonstrate that onalespib enhances the efficiency of cisplatin in a dose-dependent manner. Tumor cells treated with both drugs displayed lower viability and a decreased migration rate compared to vehicle-control cells and cells treated with individual compounds. An increase of DNA double strand breaks was observed in both cisplatin and onalespib treated cells. The damage was highest and most persistent in the combination group, delaying the DNA repair machinery. Further, the cisplatin and onalespib co-treated cells had greater apoptotic activity compared to controls. Conclusion: The results of this study demonstrate that the reduced therapeutic efficacy of cisplatin due to drug-resistance could be overcome by combination treatment with onalespib. We speculate that the increased apoptotic signaling, DNA damage as well as the downregulation of HSP90 client proteins are important mechanisms promoting increased sensitivity to cisplatin treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

Overcoming Limitations of Cisplatin Therapy by Additional Treatment With the HSP90 Inhibitor Onalespib

et al. 2020

View full text Add to dashboard Cite

show abstract

“…As a result, patients with GBM currently have a median survival of only 15 mo (Parsons et al 2008;Weller et al 2015;Ostrom et al 2016). This poor prognosis is due, in part, to the diffusive invasive growth of GBM cells, which prevents the possibility of complete resection and limits the effect of local radiotherapy (Naumman et al 2013;Memmel et al 2017). Poor prognosis can also be attributed to large inter-and intratumoral heterogeneity, wherein tumor subpopulations associated with different molecular characteristics develop resistance to radiation and chemotherapies (Liu et al 2018;Akgül et al 2019).…”

Section: Introductionmentioning

confidence: 99%

Molecular and clonal evolution in recurrent metastatic gliosarcoma

Anderson

Tan

Parkinson

et al. 2020

Cold Spring Harb Mol Case Stud

View full text Add to dashboard Cite

We discuss the molecular evolution of gliosarcoma, a mesenchymal type of glioblastoma (GBM), using the case of a 37-yr-old woman who developed two recurrences and an extracranial metastasis. She was initially diagnosed with isocitrate dehydrogenase (IDH) wild-type gliosarcoma in the frontal lobe and treated with surgery followed by concurrent radiotherapy with temozolomide. Five months later the tumor recurred in the left frontal lobe, outside the initially resected area, and was treated with further surgery and radiotherapy. Six months later the patient developed a second left frontal recurrence and was again treated with surgery and radiotherapy. Six weeks later, further recurrence was observed in the brain and bone, and biopsy confirmed metastases in the pelvic bones. To understand the clonal relationships between the four tumor instances and the origin of metastasis, we performed whole-genome sequencing of the intracranial tumors and the tumor located in the right iliac bone. We compared their mutational and copy-number profiles and inferred the clonal phylogeny. The tumors harbored shared alterations in GBM driver genes, including mutations in TP53, NF1, and RB1, and CDKN2A deletion. Whole-genome doubling was identified in the first recurrence and the extracranial metastasis. Comparisons of the metastatic to intracranial tumors highlighted a high similarity in molecular profile but contrasting evidence regarding the origin of the metastasis. Subclonal reconstruction suggested a parallel evolution of the recurrent tumors, and that the metastatic tumor was largely derived from the first recurrence. We conclude that metastasis in glioma can be a late event in tumorigenesis.

show abstract

“…Our results suggest a novel timescale that can be targeted by parallel anti-migratory drugs, especially those that have reversible action such as certain cytochalasins [49,50], during radiotherapy and chemotherapy. Interestingly, anti-migratory drugs have recently been suggested by others for the improvement of radiotherapy [17,25] and chemotherapy [51,52]. Based on our results, the first 24 to 48 hours should be prime time to use the anti-migratory strategies.…”

Section: Timescales In Alteration Of Migration Reversible Interventimentioning

confidence: 60%

“…Several studies have since then been carried out to document the effects of radiotherapy on cancer cell migration and extensive reviews of these have been done [4,5]. Majority of the results showed that ionizing radiation enhanced the migration of cancer cells including GBM [21,[24][25][26]. A few cases [27,28] of purportedly reduced migration were included in the review [5] but it turns out that one of these [28] actually reported radiation-induced enhancement of migration and not reduction.…”

Section: Introductionmentioning

confidence: 99%

Radiotherapy and chemotherapy alter migration of brain cancer cells before cell death

Merrick

Mimlitz

Weeder

et al. 2020

Preprint

View full text Add to dashboard Cite

Although radiotherapy and most cancer drugs target the proliferation of cancer cells, it is metastasis, the complex process by which cancer cells spread from the primary tumor to other tissues and organs of the body where they form new tumors, that leads to over 90% of all cancer deaths. Thus, there is an urgent need for anti-metastasis strategies alongside chemotherapy and radiotherapy. An important step in the metastatic cascade is migration. It is the first step in metastasis via local invasion. Here we address the question whether ionizing radiation and/or chemotherapy might inadvertently promote metastasis and/or invasiveness by enhancing cell migration. We used a standard laboratory irradiator, Faxitron CellRad, to irradiate both non-cancer (HCN2 neurons) and cancer cells (T98G glioblastoma) with 2 Gy, 10 Gy and 20 Gy of X-rays. Paclitaxel (5 μM) was used for chemotherapy. We then measured the attachment and migration of the cells using an electric cell substrate impedance sensing device. Both the irradiated HCN2 cells and T98G cells showed significantly (p < 0.01) enhanced migration compared to non-irradiated cells, within the first 20 to 40 hours following irradiation with 20 Gy. Our results suggest that cell migration should be a therapeutic target in anti-metastasis/anti-invasion strategies for improved radiotherapy and chemotherapy outcomes.

show abstract

Migration pattern, actin cytoskeleton organization and response to PI3K-, mTOR-, and Hsp90-inhibition of glioblastoma cells with different invasive capacities

Cited by 29 publications

References 49 publications

Overcoming Limitations of Cisplatin Therapy by Additional Treatment With the HSP90 Inhibitor Onalespib

Overcoming Limitations of Cisplatin Therapy by Additional Treatment With the HSP90 Inhibitor Onalespib

Molecular and clonal evolution in recurrent metastatic gliosarcoma

Radiotherapy and chemotherapy alter migration of brain cancer cells before cell death

Contact Info

Product

Resources

About