Mutant Kras Alters Extracellular Vesicle Microrna Sorting In Pancreatic Cystic Neoplasms

<p>Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers by organ site with a 5-year survival rate of just 10.8%. This is largely because most patients do not experience symptoms until the disease has already metastasized. The best hope to cure PDAC is surgery, which can only be done with a curative intent at an early stage when the disease is localized. There are no reliable circulating, body-fluid-based biomarkers to detect early stage PDAC or its precursor lesions in a timely manner for effective surgical intervention. When potential PDAC precursor lesions, such as mucinous pancreatic cysts are found, there are no reliable molecular markers to determine which of these lesions will become to PDAC.</p> <p>The most frequently mutated gene in PDAC, the oncogene <em>KRAS</em>, remains largely undruggable, except for <em>KRAS^G12C </em>mutations, which may be inhibited by sotorasib. Activating mutations in the oncogene <em>KRAS</em> are believed to be the earliest genetic mutation in the development of this disease, occurring in up to 95% of PDACs and 60% of mucinous cysts. While it is well-known that mutant <em>KRAS</em> deregulates many biological processes, little is known about the effect of <em>KRAS</em> on loading of cargo into extracellular vesicles (EVs). EVs are released into body fluids by normal and pre-malignant/malignant cells, which, by virtue of their function involvement in intercellular communications, play critical roles in the development and progression of cancer. These vesicles harbor an assortment of biomolecules shielded from degradation within their membrane bound lumen. For this reason, EVs offer a unique opportunity to study biomolecules in circulation and could provide a snapshot of disease biology, including cancer, in real time. In recent years, EV microRNAs (miRNAs) small, noncoding, epigenetic modulators of gene expression, have been of interest due to their well-documented role in cancer.</p> <p>Herein, we demonstrate that mutations in <em>KRAS</em> are associated with alteration to the EV miRNome in a cell line disease progression model system and mucinous pancreatic cysts. We have investigated the functional significance of mutant <em>KRAS </em>in the generation of altered EV miRNA content.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2021

Authors dc:creator

• Dittmar, Rachel L
• <p>https://orcid.org/0000-0002-0567-2450</p>

Contributors dc:contributor

• Subrata Sen, Ph.D.
• Ann Killary, Ph.D.
• Anirban Maitra, M.B.B.S.

• pancreatic cancer
• extracellular vesicle
• exosome
• liquid biopsy
• KRAS
• early detection
• pancreatic cyst
• microRNA
• genetics
• SRSF1
• Biology
• Cancer Biology
• Cell Biology
• Gastroenterology
• Genetics and Genomics
• Genomics
• Medicine and Health Sciences
• Molecular Genetics
• Oncology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1147

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2203