Therapy-Naive and Radioresistant 3-Dimensional Pancreatic Cancer Cell Cultures Are Effectively Radiosensitized by ß1 Integrin Targeting.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a cancer with unmet needs. The role of highly conformal radiation therapy is still under debate for PDAC. Owing to its desmoplastic nature, integrin-mediated interactions between PDAC cells and extracellular matrix (ECM) profoundly contribute to PDAC therapy resistance. In this study, we investigated the radiochemosensitizing potential of ß1 integrin targeting in therapy-naive and radioresistant PDAC cell cultures grown in 3-dimensional (3D) ECM. METHODS AND MATERIALS: In a panel of 3D, ECM-based PDAC cell cultures, ß1 integrin was inhibited by antibodies or siRNA-mediated knockdown. Together with x-ray irradiation and specific chemotherapies, we determined 3D colony formation capacity in therapy-naive and radioresistant PDAC cultures. We used kinome profiling, Western blotting, and immunofluorescence stainings to characterize these cell lines. Various siRNA screens were conducted to identify novel therapeutic targets. RESULTS: We found a significant radiosensitizing potential of ß1 integrin inhibition both in therapy-naive and radioresistant PDAC cell cultures. Kinome profiling upon ß1 integrin targeting identified a generally declined tyrosine and serine/threonine kinase activity, which presented less prominent in radioresistant than in therapy-naive PDAC cells. siRNA screens employing the top 34 deregulated kinases in combination with ß1 integrin inhibition revealed less efficacy and less radiosensitization in radioresistant relative to therapy-naive PDAC cell cultures. Triple inhibition of ß1 integrin, protein kinase D1, and rearranged during transfection turned out to be most effective in reducing 3D colony formation of radioresistant PDAC cells. CONCLUSIONS: Our study clearly shows that ß1 integrins are robust targets for overcoming radioresistance in PDAC. This seems to apply equally to therapy-sensitive and radioresistant cells. Concerning tumor heterogeneity, this dual therapy-sensitizing potential might be exploitable for a significant improvement of patient survival.

Correction: Görte et al. Comparative Proton and Photon Irradiation Combined with Pharmacological Inhibitors in 3D Pancreatic Cancer Cultures. Cancers 2020, 12, 3216.

The authors wish to make the following corrections to this paper [...].

Comparative Proton and Photon Irradiation Combined with Pharmacological Inhibitors in 3D Pancreatic Cancer Cultures.

Pancreatic ductal adenocarcinoma (PDAC) is a highly therapy-resistant tumor entity of unmet needs. Over the last decades, radiotherapy has been considered as an additional treatment modality to surgery and chemotherapy. Owing to radiosensitive abdominal organs, high-precision proton beam radiotherapy has been regarded as superior to photon radiotherapy. To further elucidate the potential of combination therapies, we employed a more physiological 3D, matrix-based cell culture model to assess tumoroid formation capacity after photon and proton irradiation. Additionally, we investigated proton- and photon-irradiation-induced phosphoproteomic changes for identifying clinically exploitable targets. Here, we show that proton irradiation elicits a higher efficacy to reduce 3D PDAC tumoroid formation and a greater extent of phosphoproteome alterations compared with photon irradiation. The targeting of proteins identified in the phosphoproteome that were uniquely altered by protons or photons failed to cause radiation-type-specific radiosensitization. Targeting DNA repair proteins associated with non-homologous endjoining, however, revealed a strong radiosensitizing potential independent of the radiation type. In conclusion, our findings suggest proton irradiation to be potentially more effective in PDAC than photons without additional efficacy when combined with DNA repair inhibitors.

Comparative proteomic analysis of silver nanoparticle effects in human liver and intestinal cells.

Consumers are orally exposed to nanoparticulate or soluble species of the non-essential element silver due to its use in food contact materials or as a food additive. Potential toxicity of silver nanoparticles has gained special scientific attention. A fraction of ingested ionic or particulate silver is taken up in the intestine and transported to the liver, where it may induce oxidative stress and elicit subsequent adverse responses. Here, we present a comprehensive analysis of global proteomic changes induced in human Hep G2 hepatocarcinoma cells by different concentrations of AgPURE silver nanoparticles or by corresponding concentrations of ionic silver. Bioinformatic analysis of proteomic data confirms and substantiates previous findings on silver-induced alterations related to redox stress, mitochondrial dysfunction, intermediary metabolism, inflammatory responses, posttranslational protein modification and other cellular parameters. Similarities between the effects exerted by the two silver species are in line with the assumption that silver ions released from nanoparticles substantially contribute to their toxicity. Moreover, a comparative bioinformatic evaluation of proteomic effects in hepatic and intestinal cells exerted either by silver nanoparticles or bionic silver is presented. Our results show that, despite remarkable differences at the level of affected proteins in the different cell lines, highly similar biological consequences, corresponding to previous in vivo findings, can be deduced by applying appropriate bioinformatic data mining.