16 research outputs found
Abstract PR05: Lineage specifiers SOX2 and NKX2-1 inversely regulate lung tumor immune microenvironment
No full textAbstract
The tumor microenvironment is a critical effector of therapeutic response to diverse stimuli including immunotherapies. Lineage-specific drivers of cancer are known to dictate tumor differentiation and response to therapy, but how they influence the tumor immune microenvironment is largely unknown. SOX2 and NKX2-1 are critical regulators of lung development and cancer, with SOX2 amplifications associated with squamous lung cancer and NKX2-1 amplifications associated with lung adenocarcinoma. Here we employ and develop new genetically engineered mouse models (GEMMs) of lung cancer to interrogate the impact of SOX2 and NKX2-1 on innate immune infiltration. Squamous and adenocarcinoma GEMMs accurately recapitulate features of their human counterparts, including an enrichment of tumor-associated neutrophils (TANs) specifically in squamous lung cancer. We show that SOX2 recruits TANs, whereas NKX2-1 suppresses TANs, in the absence of histopathologic changes. SOX2 and NKX2-1 inversely regulate the neutrophil chemoattractant, Cxcl5, which is also upregulated in human squamous lung tumors. Using a novel GEMM of squamous lung cancer with a rapid latency of 3-4 months, preliminary data suggest that neutrophils can regulate adeno- to squamous transdifferentiation in vivo. Together these data reveal how lineage specifiers influence the tumor immune microenvironment, which in turn may regulate cancer cell fate.
This abstract is also being presented as Poster B19.
Citation Format: Gurkan Mollaoglu, Alex Jones, Anandaroop Mukhopadhyay, Jason Gertz, Kevin Jones, Eric Snyder, Trudy G. Oliver. Lineage specifiers SOX2 and NKX2-1 inversely regulate lung tumor immune microenvironment [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr PR05.</jats:p
Doctor of Philosophy
No full textdissertationThe clinical management of small cell lung cancer (SCLC) has primarily relied on chemotherapy for the last 40 years where all tumors are treated the same way regardless of their mutational status. MYC family member genes are frequently amplified in small cell lung tumors and cell lines in a mutually exclusive way. We developed a novel genetically engineered mouse model, in which we combined Myc ectopic expression with deletions of Trp53 and Rb1, two tumor-suppressor genes orthologs of which (i.e., TP53 and RB1) are almost universally lost together in human SCLC. For the first time, we demonstrated that MYC drives a neuroendocrine-low variant subtype of SCLC. In addition to the aggressive nature of these tumors such as rapid tumor growth and metastasis, we found that MYC-driven SCLC is specifically sensitive to Aurora kinase inhibition. Therefore, our findings not only revealed that MYC family oncogenes are responsible for tumor heterogeneity but also that SCLC should be stratified based on their genetics for subtype-specific targeted therapies. The majority of non-small cell lung cancers (NSCLC) are classified as lung adenocarcinoma (LADC) or lung squamous cell carcinoma (LSCC). SOX2 and NKX2-1 are the most frequently amplified genes in LSCC and LADC, respectively. SOX2 is a wellknown oncogene for LSCC while NKX2-1 has context-dependent oncogenic and tumorsuppressive functions in LADC. We report that SOX2-driven squamous mouse tumors recapitulate cellular and molecular features of human lung squamous tumors faithfully, iv including the tumor immune microenvironment (TIME). We found that NKX2-1 is a tumorsuppressor gene for LSCC, and deletion of Nkx2-1 significantly accelerates squamous tumorigenesis. Importantly, we discovered the genetic mechanism behind differential neutrophil recruitment in lung cancer. Specifically, SOX2 and NKX2-1 inversely regulate neutrophil chemotaxis to lung cancer, partly through transcriptional regulation of the chemokine Cxcl5. We identified that a subset of tumor-associated neutrophils in LSCC is protumorigenic and surprisingly provides preferential support to squamous tumors over adenocarcinomas. These findings provide a novel example of the emerging paradigm of how cancer cell intrinsic genetic programs can shape the TIME in addition to the unexpected biology of how the modified TIME, in turn, can influence cancer cell fate
Spatial genomics uncovers cytokines promoting ovarian tumour heterogeneity and immunotherapy resistance
No full textTHE DESTRUCTION OF CRETE (TIS KRITIS O CHALASMOS): A POEM ON THE EARTHQUAKE IN CRETE IN 1508
No full textThe Destruction of Crete (Tis Kritis o chalasmos) is a poem of 282 verses. Its subject is the major earthquake of 29 May 1508, and it seems that the poem was written in the same year. Half of it is an account of the disaster in Candia, together with people's reactions to it, and a description of a storm on 5 June. In the second part the author ascribes the disaster to the sinfulness of people and he exhorts them to ask God for forgiveness and to pray for the victims. The name Crete in the poem mostly refers to its capital city rather than the entire island. The Destruction of Crete is one of the most important historical sources of this earthquake, as Manolis Sklavos was an eyewitness of the disaster. Another significant source of information about the 1508 earthquake in Crete is the letter of Girolamo Donato, the Venetian Duke of Crete, dated July 15, 1508
Interval Type-2 Trapezoidal Fuzzy AHP: Evaluation of Sustainable Port Service Quality Factors
No full textPort service quality stands in a vital position in port competitiveness. In this study, we aimed to prioritize the Sustainable Port Service Quality (SPSQ) factors. Firstly, we investigated the SPSQ factors with the help of the related literature. We determined 3 main, and 15 sub-criteria evaluate the SPSQ. Survey questionnaire forms were sent to the experts who perform in several different areas in the port sector. Afterward, we employed the interval type-2 fuzzy analytic hierarchy process (IT2-FAHP) to weighting the identified criteria. According to the results, the economic main criteria were selected as the most prioritized criteria for experts’ evaluations. Furthermore, C1.2. “Efficiency of Loading and Discharging Operations” and C1.5 “Port Infrastructure” and C3.1. “Environmentally Responsible Operations (Waste Management etc.)” were evaluated as the most three prioritized sub-criteria with the highest scores respectively. This study contributed to the literature in two different unique ways; (1) revealing the SPSQ criteria and (2) employing the IT2-FAHP method to prioritize the port service quality criteria. Identified service quality model can be used for port practitioners and findings may be applied as recommendations for port practitioners to have a greater influence on their customers. © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
CLIC4 and CLIC1 bridge plasma membrane and cortical actin network for a successful cytokinesis
No full textCLIC4 and CLIC1 are members of the well-conserved chloride intracellular channel proteins (CLICs) structurally related to glutathione-S-transferases. Here, we report new roles of CLICs in cytokinesis. At the onset of cytokinesis, CLIC4 accumulates at the cleavage furrow and later localizes to the midbody in a RhoA-dependent manner. The cell cycle-dependent localization of CLIC4 is abolished when its glutathione S-transferase activity-related residues (C35A and F37D) are mutated. Ezrin, anillin, and ALIX are identified as interaction partners of CLIC4 at the cleavage furrow and midbody. Strikingly, CLIC4 facilitates the activation of ezrin at the cleavage furrow and reciprocally inhibition of ezrin activation diminishes the translocation of CLIC4 to the cleavage furrow. Furthermore, knockouts of CLIC4 and CLIC1 cause abnormal blebbing at the polar cortex and regression of the cleavage furrow at late cytokinesis leading to multinucleated cells. We conclude that CLIC4 and CLIC1 function together with ezrin where they bridge plasma membrane and actin cytoskeleton at the polar cortex and cleavage furrow to promote cortical stability and successful completion of cytokinesis in mammalian cells
Quantitative comparison of a human cancer cell surface proteome between interphase and mitosis
No full textThe cell surface is the cellular compartment responsible for communication with the environment. The interior of mammalian cells undergoes dramatic reorganization when cells enter mitosis. These changes are triggered by activation of the CDK1 kinase and have been studied extensively. In contrast, very little is known of the cell surface changes during cell division. We undertook a quantitative proteomic comparison of cell surface-exposed proteins in human cancer cells that were tightly synchronized in mitosis or interphase. Six hundred and twenty-eight surface and surface-associated proteins in HeLa cells were identified; of these, 27 were significantly enriched at the cell surface in mitosis and 37 in interphase. Using imaging techniques, we confirmed the mitosis-selective cell surface localization of protocadherin PCDH7, a member of a family with anti-adhesive roles in embryos. We show that PCDH7 is required for development of full mitotic rounding pressure at the onset of mitosis. Our analysis provided basic information on how cell cycle progression affects the cell surface. It also provides potential pharmacodynamic biomarkers for anti-mitotic cancer chemotherapy
Abstract B72: Lineage specifiers SOX2 and NKX2-1 inversely regulate tumor cell fate and neutrophil recruitment in lung cancer
No full textThe Lineage-Defining Transcription Factors SOX2 and NKX2-1 Determine Lung Cancer Cell Fate and Shape the Tumor Immune Microenvironment
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