Theodora Agalioti

University Medical Center Hamburg-Eppendorf

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Anastasios D. Giannou

Universität Hamburg

Georgios T. Stathopoulos

Helmholtz Zentrum München

Malamati Vreka

Helmholtz Zentrum München

ΜΣ

Μάγδα Σπέλλα

University of Patras

Antonia Marazioti

University of Patras

Ioanna Giopanou

University of Patras

Ioannis Lilis

University of Patras

Nikolaos I. Kanellakis

Oxford University Hospitals NHS Trust

Dimitra E. Zazara

University Medical Center Hamburg-Eppendorf

Nicola Gagliani

Universität Hamburg

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Universität Hamburg

152

University Medical Center Hamburg-Eppendorf

152

University of Patras

Yale University

Martini-Klinik

Ludwig-Maximilians-Universität München

German Center for Lung Research

Heidelberg University

Helmholtz Zentrum München

Howard Hughes Medical Institute

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TGF-β signaling in Th17 cells promotes IL-22 production and colitis-associated colon cancer

Nature Communications (2020)

Laura García Pérez Jan Kempski Heather M. McGee Penelope Pelzcar Theodora Agalioti

IL-22 has dual functions during tumorigenesis. Short term IL-22 production protects against genotoxic stress, whereas uncontrolled IL-22 activity promotes tumor growth; therefore, tight regulation of IL-22 is essential. TGF-β1 promotes the differentiation of Th17 cells, which are known to be a major source of IL-22, but the effect of TGF-β signaling on the production of IL-22 in CD4+ T cells is controversial. Here we show an increased presence of IL-17+IL-22+ cells and TGF-β1 in colorectal cancer compared to normal adjacent tissue, whereas the frequency of IL-22 single producing cells is not changed. Accordingly, TGF-β signaling in CD4+ T cells (specifically Th17 cells) promotes the emergence of IL-22-producing Th17 cells and thereby tumorigenesis in mice. IL-22 single producing T cells, however, are not dependent on TGF-β signaling. We show that TGF-β, via AhR induction, and PI3K signaling promotes IL-22 production in Th17 cells.

10.1038/s41467-020-16363-w

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Mutant KRAS promotes malignant pleural effusion formation

Nature Communications (2017)

Theodora Agalioti Anastasios D. Giannou Anthi C. Krontira Nikolaos I. Kanellakis Danai Kati

Abstract Malignant pleural effusion (MPE) is the lethal consequence of various human cancers metastatic to the pleural cavity. However, the mechanisms responsible for the development of MPE are still obscure. Here we show that mutant KRAS is important for MPE induction in mice. Pleural disseminated, mutant KRAS bearing tumour cells upregulate and systemically release chemokine ligand 2 (CCL2) into the bloodstream to mobilize myeloid cells from the host bone marrow to the pleural space via the spleen. These cells promote MPE formation, as indicated by splenectomy and splenocyte restoration experiments. In addition, KRAS mutations are frequently detected in human MPE and cell lines isolated thereof, but are often lost during automated analyses, as indicated by manual versus automated examination of Sanger sequencing traces. Finally, the novel KRAS inhibitor deltarasin and a monoclonal antibody directed against CCL2 are equally effective against an experimental mouse model of MPE, a result that holds promise for future efficient therapies against the human condition.

Sanger sequencing

10.1038/ncomms15205

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Supplementary Figure Legends 1-2 from A Tumor-Protective Role for Human Kallikrein-Related Peptidase 6 in Breast Cancer Mediated by Inhibition of Epithelial-to-Mesenchymal Transition

Georgios Pampalakis Evangelia Prosnikli Theodora Agalioti Antonia Vlahou Vassilis Zoumpourlis

Supplementary Figure Legends 1-2 from A Tumor-Protective Role for Human Kallikrein-Related Peptidase 6 in Breast Cancer Mediated by Inhibition of Epithelial-to-Mesenchymal Transition

10.1158/0008-5472.22379991

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Supplementary Figure 2 from A Tumor-Protective Role for Human Kallikrein-Related Peptidase 6 in Breast Cancer Mediated by Inhibition of Epithelial-to-Mesenchymal Transition

Georgios Pampalakis Evangelia Prosnikli Theodora Agalioti Antonia Vlahou Vassilis Zoumpourlis

Supplementary Figure 2 from A Tumor-Protective Role for Human Kallikrein-Related Peptidase 6 in Breast Cancer Mediated by Inhibition of Epithelial-to-Mesenchymal Transition

10.1158/0008-5472.22379994

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LSC Abstract – A requirement for IKKa in lung adenocarcinoma

Malamati Vreka Ioannis Lilis Maria Papageorgopoulou Μάγδα Σπέλλα Antonia Marazioti

Background: Nuclear factor (NF)-kB activation is essential for KRAS-mutant lung adenocarcinoma (Stathopoulos, G.T. et al. Proc Natl Acad Sci U S A 2007;104:18514-9 and Meylan, E. et al. Nature 2009;462:104-7). However, the relative contributions of NF-kB-activating kinases IKKa and IKKb are unknown. Aims: To monitor and block NF-kB activation and IKK functions in lung adenocarcinoma. Methods: NF-kB reporter mice and conditional IKKa/b gene deleted mice were used, which, respectively, express firefly luciferase in all somatic cells upon NF-kB activation, or lose the respective IKK gene upon CRE-mediated recombination. Lung adenocarcinomas were induced in these mice via ip injection of urethane (1 g/Kg) that is a tobacco carcinogen. Mutant KRAS-IKK interactions were studied using transfected benign HEK293T cells with mutant KRAS-and/or IKK-expression vectors. IKK-inhibitors are used in ADCA cell lines and KRAS-induced mice. Results: Urethane caused strong NF-kB activation in the lungs, characterized by significant induction and nuclear translocation of IKKa, but not IKKb. Deletion of IKKa from the respiratory epithelium resulted in almost complete eradication of urethane-induced KRAS-mutant lung tumors, while deletion of IKKb was less protective. IKKb, but not IKKa, functioned as a tumor promoter in KRAS-wild-type HEK293T cells. However, only IKKa, and not IKKb, could render mutant KRAS-expressing HEK293T cells oncogenic in immunocompromized mice. In KRAS-IKKa-addicted tumorigenic HEK293T cells, IKKa resided in the nucleus.Dual IKK inhibitor is more effective in our models than IKKb inhibitor. Conclusions: IKKa is required for KRAS-mediated lung adenocarcinoma. Funding: European Research Council Starting Independent Investigator Grant #260524.

IκB kinase

HEK 293 cells

10.1183/13993003.congress-2016.pp140

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ActivatedKRASsignaling triggers malignant pleural effusion

Theodora Agalioti Anastasios D. Giannou Antonia Marazioti Nikolaos I. Kanellakis Μάγδα Σπέλλα

Background: EGFR/KRAS axis mutations are frequent in human malignantpleuraleffusions (MPE). Aims: To investigate the relationship between perturbations in the EGFR-KRAS axis and malignant pleural effusion development. Methods: Several mouse and human cancer cell lines were characterized for EGFR/KRAS status and for their MPE competence in appropriate hosts. EGFR/KRAS signalling was modulated in various cell lines via standard molecular techniques. MPE-associated inflammation was monitored by bioluminescence imaging, immunophenotyped by flow cytometry, and modulated by splenectomy and adoptive bone marrow transfer. EGFR/KRAS axis was targeted using gefitinib, deltarasin, and anti-CCL2 antibodies. Results: A causative relationship between ΔKras and MPEwas established by showing that mouse and human cancer cell lines bearingΔKras are MPE competent and that activated Kras is capable of conferring MPE competency to human and mouse cells. Furthermore, Kras dependent downstream paracrine signaling to bone marrow activated a distinct GR1+/CD11B+ myeloid cell population, which is maturing in the spleen and is consequently recruited to the pleural cavity in a cancer-elaborated CCL2-dependent way. Splenectomy partially protects hosts from MPE. The pharmacological manipulation of ΔEGFR/ΔKRAS axis with Gefitinib (targeting ΔEGFR) or Deltarasin (targeting ΔKRAS) and the antibody-mediated neutralization of CCL2 completely annihilate MPE formation and the recruitment of CD11b+/GR1+ cells to the pleura. Conclusions: Our work provides insights to MPE pathobiology and a multitude of strategies to target a currently untreatable terminal human condition. Funding: European Research Council Starting Independent Investigator Grant #260524.

10.1183/13993003.congress-2015.oa5007

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LSC Abstract – Osteopontin as an airway epithelial tumor promoter

Ioannis Psallidas N Kanellakis Malamati Vreka Anastasios D. Giannou L Maniatis

Osteopontin (SPP1) expression has been identified in human lung cancer and has been linked with enhanced tumor progression. To examine its functional role, we induced lung tumors by repetitive urethane or MCA/BHT lung carcinogens in C57BL/6 mice lacking both (Spp1-/-), one (Spp1+/-), or no (Spp1+/+) copy of the endogenous Spp1 gene. Primary end-points were lung tumor number and size; secondary end-points were SPP1 expression, epithelial cell survival, carcinogen-induced inflammation, and angiogenesis. Data are presented as mean±SD. Compared with Spp1+/+ mice (n=22), Spp1-/- mice (n=25) developed dramatically fewer and significantly smaller lung tumors in response to urethane, while Spp1+/- mice (n=12) behaved similar to Spp1-/- mice (number/diameter of lung tumors in Spp1+/+, Spp1+/-, and Spp1-/- mice, respectively: 16.1±12.7/1.2±0.3 mm, 2.4±2.3/0.9±0.2 mm, and 1.3±1.6/0.7±0.2 mm; P<0.05 for comparison of Spp1+/+ with Spp1-/- and Spp1+/- mice). Spp1-/- mice were also protected from two-hit MCA/BHT-oncogenesis compared with Spp1+/+ controls. Spp1-/- mice displayed decreased epithelial cell survival and reduced numbers of airspace macrophages early after urethane, and enhanced tumor cell apoptosis and limited tumor angiogenesis at late stages of lung tumor progression. SPP1 was expressed in the naïve lung by non-ciliated airway epithelial cells and alveolar macrophages and was significantly up-regulated during multi-stage lung carcinogenesis. SPP1 also initiated the survival of mutant Kras cells. Our data indicate that SPP1 is functionally involved in airway epithelial carcinogenesis via survival of mutant Kras cells and may present a target for lung cancer treatment and prevention.

Osteopontin

Tumor progression

10.1183/13993003.congress-2016.pp232

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Osteopontin As An Airway Epithelial Tumor Promoter

American Journal of Respiratory and Critical Care Medicine (2016)

Ioannis Psallidas N Kanellakis Malamati Vreka Anastasios D. Giannou L Maniatis

Osteopontin

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Pleural involvement in lung cancer.

PubMed (2015)

Theodora Agalioti Anastasios D. Giannou Georgios T. Stathopoulos

The pleural space, a sterile secluded environment in the thoracic cavity, represents an attractive metastatic site for various cancers of lung, breast and gastrointestinal origins. Whereas lung and breast adenocarcinomas could invade the pleural space because of their anatomic proximity, "distant" cancers like ovarian or gastrointestinal tract adenocarcinomas may employ more active mechanisms to the same end. A pleural metastasis is often accompanied by a malignant pleural effusion (MPE), an unfavorable complication that severely restricts the quality of life and expectancy of the cancer patient. MPE is the net "product" of three different processes, namely inflammation, enhanced angiogenesis and vascular leakage. Current efforts are focusing on the identification of cancer cell autocrine (specific mutation spectra and biochemical pathways) and paracrine (cytokine and chemokine signals) characteristics as well as host features (immunological or other) that underlie the MPE phenotype. Herein we examine the pleural histology, cytology and molecular characteristics that make the pleural cavity an attractive metastasis destination for lung adenocarcinoma. Mesothelial and tumor features that may account for the tumor's ability to invade the pleural space are highlighted. Finally, possible therapeutic interventions specifically targeting MPE are discussed.

Pleural cavity

10.3978/j.issn.2072-1439.2015.04.23

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Supplementary Data from IκB Kinase α Is Required for Development and Progression of <i>KRAS</i>-Mutant Lung Adenocarcinoma

Malamati Vreka Ioannis Lilis Maria Papageorgopoulou Georgia A. Giotopoulou Marina Lianou

<p>Supplementary file containing Supplementary Methods (pertaining to reagents, imaging, immunoblotting, cellular studies, microarray data, NF-κB ELISA, PCR, cell culture, histology, cytology, flow cytometry, constructs, and cellular Assays), 4 Supplementary Tables (pertaining to number of experimental mice, PCR primers, antibodies, and lentiviral shRNA pools), and 7 Supplementary Figures (described in the main and Supplementary text).</p>

10.1158/0008-5472.22417056

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