Deconstructing the cell of origin and the role of the p53 pathway in pancreatic cancer development
Abstract/Contents
- Abstract
- Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a 5-year survival rate of ~10% and is projected to be the second-leading cause of cancer-related death in the United States by 2026, increasing the urgency to improve our understanding of PDAC initiation and progression to develop better diagnostic and therapeutic strategies. The tumor suppressor gene TP53 (Trp53 in mice) is mutated in ~75% of human pancreatic tumors. TP53 encodes the p53 transcription factor which is critical for suppressing PDAC tumorigenesis driven by oncogenic KRAS. TP53 mutations, which are commonly missense mutations in the DNA binding domain, are proposed to result in both loss of wild-type p53 function and gain of novel, oncogenic functions. However, there is a limited understanding of the molecular pathways through which TP53 mutations contribute to PDAC tumorigenesis. Moreover, the upstream signals necessary to activate p53-mediated PDAC suppression and the critical cellular functions for PDAC suppression remain enigmatic. In this dissertation, I have used genetically engineered mouse models to deconstruct p53 loss-of-function and gain-of-function pathways and the upstream signals of p53-mediated pancreatic tumor suppression. To understand the origins of human pancreatic cancer, I have studied p53 function in adult mice from a defined cell of origin, pancreatic acinar or ductal cells. My studies have identified the cell of origin as one factor that influences the development of distinct PDAC molecular subtypes. I then identified ARF, a mediator of oncogenic stress signals to p53, as critical component of p53-mediated tumor suppression but not the sole activator of p53 transcriptional programs. Our studies also suggest that the loss of wild-type p53 activity conferred by Trp53 mutation is the predominant driver of PDAC development in vivo, rather than gain-of-function phenotypes. Taken together, this thesis work provides insight into the fundamental impact that the very earliest events in carcinogenesis can have on cancer evolution and the molecular mechanisms driving PDAC initiation and progression.
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource. |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2021; ©2021 |
| Publication date | 2021; 2021 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Flowers, Brittany Maria |
|---|---|
| Degree supervisor | Attardi, Laura |
| Thesis advisor | Attardi, Laura |
| Thesis advisor | Artandi, Steven E |
| Thesis advisor | Kim, Seung K |
| Thesis advisor | Winslow, Monte |
| Degree committee member | Artandi, Steven E |
| Degree committee member | Kim, Seung K |
| Degree committee member | Winslow, Monte |
| Associated with | Stanford University, Cancer Biology Program |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Brittany Maria Flowers. |
|---|---|
| Note | Submitted to the Cancer Biology Program. |
| Thesis | Thesis Ph.D. Stanford University 2021. |
| Location | https://purl.stanford.edu/zd624tb0499 |
Access conditions
- Copyright
- © 2021 by Brittany Maria Flowers
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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