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MYC is implicated in the development and progression of pancreatic cancer, yet the precise level of MYC deregulation required to contribute to tumor development has been difficult to define. We used modestly elevated expression of human MYC, driven from the Rosa26 locus, to investigate the pancreatic phenotypes arising in mice from an approximation of MYC trisomy. We show that this level of MYC alone suffices to drive pancreatic neuroendocrine tumors, and to accelerate progression of KRAS-initiated precursor lesions to metastatic pancreatic ductal adenocarcinoma (PDAC). Our phenotype exposed suppression of the type I interferon (IFN) pathway by the combined actions of MYC and KRAS, and we present evidence of repressive MYC–MIZ1 complexes binding directly to the promoters of the genes encodiing the type I IFN regulators IRF5, IRF7, STAT1, and STAT2. Derepression of IFN regulator genes allows pancreatic tumor infiltration by B and natural killer (NK) cells, resulting in increased survival. Significance: We define herein a novel mechanism of evasion of NK cell–mediated immunity through the combined actions of endogenously expressed mutant KRAS and modestly deregulated expression of MYC, via suppression of the type I IFN pathway. Restoration of IFN signaling may improve outcomes for patients with PDAC. This article is highlighted in the In This Issue feature, p. 747

Inducible genetically defined mouse models of cancer uniquely facilitate the investigation of early events in cancer progression, however, there are valid concerns about the ability of such models to faithfully recapitulate human disease. We developed an inducible mouse model of progressive lung adenocarcinoma (LuAd) that combines sporadic activation of oncogenic KRasG12D with modest overexpression of c-MYC (KM model). Histological examination revealed a highly reproducible spontaneous transition from low-grade adenocarcinoma to locally invasive adenocarcinoma within 6 weeks of oncogene activation. Laser-capture microdissection coupled with RNA-SEQ (ribonucleic acid sequencing) was employed to determine transcriptional changes associated with tumour progression. Upregulated genes were triaged for relevance to human LuAd using datasets from Oncomine and cBioportal. Selected genes were validated by RNAi screening in human lung cancer cell lines and examined for association with lung cancer patient overall survival using KMplot.com. Depletion of progression-associated genes resulted in pronounced viability and/or cell migration defects in human lung cancer cells. Progression-associated genes moreover exhibited strong associations with overall survival, specifically in human lung adenocarcinoma, but not in squamous cell carcinoma. The KM mouse model faithfully recapitulates key molecular events in human adenocarcinoma of the lung and is a useful tool for mechanistic interrogation of KRAS-driven LuAd progression.

Photodynamic therapy (PDT) represents a rapidly developing alternative treatment for various types of cancers. Although considered highly effective, cancer cells can exploit various mechanisms, including the upregulation of apoptosis inhibitors, to overcome the cytotoxic effect of PDT. Survivin, a member of the inhibitor of apoptosis protein family, is known to play a critical role in cancer progression and therapeutic resistance and therefore represents a potential therapeutic target. The aim of this study was to investigate whether YM155, a small molecule inhibitor of survivin expression, can potentiate the cytotoxic effect of hypericin-mediated PDT (HY-PDT). Accordingly, two cell lines resistant to HY-PDT, HT-29 (colorectal adenocarcinoma) and A549 (lung adenocarcinoma), were treated either with HY-PDT alone or in combination with YM155. The efficacy of different treatment regimens was assessed by MTT assay, flow cytometry analysis of metabolic activity, viability, phosphatidylserine externalisation, mitochondrial membrane potential and caspase-3 activity and immunoblotting for the cleavage of poly (ADP-ribose) polymerase (PARP). Here we show for the first time that the repression of survivin expression by YM155 is effective in sensitizing HT-29 and A549 cells to HY-PDT, as measured by the decrease in cell viability and induction of apoptosis. Combined treatment with hypericin and YM155 led to a more severe dissipation of the mitochondrial membrane potential and caused an increase in caspase-3 activation and subsequent PARP cleavage. Our results demonstrate that the repression of survivin expression by YM155 potentially represents a novel alternative strategy to increase the efficacy of HY-PDT in cancer cells that are otherwise weakly responsive or non-responsive to treatment.

Lung cancer is the main cause of all cancer-related deaths in the world, with lung adenocarcinoma (ADC) being the most common subtype of this fatal disease. Lung ADC is often diagnosed at advanced stages involving disseminated metastatic tumors. This is particularly important for the successful development of new cancer therapy approaches. The high resistance of lung ADC to conventional radio- and chemotherapies represents a major challenge to treatment effectiveness. Here we discuss recent progress in understanding the mechanisms of ADC's broad resistance to treatment and its possible therapeutic implications. A number of driving oncogenic alterations were identified in a subset of lung ADCs, making them suitable for targeted therapies directed towards specific cancer-associated molecular changes. In addition, we discuss the molecular aberrations common in lung ADC that are currently being exploited or are potentially important for targeted cancer therapy, as well as limitations of this type of therapy. Furthermore, we highlight possible treatment modalities that hold promise for overcoming resistance to targeted therapies as well as alternative treatment options such as immunotherapies that are potentially promising for improving the clinical outcome of lung ADC patients.

// Anna Zagryazhskaya 1 , Olga Surova 1, 2 , Nadeem S. Akbar 1 , Giulia Allavena 1, 3 , Katarina Gyuraszova 1, 4 , Irina B. Zborovskaya 5, 6 , Elena M. Tchevkina 5, 6 , Boris Zhivotovsky 1, 6 1 Institute of Environmental Medicine, Division of Toxicology, Stockholm, Sweden 2 Ludwig Institute for Cancer Research Ltd, Karolinska Institutet, Stockholm, Sweden 3 Department of Molecular and Developmental Medicine, University of Siena, Siena, Italy 4 Institute of Biology and Ecology, Faculty of Science, Pavol Jozef Safarik University in Kosice, Kosice, Slovakia 5 NN Blokhin Russian Cancer Research Center, Moscow, Russia 6 Faculty of Fundamental Medicine, ML Lomonosov State University, Moscow, Russia Correspondence to: Boris Zhivotovsky, e-mail: Boris.Zhivotovsky@ki.se Keywords: tudor staphylococcal nuclease, S100A11, phospholipase A 2 , non-small cell lung cancer, apoptosis Received: December 19, 2014 Accepted: March 07, 2015 Published: March 26, 2015 ABSTRACT Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC), the major lung cancer subtype, is characterized by high resistance to chemotherapy. Here we demonstrate that Tudor staphylococcal nuclease (SND1 or TSN) is overexpressed in NSCLC cell lines and tissues, and is important for maintaining NSCLC chemoresistance. Downregulation of TSN by RNAi in NSCLC cells led to strong potentiation of cell death in response to cisplatin. Silencing of TSN was accompanied by a significant decrease in S100A11 expression at both mRNA and protein level. Downregulation of S100A11 by RNAi resulted in enhanced sensitivity of NSCLC cells to cisplatin, oxaliplatin and 5-fluouracil. AACOCF 3 , a phospholipase A 2 (PLA 2 ) inhibitor, strongly abrogated chemosensitization upon silencing of S100A11 suggesting that PLA 2 inhibition by S100A11 governs the chemoresistance of NSCLC. Moreover, silencing of S100A11 stimulated mitochondrial superoxide production, which was decreased by AACOCF 3 , as well as N -acetyl- L -cysteine, which also mimicked the effect of PLA 2 inhibitor on NSCLC chemosensitization upon S100A11 silencing. Thus, we present the novel TSN-S100A11-PLA 2 axis regulating superoxide-dependent apoptosis, triggered by platinum-based chemotherapeutic agents in NSCLC that may be targeted by innovative cancer therapies.

Summary Background Photodynamic therapy (PDT) is a highly efficient approach for tumour therapy, though it also has its drawbacks, too. There are multiple mechanisms involved in cell death regulation that can be successfully targeted for improvement of PDT in particular cases. We assumed, however, that the potential to manage radical stress might be the primary factor responsible for resistance to hypericin-mediated PDT (HY-PDT). Methods We compared the sensitivity of six colon-derived cancer cell lines to HY-PDT at IC50 equitoxic doses acquired by formazan-based (MTT) assay. Intracellular hypericin content, cell survival/metabolic activity, caspase-3 activation/mitochondrial membrane potential dissipation, apoptosis, glutathione level, redox status (NAD(P)H/oxidized flavins ratio) and Western blot analyses of proteins relevant in apoptosis regulation were measured to demonstrate differences between tested cell lines. Results Analyses revealed a whole spectrum of responses from insignificant to high cytotoxicity, despite the MTT-based “equitoxicity”. Further critical evaluation of multiple parameters linked to cell physiology and proteomics proved that intracellular hypericin content, glutathione level or redox status demonstrate partial but not direct correlation with resistance to HY-PDT, when considered separately. However, their logical conjunction did copy the trend of cellular resistance. Conclusions We may conclude that intracellular level of hypericin and glutathione together with redox state of the target cell represent a potential combination of parameters responsible for the primary cytotoxicity of HY-PDT. We also present evidence that cytotoxic assays, such as the MTT, should be accompanied with other tests of cell survival/cytotoxicity in order to avoid incorrect conclusions.