Search

Simple Summary: Although the involvement of the H3.3K27M mutation in Diffuse Midline Glioma tumorigenesis is now established, its role in their resistance to treatments and, therefore, in their fatal outcome remains poorly documented. Here, thanks to our models of H3.3K27M induction in pediatric glioma cells, we finally shed light on this crucial issue. Hence, we demonstrate here for the first time that H3.3K27M can increase cell radioresistance capabilities independently of TP53 alterations. Moreover, thanks to a drug library screening, we evidenced that this mutation can, depending on the cellular context, drastically modulate the response of these cells to different classes of compounds, thus paving the way for new therapeutic strategies. Altogether, our results provide here the proof that, beyond its role in tumorigenesis, the presence of H3.3K27M mutation by itself alters the response to treatments of pediatric glioma cells. High-grade gliomas represent the most lethal class of pediatric tumors, and their resistance to both radio- and chemotherapy is associated with a poor prognosis. Recurrent mutations affecting histone genes drive the tumorigenesis of some pediatric high-grade gliomas, and H3K27M mutations are notably characteristic of a subtype of gliomas called DMG (Diffuse Midline Gliomas). This dominant negative mutation impairs H3K27 trimethylation, leading to profound epigenetic modifications of genes expression. Even though this mutation was described as a driver event in tumorigenesis, its role in tumor cell resistance to treatments has not been deciphered so far. To tackle this issue, we expressed the H3.3K27M mutated histone in three initially H3K27-unmutated pediatric glioma cell lines, Res259, SF188, and KNS42. First, we validated these new H3.3K27M-expressing models at the molecular level and showed that K27M expression is associated with pleiotropic effects on the transcriptomic signature, largely dependent on cell context. We observed that the mutation triggered an increase in cell growth in Res259 and SF188 cells, associated with higher clonogenic capacities. Interestingly, we evidenced that the mutation confers an increased resistance to ionizing radiations in Res259 and KNS42 cells. Moreover, we showed that H3.3K27M mutation impacts the sensitivity of Res259 cells to specific drugs among a library of 80 anticancerous compounds. Altogether, these data highlight that, beyond its tumorigenic role, H3.3K27M mutation is strongly involved in pediatric glioma cells' resistance to therapies, likely through transcriptomic reprogramming. [ABSTRACT FROM AUTHOR]

Tremendous data have been accumulated in the effort to understand chemoresistance of triple negative breast cancer (TNBC). However, modifications in cancer cells surviving combined and sequential treatment still remain poorly described. In order to mimic clinical neoadjuvant treatment, we first treated MDA-MB-231 and SUM159-PT TNBC cell lines with epirubicin and cyclophosphamide for 2 days, and then with paclitaxel for another 2 days. After 4 days of recovery, persistent cells surviving the treatment were characterized at both cellular and molecular level. Persistent cells exhibited increased growth and were more invasive in vitro and in zebrafish model. Persistent cells were enriched for vimentinhigh sub-population, vimentin knockdown using siRNA approach decreased the invasive and sphere forming capacities as well as Akt phosphorylation in persistent cells, indicating that vimentin is involved in chemotherapeutic treatment-induced enhancement of TNBC aggressiveness. Interestingly, ectopic vimentin overexpression in native cells increased cell invasion and sphere formation as well as Akt phosphorylation. Furthermore, vimentin overexpression alone rendered the native cells resistant to the drugs, while vimentin knockdown rendered them more sensitive to the drugs. Together, our data suggest that vimentin could be considered as a new targetable player in the ever-elusive status of drug resistance and recurrence of TNBC. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite many therapeutic approaches attempted over the last years, the prognosis of children with high-grade glioma or diffuse intrinsic pontine glioma remains dismal. Hypoxia-activated prodrugs (HAPs) were developed to target hypoxic areas within solid tumors as gliomas. Evofosfamide (Evo) is a 2nd generation HAP exhibiting significant preclinical and clinical activities against adult glioblastoma. We thus investigated the potential of Evo in six pediatric glioma cell lines. Interestingly, we showed that the growth of all cell lines was inhibited by Evo, mainly under hypoxia as expected. We also evidenced a significant synergism between Evo and three drugs widely used in pediatric oncology. Finally, Evo appeared able to potentiate the effect of ionizing radiations. Since these tumors are highly hypoxic and Evo appears effective in hypoxic glioma cells as a single drug and in combination with radio- and chemotherapy, hypoxia-activated prodrugs could represent a promising therapeutic option for children with brain tumors. Hypoxia is a hallmark of many solid tumors and is associated with resistance to anticancer treatments. Hypoxia-activated prodrugs (HAPs) were developed to target the hypoxic regions of these tumors. Among 2nd generation HAPs, Evofosfamide (Evo, also known as TH-302) exhibits preclinical and clinical activities against adult glioblastoma. In this study, we evaluated its potential in the field of pediatric neuro-oncology. We assessed the efficacy of Evo in vitro as a single drug, or in combination with SN38, doxorubicin, and etoposide, against three pediatric high-grade glioma (pHGG) and three diffuse intrinsic pontine glioma (DIPG) cell lines under hypoxic conditions. We also investigated radio-sensitizing effects using clonogenic assays. Evo inhibited the growth of all cell lines, mainly under hypoxia. We also highlighted a significant synergism between Evo and doxorubicin, SN38, or etoposide. Finally, Evo radio-sensitized the pHGG cell line tested, both with fractionated and single-dose irradiation schedules. Altogether, we report here the first preclinical proof of evidence about Evofosfamide efficiency against hypoxic pHGG and DIPG cells. Since such tumors are highly hypoxic, and Evo potentiates the effect of ionizing radiation and chemotherapy, it appears as a promising therapeutic strategy for children with brain tumors. [ABSTRACT FROM AUTHOR]