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dc.contributor.advisorRichard O. Hynes.en_US
dc.contributor.authorBista, Bigyan R. (Bigyan Raj)en_US
dc.contributor.otherMassachusetts Institute of Technology. Department of Biology.en_US
dc.date.accessioned2016-09-13T19:08:04Z
dc.date.available2016-09-13T19:08:04Z
dc.date.copyright2016en_US
dc.date.issued2016en_US
dc.identifier.urihttp://hdl.handle.net/1721.1/104169
dc.descriptionThesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2016.en_US
dc.descriptionCataloged from student-submitted PDF version of thesis.en_US
dc.descriptionIncludes bibliographical references.en_US
dc.description.abstractAdhesion-GPCRs, a novel family of G protein-coupled receptors (GPCRs), are characterized by an extended extracellular region linked to a seven-pass transmembrane moiety via GPCR proteolytic site (GPS)-containing stalk region known as GAIN domain. The name adhesion refers to the presence of functional domains in the extracellular region that commonly mediate cell-cell and cell-matrix interactions in various contexts. Recently, many genome-scale analyses of genetic alterations across diverse cancer types have revealed significant alterations (copy number and mutational) in adhesion-GPCRs, yet no comprehensive examination of their roles in cancer biology exists. Through a systematic screening for all adhesion-GPCRs by RT-qPCR in murine mammary carcinoma cell lines with varying metastatic abilities as well as tumor samples of different grades, I have identified several candidate genes with possible roles in breast cancer progression and metastasis. Based on these analyses and cross-referencing with the published gene expression data on human breast cancer cell lines and patient samples, I chose two candidate genes, CELSR2 and GPR126, for more detailed investigation. To elucidate their functions in cancer biology, I investigated the effects of their perturbations using RNAi (loss-of-function) methods both in vitro and in vivo. The results from my work reveal that loss of CELSR2 affects neither tumor growth nor lung metastasis in a xenograft mouse model of breast cancer, despite enhancing invadopodial activity in vitro. I also show that highly metastatic breast cancer and melanoma cells have elevated levels of GPR126, and confirm the significance of this result by revealing (a) reduction in pulmonary metastasis without affecting primary tumor growth in a spontaneous metastasis model of breast cancer, and (b) reduction in lung metastasis in three different experimental metastasis models of breast cancer and melanoma, upon shRNA-mediated knockdown of GPR126. After probing the different steps in the metastatic cascade to investigate how GPR126 promotes metastasis, I demonstrate that GPR126 specifically affects extravasation, most likely through its engagement with type IV collagen in the sub-endothelial basement membrane. Thus, the work described in this thesis contributes to our overall understanding of the perplexing problem of cancer metastasis via identification of novel regulators of distinct steps along the ominous path of malignant cells from primary sites to distant organs.en_US
dc.description.statementofresponsibilityby Bigyan R. Bista.en_US
dc.format.extent161 pagesen_US
dc.language.isoengen_US
dc.publisherMassachusetts Institute of Technologyen_US
dc.rightsM.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission.en_US
dc.rights.urihttp://dspace.mit.edu/handle/1721.1/7582en_US
dc.subjectBiology.en_US
dc.titleAdhesion-GPCRs in cancer progression and metastasisen_US
dc.typeThesisen_US
dc.description.degreePh. D.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biology.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biology
dc.identifier.oclc958132182en_US


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