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dc.contributor.advisorJacqueline A. Lees.en_US
dc.contributor.authorNeupane, Rachit.en_US
dc.contributor.otherMassachusetts Institute of Technology. Department of Biology.en_US
dc.date.accessioned2019-09-16T16:38:14Z
dc.date.available2019-09-16T16:38:14Z
dc.date.issued2019en_US
dc.identifier.urihttps://hdl.handle.net/1721.1/122061
dc.descriptionThis electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.en_US
dc.descriptionThesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, 2019en_US
dc.descriptionCataloged from student-submitted PDF version of thesis. "May 2019."en_US
dc.descriptionIncludes bibliographical references.en_US
dc.description.abstractPredictive value is expected when preclinical models of disease are used for research. However, not all models appropriately mimic the disease progression or the treatment paradigm in the clinic. This thesis addresses an epigenetic regulator, Bmi1, which acts in stem cells to maintain their proliferative and self-renewal capacity primarily through silencing of the Ink4a/Arf locus. Bmi1 has been proposed as a good therapeutic candidate in cancer because of its presumed role in maintaining tumor propagating cells (TPCs). This conclusion is based on the observed tumor suppressive effects of Bmi1 deletion in in vitro cell culture models, in vivo transplant models, and autochthonous models in which Bmi1 was absent throughout development. However, to date, no one has assessed the consequences of deleting Bmi1 in existing autochthonous tumors, to mimic patient treatment in the clinic.en_US
dc.description.abstractTo accomplish this, we have generated a mouse model that allows induction of autochthonous lung adenocarcinoma, driven by oncogenic Kras and Tp53 loss (KP LUAD), and subsequent deletion of Bmi1 specifically within the tumor cells once more than half the tumors progress to grade 3 or higher. We confirmed that this model yielded Bmi1 loss that was tumor-specific and almost complete. We then aged tumor bearing mice for up to seven weeks post Bmi1 deletion to determine the impact on LUAD. Unexpectedly, Bmi1 deletion did not yield significant tumor suppression. Instead, gene expression analyses of Bmi1 deficient tumor cells revealed upregulation of a gastric gene expression program that is a known marker of lung tumor progression towards a more aggressive state in the KP LUAD model. Additionally, single cell sequencing showed that Bmi1 deficient tumors contained a higher frequency of cells that expressed previously described markers of TPCs and metastasis.en_US
dc.description.abstractWe also extended these findings to colorectal cancer where we show that deletion of Bmi1 is not tumor suppressive in either in vitro organoids or orthotopic transplants. Given these findings, we conclude that deletion, or inhibition, of BMI1 in existing tumors will be ineffective for cancer treatment in the contexts examined, and potentially deleterious because it can enable acquisition of alternate differentiation states that promote tumor progression.en_US
dc.description.statementofresponsibilityby Rachit Neupane.en_US
dc.format.extent138 pagesen_US
dc.language.isoengen_US
dc.publisherMassachusetts Institute of Technologyen_US
dc.rightsMIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission.en_US
dc.rights.urihttp://dspace.mit.edu/handle/1721.1/7582en_US
dc.subjectBiology.en_US
dc.titleBMI1 is a context-dependent tumor suppressor that is a barrier to dedifferentiation in non-small cell lung adenocarcinomaen_US
dc.typeThesisen_US
dc.description.degreePh. D.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.identifier.oclc1117709230en_US
dc.description.collectionPh.D. Massachusetts Institute of Technology, Department of Biologyen_US
dspace.imported2019-09-16T16:38:12Zen_US
mit.thesis.degreeDoctoralen_US
mit.thesis.departmentBioen_US


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