Heterogeneous intracellular TRAIL-receptor distribution predicts poor outcome in breast cancer patients

Heilmann, Thorsten; Vondung, Florian; Borzikowsky, Christoph; Szymczak, Silke; Krüger, Sandra; Alkatout, İbrahim; Wenners, Antonia; Bauer, M.; Klapper, Wolfram; Röcken, Christoph; Maass, Nicolaì; Karstedt, Silvia von; Schem, Christian; Trauzold, Anna

doi:10.1007/s00109-019-01805-w

Cited by 10 publications

(8 citation statements)

References 41 publications

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“…Intriguingly, many biological effects observed for endogenous TRAIL-TRAIL-R signaling are reminiscent of the effects observed for immune checkpoints preventing autoimmune disease 12 . In a similar manner to the PD-1-PD-L1 system, expression of TRAIL and its receptors is frequently upregulated in cancer 38,[77][78][79] . Interestingly, in PDAC, a cancer in which conventional ICB failed to provide clinical benefit, high PD-L1 expression only correlates with shortened progression-free but not overall survival (Fig.…”

Section: Oncogenic Kras-mediated Rewiring Of Trail Signalingmentioning

confidence: 99%

An unexpected turn of fortune: targeting TRAIL-Rs in KRAS-driven cancer

Karstedt

Walczak

2020

Cell Death Discov.

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Twenty-one percent of all human cancers bear constitutively activating mutations in the proto-oncogene KRAS. This incidence is substantially higher in some of the most inherently therapy-resistant cancers including 30% of non-small cell lung cancers (NSCLC), 50% of colorectal cancers, and 95% of pancreatic ductal adenocarcinomas (PDAC). Importantly, survival of patients with KRAS-mutated PDAC and NSCLC has not significantly improved since the 1970s highlighting an urgent need to reexamine how oncogenic KRAS influences cell death signaling outputs. Interestingly, cancers expressing oncogenic KRAS manage to escape antitumor immunity via upregulation of programmed cell death 1 ligand 1 (PD-L1). Recently, the development of next-generation KRAS G12C-selective inhibitors has shown therapeutic efficacy by triggering antitumor immunity. Yet, clinical trials testing immune checkpoint blockade in KRASmutated cancers have yielded disappointing results suggesting other, additional means endow these tumors with the capacity to escape immune recognition. Intriguingly, oncogenic KRAS reprograms regulated cell death pathways triggered by death receptors of the tumor necrosis factor (TNF) receptor superfamily. Perverting the course of their intended function, KRAS-mutated cancers use endogenous TNF-related apoptosis-inducing ligand (TRAIL) and its receptor(s) to promote tumor growth and metastases. Yet, endogenous TRAIL-TRAIL-receptor signaling can be therapeutically targeted and, excitingly, this may not only counteract oncogenic KRAS-driven cancer cell migration, invasion, and metastasis, but also the immunosuppressive reprogramming of the tumor microenvironment it causes. Here, we provide a concise summary of the current literature on oncogenic KRAS-mediated reprogramming of cell death signaling and antitumor immunity with the aim to open novel perspectives on combinatorial treatment strategies involving death receptor targeting. Facts • KRAS is the most frequently mutated protooncogene in human cancers. • KRAS-mutated cancers show poor checkpoint blockade response. • TNF superfamily ligand signaling is reprogrammed to mediate migration, invasion, and metastasis in KRAS-mutated cancer.

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Section: Oncogenic Kras-mediated Rewiring Of Trail Signalingmentioning

confidence: 99%

An unexpected turn of fortune: targeting TRAIL-Rs in KRAS-driven cancer

Karstedt

Walczak

2020

Cell Death Discov.

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“…Research performed by Furukawa et al [30] demonstrated that the MCP-1 chemokine promoted the invasion and adhesion of the ovarian cancer cell line SKOV3, contributing to the progression of tumors. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-R3 and -R4 are known as the negative regulators of TRAIL-mediated apoptosis in cancer cells [31][32][33]. The internalization of HATMSC2-MVs by the examined cell lines exerts a different effect on ovarian cancer cells, and decrease the level of TRAIL-R3 and TRAIL-R4 in ES-2 cells and increase their level in OAW-42 cell lines.…”

Section: Effect Of Hatmsc2-mvs On the Secretion Profile Of Ovarian Camentioning

confidence: 99%

Suppression of Ovarian Cancer Cell Growth by AT-MSC Microvesicles

Szyposzynska

Bielawska‐Pohl

Krawczenko

et al. 2020

IJMS

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Transport of bioactive cargo of microvesicles (MVs) into target cells can affect their fate and behavior and change their microenvironment. We assessed the effect of MVs derived from human immortalized mesenchymal stem cells of adipose tissue-origin (HATMSC2-MVs) on the biological activity of the ovarian cancer cell lines ES-2 (clear cell carcinoma) and OAW-42 (cystadenocarcinoma). The HATMSC2-MVs were characterized using dynamic light scattering (DLS), transmission electron microscopy, and flow cytometry. The anti-tumor properties of HATMSC2-MVs were assessed using MTT for metabolic activity and flow cytometry for cell survival, cell cycle progression, and phenotype. The secretion profile of ovarian cancer cells was evaluated with a protein antibody array. Both cell lines internalized HATMSC2-MVs, which was associated with a decreased metabolic activity of cancer cells. HATMSC2-MVs exerted a pro-apoptotic and/or necrotic effect on ES-2 and OAW-42 cells and increased the expression of anti-tumor factors in both cell lines compared to control. In conclusion, we confirmed an effective transfer of HATMSC2-MVs into ovarian cancer cells that resulted in the inhibition of cell proliferation via different pathways, apoptosis and/or necrosis, which, with high likelihood, is related to the presence of different anti-tumor factors secreted by the ES-2 and OAW-42 cells.

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“…The TRAIL apoptotic process occurs by its binding to death receptors but the competitive interaction with decoy receptors 1 (DcR1 /TRAILR3 /TNFRSF10C ) and 2 (DcR2 /TRAILR4 /TNFRSF10D) can induce an inhibitory effect [72]. The overexpression of TN-FRSF10D was shown to be able to protect cells against apoptosis and its expression was associated with BC risk [74,75]. Furthermore, aberrant promoter methylation of TRAIL decoy receptors can be affected by DNMT3A which can be a direct target of microRNAs [76,77].…”

Section: Discussionmentioning

confidence: 99%

Integrative analysis of mRNA and miRNA proﬁles identifies miR-193 and miR-210 as potential regulatory biomarkers in diﬀerent molecular subtypes of breast cancer

Evangelista

Oliveira

Silva

et al. 2021

Preprint

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Background: Breast cancer is the most frequently diagnosed malignancy among women. However, the role of microRNA (miRNA) expression in breast cancer progression is not fully understood. In this study we examined predictive interactions between differentially expressed miRNAs and mRNAs in breast cancer cell lines representative of the common molecular subtypes. Integrative bioinformatics analysis identified miR-193 and miR-210 as potential regulatory biomarkers of mRNA in breast cancer. Several recent studies have investigated these miRNAs in a broad range of tumors, but the mechanism of their involvement in cancer progression has not previously been investigated.Methods: The miRNA-mRNA interactions in breast cancer cell lines were identified by parallel expression analysis and miRNA target prediction programs. The expression profiles of mRNA and miRNAs from luminal (MCF-7, MCF-7/AZ and T47D), HER2 (BT20 and SK-BR3) and triple negative subtypes (Hs578T e MDA-MB-231) could be clearly separated by unsupervised analysis using HB4A cell line as a control. Breast cancer miRNA data from TCGA patients were grouped according to molecular subtypes and then used to validate these findings. Expression of miR-193 and miR-210 was investigated by miRNA transient silencing assays using the MCF7, BT20 and MDA-MB-231 cell lines. Functional studies included, xCELLigence system, ApoTox-Glo triplex assay, flow cytometry and transwell inserts were performed to determine cell proliferation, cytotoxicity, apoptosis, migration and invasion, respectively.Results: The most evident effects were associated with cell proliferation after miR-210 silencing in triple negative subtype cell line MDA-MB-231. Using in silico prediction algorithms, TNFRSF10 was identified as one of the potential regulated downstream targets for both miRNAs. The TNFRSF10C and TNFRSF10D mRNA expression inversely correlated with the expression levels of miR-193 and miR210 in breast cell lines and breast cancer patients, respectively. Other potential regulated genes whose expression also inversely correlated with both miRNAs were CCND1, a known mediator on invasion and metastasis, and the tumor suppressor gene RUNX3.Conclusions: In summary, our findings identify miR-193 and miR-210 as potential regulatory miRNA in different molecular subtypes of breast cancer and suggest that miR-210 may have a specific role in MDA-MB-231 proliferation. Our results highlight important new downstream regulated targets that may serve as promising therapeutic pathways for aggressive breast cancers

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Heterogeneous intracellular TRAIL-receptor distribution predicts poor outcome in breast cancer patients

Cited by 10 publications

References 41 publications

An unexpected turn of fortune: targeting TRAIL-Rs in KRAS-driven cancer

An unexpected turn of fortune: targeting TRAIL-Rs in KRAS-driven cancer

Suppression of Ovarian Cancer Cell Growth by AT-MSC Microvesicles

Integrative analysis of mRNA and miRNA proﬁles identifies miR-193 and miR-210 as potential regulatory biomarkers in diﬀerent molecular subtypes of breast cancer

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