Ataxia Telangiectasia Mutated (ATM) gene helps to repair DNA damage and that increased cancer risks are associated with having a mutation in an ATM gene. ATM gene is newer compared to other known hereditary cancer genes. We present a rare care of 66-year-old female with extensive personal and family history of breast and pancreatic cancer had negative imaging surveillance until recent systemic imaging showed new pancreatic head 2.5x2.5 cm mass. Endoscopic ultrasound confirmed invasion of superior mesenteric vein with near confluence. No regional adenopathy was seen. She was felt to be borderline resectable and neoadjuavant chemotherapy was planned. She had a personal history of right breast cancer diagnosed in 1998 status post lumpectomy and axillary lymph node dissection and adjuvant chemotherapy with CMF regimen x 5 cycles and radiation therapy and endocrine therapy with tamoxifen for 5 years. In 2011 she was also diagnosed with rectal well to moderately differentiated adenocarcinoma status post abdominoperitoneal resection on 3/15/2011, 36 lymph nodes were negative, but the surgical circumferential radial margin was positive. She underwent adjuvant radiation therapy with total dose of 45 Gy. There was recurrence in vaginal and bladder wall adenocarcinoma in 2014 for which patient underwent an anterior exenteration. Pathology felt this was endocervical origin of malignancy and patient received megace therapy for 3 years based on hormone receptor positive status. For new diagnosis of pancreatic adenocarcinoma, she was started on Gemcitabine and Abraxane chemotherapy. Given extensive personal and family history of malignancy, she was referred to genetic counsellor. Hereditary cancers panel at invitae laboratory was positive for a heterozygous pathological variant in the ATM gene deletion (exons 62-63). ATM gene is associated with an increased risk for autosomal dominant breast, pancreatic and prostate cancer. Close relatives (children, siblings, and each parent) have up to a 50% chance of being a carrier of this variant. It is essential for treating physicians to educate patients and family members on the risk for subsequent malignancies.

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common cancer in the United States: in 2017 there will be around 54,000 new cases and 43,000 patient deaths. (SEER, 2017) The high mortality of PDAC is related to late disease presentation and aggressiveness; nearly 52% of patients present with metastatic disease at the time of diagnosis. (SEER, 2017) Current treatments have marginal improvements on survival, with the most efficacious treatment, gemcitabine and nab-paclitaxel, having a median survival of 12.2 months. (Wu 2018) Failure of current PDAC treatments is attributed to the inefficacy of systemic chemotherapeutics and the development of resistance. (Rahib, 2014) The Dual Endothelin1/Signal PeptideVEGF receptor (DEspR), represents a promising therapeutic target for the treatment of PDAC: it is a highly expressed, specific tumor antigen, which is involved in tumor vasculogenesis and cancer stem cell (CSC) survival. DEspR is a developmentally crucial receptor, responsible for early angiogenesis and neural crest migration, with minimal expression in normal adult tissue. In vitro and in vivo studies of anti-DEspR therapy in PDAC have shown efficacy in decreasing CSC survival, tumor angiogenesis, and improving overall survival in xenograft models of PDAC, with anti-DEspR therapy being a promising candidate for clinical use. Furthermore, anti-DEspR therapy seems to augment chemotherapeutic therapy in vitro and in vivo, suggesting that a DEspR-targeted antibody drug conjugate (ADC) would be highly effective. ADCs are a re-emerging drug class with significant promise. Initial failures of ADCs in clinic were related to poor antigen specificity and failures in drug conjugation chemistry to minimally impact the antibody. To develop our ADC, I have developed a novel method of site-specific conjugation that relies on a novel method of supramolecular assembly. My system employs two specific protein sequences that do not self-interact, and tightly assemble through coulombic and hydrophobic interactions, allowing site-specific, stoichiometric self-assembly. To facilitate stable drug delivery, I have synthesized a novel enzymatically cleavable tyrosine-clickable linker, which prevents drug release prior to tumor delivery. Both further investigation into the efficacy of anti-DEspR therapy, and the development of a stoichiometric, site-specific, stable method for drug loading will provide an advancement in anti-cancer therapy.

<p> Fetal exposure to cigarette smoke is associated with an increased risk of adult-onset metabolic abnormalities. In Canada, nicotine replacement therapy (NRT) is recommended as a safe smoking cessation aid for pregnant women. However, our laboratory has demonstrated that fetal and neonatal nicotine exposure results in glucose intolerance in adult rats. The goal of this thesis was to determine the mechanism(s) underlying the observed dysglycemia following fetal and neonatal nicotine exposure, with a specific focus on the effects of nicotine on pancreatic development and postnatal beta cell function.</p> <p> Nulliparous female Wistar rats received daily subcutaneous injections of either saline or nicotine bitartrate (1 mg/kg/d) for 2 weeks prior to mating until weaning (postnatal day 21 - PND21 ). Pancreatic tissue was collected from male offspring at birth (PND1), 3, 7, 15 and 26 weeks of age. For the critical windows study, dams received nicotine or saline during different stages of pancreatic development, including: A) pre-mating only, B) pre-mating + pregnancy only, C) pre-mating, pregnancy and lactation, or D) pre-mating + lactation only. For the intervention study, nicotine-exposed dams received either normal chow or diet containing antioxidants (1000 IU/kg vitamin E, 0.25% w/w coenzyme Q10 and 0.05% w/w α-lipoic acid) during mating, pregnancy and lactation.</p> <p> Results from this thesis demonstrate that exposure to nicotine during both fetal and neonatal development (but neither stage alone) causes a permenant loss of beta cell mass beginning at birth, and adult-onset dysglycemia in rodents. Furthermore, nicotine exposure induces pancreatic oxidative stress and mitochondrial-mediated beta cell apoptosis in neonates, followed by a progressive decline in mitochondrial structure and function. Maternal treatment with a dietary antioxidant cocktail during pregnancy and lactation protected the developing beta cells from nicotine-induced apoptosis and mitochondrial swelling. These data indicate that the safety of NRT use during pregnancy should be re-evaluated.</p> / Thesis / Doctor of Philosophy (PhD)

OBJECTIVE: Obesity is a chronic disease with high incidence worldwide, which promotes the risk of incidence of type 2 diabetes (T2D). Obesity-induced adipocyte expansion promotes local chronic inflammation in the adipose tissue which is considered a contributing factor to insulin resistance, hyperinsulinemia, and T2D. Many organs, including adipose tissue, involve in the dysregulation of glucose homeostasis in T2D. The crosstalk between adipose tissue/adipocytes and pancreatic ß-cells has provoked scientists' interest for years. Here in this thesis, we focused on the effect carried out by adipocyte-specific GPS2 depletion on insulin secretion from pancreatic ß-cells. METHODS: Conditioned media collected over 24 h from both primary adipocyte and adipose tissue explant cultures from high fat diet (HFD)-fed WT and adipocyte-specific GPS2 knock-out (GPS2-AKO) mice were used to treat INS-1 clonal pancreatic ß-cells or primary islets from chow-diet WT mice. Conditioned media was diluted 1:8 in culture media of clonal INS-1 cells (cultured in media with 4 mM or 11 mM glucose chronically) and primary islets (cultured in media with 11 mM glucose) and incubated for 18 h before measuring insulin secretion. The isolated islets from chow-diet WT mice were also be treated with the primary adipocytes conditioned media from eWAT (epididymal white adipose tissue) of HFD-fed WT and GPS2-AKO mice. In addition, the effect of exosomes extracted from primary adipocyte conditioned media of HFD-fed WT and GPS2-AKO mice on GSIS was investigated in clonal INS-1 cells. Glucose-stimulated insulin secretion (GSIS) was measured to assess differences in insulin secretion by INS-1 cells and islets from mice in response to signaling from WT or GPS2-AKO adipocytes. RESULTS: Adipocyte conditioned media from both WT and GPS2-AKO mice reduced GSIS from INS-1 cells by the same extent compared to a non-treated control. The same result was obtained using media conditioned by adipose tissue explant culture. Exosomes isolated from adipocyte conditioned media from both WT and GPS2-AKO mice also reduced GSIS from INS-1 cells with no significant difference between WT and GPS2-AKO. Islets isolated from chow-diet WT mice treated with adipocyte conditioned media from eWAT of WT and GPS2-AKO mice also showed no significant difference between WT and GPS2-AKO in GSIS compared to our non-treated control. CONCLUSIONS: Both conditioned media and exosomes from primary adipocytes of HFD-fed mice inhibits GSIS from INS-1 cells and isolated islets, but no difference was observed between WT and GPS2-AKO mice. We conclude that the deletion of GPS2 in adipocytes does not influence GSIS from pancreatic ß-cells under our experimental conditions. Conditioned media-induced inhibition of GSIS is mediated by factors that may contribute to adipocyte-ß-cell crosstalk in-vivo. / 2025-11-02T00:00:00Z

Pancreatic ductal adenocarcinoma (PDAC) is the 3rd deadliest cancer in the United States with a projected 12% 5-year survival rate. Acinar cells have been proposed as a potential cell-of-origin for PDAC after undergoing acinar to ductal metaplasia (ADM). In the absence of oncogenic mutations (e.g. Kras), ADM lesions form as an adaptive response and eventually resolve to regenerate the acinar compartment, which we term as adaptive ADM. However, in the presence of oncogenic Kras mutations, the ADM lesions can transform to a pre-invasive state called pancreatic intraepithelial neoplasia (PanIN). Thus, a normally adaptive metaplastic response becomes maladaptive, which we term as oncogenic ADM. The mechanisms that drive PanIN formation in the context of injury and oncogenic mutations are poorly understood, resulting in an absence of targets to combat persistent ADM. This thesis investigates the role of FRA1 (gene name Fosl1) in acinar cell de-differentiation, PanIN transformation, and eventual PDAC tumorigenesis. Through CUT&RUN sequencing of mice undergoing recovery from caerulein-induced acute pancreatitis, we identify FRA1 as the most active transcription factor during KrasG12D mediated acute pancreatitis- mediated injury. We have elucidated a functional role of FRA1 by generating an acinar-specific Fosl1 knockout mouse expressing KrasG12D. Using a gene regulatory network and pseudotime trajectory inferred from single nuclei ATAC-seq and bulk-RNA seq, we hypothesize a regulatory model of the acinar-ADM-PanIN continuum and experimentally validate that Fosl1 knockout mice are delayed in the onset of ADM and PanIN. Furthermore, deletion of Fosl1 in an autochthonous PDAC mouse model revealed that this ADM-initiated delay eventually culminates in a significant survival advantage and a less aggressive tumor phenotype. Through investigation of upstream regulators of FRA1, we identified G-CSF as an ADM-promoting cytokine. Fosl1 depletion prevented the pro-inflammatory effects of G-CSF, indicating that the G-CSF/FRA1 signaling axis can modulate ADM. Using ex vivo acinar cultures, we also showed that G-CSF can induce FRA1 through MEK/ERK signaling. Our findings reveal that FRA1 is a mediator of acinar cell plasticity and contributes to acinar cell de-differentiation and malignant transformation. Although the majority of this thesis focuses on oncogenic ADM, we also include a chapter on the role of Prrx1 in adaptive ADM. Our comprehensive and unbiased approach identified previously the Paired-Related homebox1 (Prrx1) as the most upregulated transcription factor in the intersection of pancreatic ductal development, regeneration, and evolution of PanIN. We have demonstrated previously that Prrx1 can promote a ductal phenotype by binding the Sox9 promotor and inducing its expression during pancreatitis. In this body of work, we present a novel mechanism by which Prrx1 regulates maintenance of adaptive ADM. Using novel mouse models and ex vivo acinar culture systems, we demonstrate that Prrx1 can induce TGFβ signaling and reduce E-Cadherin expression to promote ADM. We do not know if there is any potential epistatic interaction between FRA1 and PRXX1. Overall, we reveal the rippling effects of FRA1 can have during the early stages of pre-neoplasia, and we unveil an alternative function of PRRX1 for stimulating an adaptive response to stress. This thesis presents a new understanding of how acinar cell de-differentiation occurs in the pancreas by revealing novel roles of two transcription factors, FRA1 and PRRX1, and furthers our understanding of tissue regeneration in an injured pancreas.

BACKGROUND: Pancreatic ductal adenocarcinoma maintains a formidable mortality rate with rising incidence despite extensive research efforts. As of 2021 pancreatic cancer is the third leading cause of cancer-related deaths in the United States despite its incidence representing only 3% of all cancer diagnoses. Given the high mortality rate, research efforts push to improve prognosis by expanding knowledge and tools in the realms of diagnostics, genetics, development of screening modalities, and targeted treatments. Modifications in treatment algorithms have led to only modest improvements in outcome. Current research efforts focus on primary and secondary prevention aimed at modifications of known environmental and hereditary risk factors. Available studies highlight the relationship between relative geography and cancers; however, there is a paucity of research available on the Social Determinants of Health on access to pancreatic cancer care and outcomes. PROPOSED PROJECT: Data will be extracted from the Surveillance, Epidemiology, and End Results (SEER) database and combined with US Census data along with medical record information as relevant over a seven-year period from January 1, 2010, through December 31, 2017. Social Vulnerability Index scores will be derived from the available data as a surrogate for Social Determinant of Health and be assigned to each case of pancreatic cancer from 2010-2017. These scores will be grouped by zip code. Analysis will then be performed to identify the mean stage at time of diagnosis for each zip code. Further analysis will be performed to calculate survival curves for each zip code and cox proportional-hazards will be performed on results to determine statistical significance of SVI with respect to geography. CONCLUSIONS: The proposed study will investigate the impact of geography as a Social Determinant of Health (SDoH) within the United States on the stage at time of diagnosis for pancreatic ductal adenocarcinoma. As a secondary measure, overall survival following diagnosis of pancreatic ductal adenocarcinoma will be examined. SIGNIFICANCE: This study will identify the impact of social determinants of health on geography and correlate the impact on outcomes in pancreatic ductal adenocarcinoma in the United States of America. This study may also identify geographic regions in which the incidence of PDAC is higher than expected which would present a population to investigate for additional screening studies and development of risk prediction models.

Sex-dependent differences in the prevalence of diabetes and cardiovascular diseases are well established. The objective of this project is to investigate the molecular mechanisms by which estrogen modulates chronic disease progression. Our lab, and others, have previously implicated endoplasmic reticulum (ER) stress in the development and progression of diabetes and cardiometabolic disease. We hypothesize that estrogens protect pancreatic beta cell health, and slow the progression of cardiometabolic disease, by modulating the unfolded protein response (UPR) in response to ER stress. Two distinct mouse models were used in these studies. The ApoE-/-Ins2+/Akita mouse model of hyperglycemia-induced atherosclerosis, in which females are significantly protected from hyperglycemia and atherosclerosis relative to males, and the TALLYHO/JngJ mouse model, in which females are protected from chronic hyperglycemia relative to males. We found that ovariectomy of female ApoE-/-Ins2+/Akita or TALLYHO/JngJ mice promoted chronic hyperglycemia. Supplementation with exogenous 17-beta estradiol significantly lowered blood glucose levels in ovariectomized ApoE-/-Ins2+/Akita mice and reduced atherosclerotic lesion development in both male and ovariectomized female mice. Pancreatic islets from sham operated ApoE-/-Ins2+/Akita female mice showed a significant increase in the expression of protective UPR factors and a decrease in pro-apoptotic factors, compared to males or ovariectomized females. To determine if alleviating ER stress could moderate hyperglycemia, male and ovariectomized female TALLYHO/JngJ mice were treated with the chemical chaperone 4-phenylbutryic acid (4-PBA). We showed that 4-PBA treatment significantly lowered fasting blood glucose levels and improved glucose tolerance. The results of this thesis suggest that estrogens play a protective role in the maintenance of beta cell health and blood glucose regulation by activating the adaptive UPR. This mechanism may explain the protection observed in premenopausal women and may lead to the development of targeted therapies to treat diabetes and cardiometabolic diseases. / Thesis / Doctor of Philosophy (PhD) / People who suffer from diabetes mellitus have a higher risk of developing heart attack and stroke compared to those who do not have diabetes. Moreover, the risk of heart attack and stroke is higher in men than in women. We still do not understand the underlying reasons for these differences. This thesis project has used unique mouse models that display many of the same sex differences in disease progression that we see in humans to study the pathways and mechanisms that promote diabetes development. Specifically, we examined the protective effects of estrogen towards the development of diabetes and cardiovascular disease and how this hormone affected specific cells and tissues. The results of these studies are important because they will provide more information regarding the effects of menopause and aging on chronic disease progression in women.

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