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Irradiation Regulated Secretome of ADAM17


Villars, Danielle Carmen. Irradiation Regulated Secretome of ADAM17. 2018, University of Zurich, Faculty of Medicine.

Abstract

One of the biggest and most important challenges of modern science is to defeat cancer. Decades of research have significantly improved the therapeutic outcome, yet have failed to satisfactorily control all of the different types of cancer. The reasons are most likely due to the heterogeneity of the development of cancer: mutations, epigenetic changes, abnormalities and defects in multiple different genes and proteins can lead to aberrant cell behavior, that can ultimately result in the disease called “cancer”. Radiotherapy is a standard treatment strategy for cancer patients, applied alone or in combination with other treatment regimes, and mostly aims to kill tumor cells by DNA damage. Interestingly, tumor cells exposed to ionizing radiation release several factors into the tumor microenvironment where they influence signaling cascades in an auto- and/or paracrine fashion. Radiotherapy kills a clear majority of tumor cells, but also induces a multilayered stress response that may interfere with optimal treatment outcome. In foresight to the development of novel drug targets that can be used to improve radiotherapy, my thesis focuses on the intra- and intercellular signaling pathways orchestrated by the metalloproteinase ADAM17. ADAM17 is localized on the outer side of the plasma membrane and cleaves multiple factors involved in tumor progression and inflammation. In several cancer types, ADAM17 expression is increased compared to healthy tissue and correlates with poor prognosis. Our previous studies also implicated ADAM17’s role in radiosensitizing cells towards ionizing radiation. In a first part, I aimed to identify the role of a shRNA-mediated downregulation of ADAM17 in two different NSCLC cell lines (A549 and H358) in response to IR. Downregulation of the protein levels concomitantly resulted in decreased enzyme activity and subsequent ligand shedding. Additionally, ADAM17-depleted cells showed decreased proliferative activity and clonogenic survival in a dose-dependent way. Based on this evidence, we conclude that ADAM17 is involved in mechanisms influencing efficacy of ionizing radiation. In a second part, we investigated ADAM17’s effect on intra- and intercellular signaling affecting migration. Astonishingly, migration was increased towards a secretome full of ADAM17-cleaved factors as compared to an ADAM17-cleaved factor scarce secretome. These results indicate an involvement of ADAM17-cleaved factors in intra- and intercellular communication affecting migration.
In conclusion, the thesis underlines the undeniable involvement of ADAM17 in orchestrating radioresistance. Additionally, it helps to further explain the intra- and intercellular regulatory mechanisms facilitated by ADAM17. Altogether, the work of this thesis supports the rational of combining radiotherapy with a potent ADAM17 inhibitor to improve treatment outcome.

Abstract

One of the biggest and most important challenges of modern science is to defeat cancer. Decades of research have significantly improved the therapeutic outcome, yet have failed to satisfactorily control all of the different types of cancer. The reasons are most likely due to the heterogeneity of the development of cancer: mutations, epigenetic changes, abnormalities and defects in multiple different genes and proteins can lead to aberrant cell behavior, that can ultimately result in the disease called “cancer”. Radiotherapy is a standard treatment strategy for cancer patients, applied alone or in combination with other treatment regimes, and mostly aims to kill tumor cells by DNA damage. Interestingly, tumor cells exposed to ionizing radiation release several factors into the tumor microenvironment where they influence signaling cascades in an auto- and/or paracrine fashion. Radiotherapy kills a clear majority of tumor cells, but also induces a multilayered stress response that may interfere with optimal treatment outcome. In foresight to the development of novel drug targets that can be used to improve radiotherapy, my thesis focuses on the intra- and intercellular signaling pathways orchestrated by the metalloproteinase ADAM17. ADAM17 is localized on the outer side of the plasma membrane and cleaves multiple factors involved in tumor progression and inflammation. In several cancer types, ADAM17 expression is increased compared to healthy tissue and correlates with poor prognosis. Our previous studies also implicated ADAM17’s role in radiosensitizing cells towards ionizing radiation. In a first part, I aimed to identify the role of a shRNA-mediated downregulation of ADAM17 in two different NSCLC cell lines (A549 and H358) in response to IR. Downregulation of the protein levels concomitantly resulted in decreased enzyme activity and subsequent ligand shedding. Additionally, ADAM17-depleted cells showed decreased proliferative activity and clonogenic survival in a dose-dependent way. Based on this evidence, we conclude that ADAM17 is involved in mechanisms influencing efficacy of ionizing radiation. In a second part, we investigated ADAM17’s effect on intra- and intercellular signaling affecting migration. Astonishingly, migration was increased towards a secretome full of ADAM17-cleaved factors as compared to an ADAM17-cleaved factor scarce secretome. These results indicate an involvement of ADAM17-cleaved factors in intra- and intercellular communication affecting migration.
In conclusion, the thesis underlines the undeniable involvement of ADAM17 in orchestrating radioresistance. Additionally, it helps to further explain the intra- and intercellular regulatory mechanisms facilitated by ADAM17. Altogether, the work of this thesis supports the rational of combining radiotherapy with a potent ADAM17 inhibitor to improve treatment outcome.

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Additional indexing

Item Type:Master's Thesis
Referees:Pruschy Martin, Knobel Philip A
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Radiation Oncology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:September 2018
Deposited On:22 Feb 2019 13:46
Last Modified:07 Apr 2020 07:19
OA Status:Green

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