Efficient DNA Repair Mitigates Replication Stress Resulting in Less Immunogenic Cytosolic DNA in Radioresistant Breast Cancer Stem Cells

Meyer, Felix; Engel, Anna Maria; Krause, Ann Kristin; Wagner, Tim; Poole, Lena; Dubrovska, Anna; Peitzsch, Claudia; Rothkamm, Kai; Petersen, Cordula; Borgmann, Kerstin

doi:10.3389/fimmu.2022.765284

Cited by 9 publications

(12 citation statements)

References 58 publications

(99 reference statements)

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“…It has been reported that metastatic spread to the brain has an impact on radioresistance of MDA-MB-231 cells as shown by a clonogenic assay (34) which could be due to the influence of the brain microenvironment on gene expression patterns of the tumor cells, as also indicated by the findings of Park et al (35). Radioresistance was verified as previously described (27). The clonogenic survival (Figure 1) confirms that the RR clones have enhanced potential to still form colonies after radiation exposure compared the non-RR clones.…”

Section: Discussionsupporting

confidence: 70%

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Clonogenicity-based radioresistance determines the expression of immune suppressive immune checkpoint molecules after hypofractionated irradiation of MDA-MB-231 triple-negative breast cancer cells

et al. 2023

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Only a subset of patients with triple-negative breast cancer (TNBC) benefits from a combination of radio- (RT) and immunotherapy. Therefore, we aimed to examine the impact of radioresistance and brain metastasizing potential on the immunological phenotype of TNBC cells following hypofractionated RT by analyzing cell death, immune checkpoint molecule (ICM) expression and activation of human monocyte-derived dendritic cells (DCs). MDA-MB-231 triple-negative breast cancer tumor cells were used as model system. Apoptosis was the dominant cell death form of brain metastasizing tumor cells, while Hsp70 release was generally significantly increased following RT and went along with necrosis induction. The ICMs PD-L1, PD-L2, HVEM, ICOS-L, CD137-L and OX40-L were found on the tumor cell surfaces and were significantly upregulated by RT with 5 x 5.2 Gy. Strikingly, the expression of immune suppressive ICMs was significantly higher on radioresistant clones compared to their respective non-radioresistant ones. Although hypofractionated RT led to significant cell death induction and release of Hsp70 in all tumor cell lines, human monocyte-derived DCs were not activated after co-incubation with RT-treated tumor cells. We conclude that radioresistance is a potent driver of immune suppressive ICM expression on the surface of TNBC MDA-MB-231 cells. This mechanism is generally known to predominantly influence the effector phase, rather than the priming phase, of anti-tumor immune responses.

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Section: Discussionsupporting

confidence: 70%

“…Four different human MDA-MB-231 cell lines with differences in radioresistance (according to their behaviour in the clonogenic assays) were investigated ( 27 ). Besides the wildtype (WT), a brain-metastasizing (BR) clone was used.…”

Section: Methodsmentioning

confidence: 99%

Clonogenicity-based radioresistance determines the expression of immune suppressive immune checkpoint molecules after hypofractionated irradiation of MDA-MB-231 triple-negative breast cancer cells

et al. 2023

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“…RS has been highlighted as a hallmark of malignant tumor radiosensitivity (6,14). Impaired responses to RS sensitize tumors to radiation (15), highlighting the importance of RSaimed therapy for radiation treatment.…”

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confidence: 99%

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

Zhang

Wang

et al. 2022

Front. Oncol.

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DNA replication is a process fundamental in all living organisms in which deregulation, known as replication stress, often leads to genomic instability, a hallmark of cancer. Most malignant tumors sustain persistent proliferation and tolerate replication stress via increasing reliance to the replication stress response. So whilst replication stress induces genomic instability and tumorigenesis, the replication stress response exhibits a unique cancer-specific vulnerability that can be targeted to induce catastrophic cell proliferation. Radiation therapy, most used in cancer treatment, induces a plethora of DNA lesions that affect DNA integrity and, in-turn, DNA replication. Owing to radiation dose limitations for specific organs and tumor tissue resistance, the therapeutic window is narrow. Thus, a means to eliminate or reduce tumor radioresistance is urgently needed. Current research trends have highlighted the potential of combining replication stress regulators with radiation therapy to capitalize on the high replication stress of tumors. Here, we review the current body of evidence regarding the role of replication stress in tumor progression and discuss potential means of enhancing tumor radiosensitivity by targeting the replication stress response. We offer new insights into the possibility of combining radiation therapy with replication stress drugs for clinical use.

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“…BCSCs isolated from triple-negative cell lines showed elevated expression of the MRN complex component RAD50, leading to enhanced HR activity [ 139 ]. Similarly, BCSCs derived from the ER + MCF-7 cell line demonstrated reduced sensitivity to IR treatment which was correlated to increased HR activity as measured by the I-Sce/GFP reporter assay [ 140 ]. Interestingly, these BCSCs also showed a more effective RS response because hydroxyurea promoted replication fork degradation and DNA damage more extensively in the bulk MCF-7 population [ 140 ].…”

Section: Dna Damage Repair In Cscs and Therapeutic Interventionmentioning

confidence: 99%

“…Similarly, BCSCs derived from the ER + MCF-7 cell line demonstrated reduced sensitivity to IR treatment which was correlated to increased HR activity as measured by the I-Sce/GFP reporter assay [ 140 ]. Interestingly, these BCSCs also showed a more effective RS response because hydroxyurea promoted replication fork degradation and DNA damage more extensively in the bulk MCF-7 population [ 140 ]. Supporting this, gene expression profiling of BCSCs from PDX breast models identified an enriched RS response gene signature compared to bulk tumour cells [ 141 ].…”

Section: Dna Damage Repair In Cscs and Therapeutic Interventionmentioning

confidence: 99%

DNA Repair and Therapeutic Strategies in Cancer Stem Cells

Gillespie

Ward

Davies

2023

Cancers

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First-line cancer treatments successfully eradicate the differentiated tumour mass but are comparatively ineffective against cancer stem cells (CSCs), a self-renewing subpopulation thought to be responsible for tumour initiation, metastasis, heterogeneity, and recurrence. CSCs are thus presented as the principal target for elimination during cancer treatment. However, CSCs are challenging to drug target because of numerous intrinsic and extrinsic mechanisms of drug resistance. One such mechanism that remains relatively understudied is the DNA damage response (DDR). CSCs are presumed to possess properties that enable enhanced DNA repair efficiency relative to their highly proliferative bulk progeny, facilitating improved repair of double-strand breaks induced by radiotherapy and most chemotherapeutics. This can occur through multiple mechanisms, including increased expression and splicing fidelity of DNA repair genes, robust activation of cell cycle checkpoints, and elevated homologous recombination-mediated DNA repair. Herein, we summarise the current knowledge concerning improved genome integrity in non-transformed stem cells and CSCs, discuss therapeutic opportunities within the DDR for re-sensitising CSCs to genotoxic stressors, and consider the challenges posed regarding unbiased identification of novel DDR-directed strategies in CSCs. A better understanding of the DDR mediating chemo/radioresistance mechanisms in CSCs could lead to novel therapeutic approaches, thereby enhancing treatment efficacy in cancer patients.

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Efficient DNA Repair Mitigates Replication Stress Resulting in Less Immunogenic Cytosolic DNA in Radioresistant Breast Cancer Stem Cells

Cited by 9 publications

References 58 publications

Clonogenicity-based radioresistance determines the expression of immune suppressive immune checkpoint molecules after hypofractionated irradiation of MDA-MB-231 triple-negative breast cancer cells

Clonogenicity-based radioresistance determines the expression of immune suppressive immune checkpoint molecules after hypofractionated irradiation of MDA-MB-231 triple-negative breast cancer cells

Replication Stress: A Review of Novel Targets to Enhance Radiosensitivity-From Bench to Clinic

DNA Repair and Therapeutic Strategies in Cancer Stem Cells

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