Medicine and Health Sciences Commons^™

The Role Of The Hypoxia-Inducible Factor 2 In Pancreatic Cancer: Mechanisms Of Tumor Immunosuppression And Intestinal Radioprotection, Carolina Garcia Garcia

Dissertations & Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with dismal prognosis. The only curative option for patients is surgery, but over 80% of patients are not surgical candidates. Unfortunately, PDAC is resistant to the three remaining options. PDAC is characterized by a profoundly hypoxic and immunosuppressive stroma, which contributes to its therapeutic recalcitrance. Alpha-smooth muscle actin+ (αSMA+) cancer-associated fibroblasts (CAFs) are the most abundant stromal component, as well as mediators of stromal deposition. The hypoxia-inducible factors (HIF1 and HIF2) coordinate responses to hypoxia, yet, despite their known association to poor patient outcomes, their functions within the PDAC tumor microenvironment (TME) …

Leveraging Single Cell Technologies For The Characterization And Treatment Of Refractory Pancreatic Cancer, Maria Monberg

Dissertations & Theses (Open Access)

Heterogeneity is a hallmark of cancer, and the advent of multimodal single-cell technologies has helped uncover heterogeneity in a high-throughput manner in different cancers across varied contexts at an unprecedented resolution. In an effort to improve precision medicine approaches in pancreatic ductal adenocarcinoma (PDAC), a highly lethal malignancy with a mere 11% 5-year survival rate, this dissertation focuses on first questioning the assumptions of the most basic models used to study PDAC via multimodal single-cell characterization methods at multiple levels of biological organization (scCNVseq and snATACseq for DNA assays, scRNAseq for transcriptomics, and paired protein assays such as multiplexed immunofluorescence …

Atr-Mediated Cd47 And Pd-L1 Upregulation Restricts Radiotherapy-Induced Immune Priming And Abscopal Responses In Colorectal Cancer, Cheng-En Hsieh, Cheng-En Hsieh

Dissertations & Theses (Open Access)

Radiotherapy of colorectal cancer (CRC) can prime adaptive immunity against tumor-associated antigen (TAA)-expressing CRC cells systemically. However, incidences of abscopal tumor remission are extremely rare, and the post-irradiation immune escape mechanisms in CRC remain elusive. We report that CRC cells utilize a common DNA repair signaling pathway — ATR/Chk1/STAT3 — to upregulate both CD47 and PD-L1 in response to radiotherapy, which through engagement of SIRPα and PD-1 suppresses the capacity of antigen-presenting cells to phagocytose them thereby preventing TAA cross-presentation and innate immune activation. This post-irradiation CD47 and PD-L1 upregulation can be observed across various human solid tumor cells. Concordantly, …

Mutant Kras Alters Extracellular Vesicle Microrna Sorting In Pancreatic Cystic Neoplasms, Rachel L. Dittmar

Dissertations & Theses (Open Access)

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 …

Genetic Evolution And Prognostic Determinants Of Pancreatic Cancer On Longitudinal Liquid Biopsies, Vincent Bernard

Dissertations & Theses (Open Access)

Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest 5-year survival rates amongst solid tumors. As early detection of PDAC is unusual and typically incidental, most patients present with locally advanced and metastatic disease where effective therapeutic strategies remain a significant unmet need. Specifically, surrogate biomarkers for tumor monitoring of PDAC may lead to improved elucidation of clinical actionability and prognostic potential. On the other hand, tumor tissue is rarely sampled in patients presenting with de novo or recurrent metastatic PDAC, apart from a fine needle aspiration or a core needle biopsy performed for diagnosis. This precludes the opportunity for …

Mismatch Repair Deficient Tumors Lacking Known Sporadic Causes: Are They All Due To Lynch Syndrome?, Katherine M. Dempsey

Dissertations & Theses (Open Access)

BACKGROUND: Mismatch repair deficient (MMRD) colorectal (CRC) or endometrial (EC) cancers in the absence of MLH1 promoter hypermethylation and BRAF mutations are suggestive of Lynch syndrome (LS). Positive germline genetic test results confirm LS. It is unclear if individuals with MMRD tumors but no identified germline mutation or sporadic cause (MMRD+/germline-) have LS.

HYPOTHESIS: Since LS is hereditary, individuals with LS should have a stronger family history of LS-related cancers than individuals with sporadic tumors. We hypothesized that MMRD+/germline- CRC and/or EC patients would have less suggestive family histories than LS CRC and/or EC patients.

METHODS: 253 individuals with an …

In-Vivo Ct Dosimetry During Virtual Colonoscopy, Jonathon W. Mueller

Dissertations & Theses (Open Access)

Virtual colonoscopy (VC) is a minimally invasive means for identifying colorectal polyps and colorectal lesions by insufflating a patient’s bowel, applying contrast agent via rectal catheter, and performing multi-detector computed tomography (MDCT) scans. The technique is recommended for colonic health screening by the American Cancer Society but not funded by the Centers for Medicare and Medicaid Services (CMS) partially because of potential risks from radiation exposure. To date, no in‐vivo organ dose measurements have been performed for MDCT scans; thus, the accuracy of any current dose estimates is currently unknown.

In this study, two TLDs were affixed to the inner …

Role Of Prostaglandin E2 In The Regulation Of Pancreatic Stellate Cells Hyper Activity Associated With Pancreatic Cancer, Chantale Charo

Dissertations & Theses (Open Access)

Pancreatic cancer is one of the most lethal type of cancer due to its high metastasis rate and resistance to chemotherapy. Pancreatic fibrosis is a constant pathological feature of chronic pancreatitis and the hyperactive stroma associated with pancreatic cancer. Strong evidence supports an important role of cyclooxygenase-2 (COX-2) and COX-2 generated prostaglandin E2 (PGE2) during pancreatic fibrosis. Pancreatic stellate cells (PSC) are the predominant source of extracellular matrix production (ECM), thus being the key players in both diseases. Given this background, the primary objective is to delineate the role of PGE2 on human pancreatic stellate cells (PSC) hyper activation associated …