Janel Kopp

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Assistant Professor

Research Classification

Research Interests

Modeling cancer
Pancreatic cancer
Pancreatic development

Relevant Degree Programs

Affiliations to Research Centres, Institutes & Clusters


Graduate Student Supervision

Doctoral Student Supervision

Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.

Hyperinsulinemia and insulin receptor signaling in pancreatic cancer development (2022)

Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer death in Canada and its incidence is increasing, largely driven by the expanding epidemics of PDAC risk factors including obesity and type 2 diabetes (T2D). Hyperinsulinemia is a cardinal feature of obesity and T2D, and is associated with increased PDAC incidence and mortality. Despite epidemiological data linking hyperinsulinemia to PDAC, there was no direct in vivo evidence of a causal role for endogenous insulin in any cancer type before this work. We studied how reduced insulin production or local insulin action affected the development of pancreatic intraepithelial neoplasia (PanIN) precursor lesions in Ptf1aCreER;KrasLSL-G12D mice. We first generated Ptf1aCreER;KrasLSL-G12D;Ins1+/+;Ins2-/- control and Ptf1aCreER;KrasLSL-G12D;Ins1+/-;Ins2-/- experimental mice. We found high fat diet (HFD)-induced hyperinsulinemia was modestly reduced in experimental mice without affecting glucose homeostasis. Genetically reduced insulin production resulted in ~50% suppression of PanIN. However, in this study, only female mice remained normoglycemic and only the gene dosage of rodent-specific Ins1 alleles was tested. Therefore, we then generated Ptf1aCreER;KrasLSL-G12D;Ins1-/-;Ins2+/+ control and Ptf1aCreER;KrasLSL-G12D;Ins1-/-;Ins2+/- experimental mice. Mice with reduced insulin production tended to develop fewer PanIN and acinar-to-ductal metaplasia (ADM) lesions. Using single-cell transcriptomics, we found hyperinsulinemia modulated pathways associated with protein translation, MAPK/ERK signaling and PI3K/AKT/mTOR signaling, which were changed in epithelial cells and subsets of immune cells. Finally, we examined whether hyperinsulinemia contributed to PDAC development directly through insulin receptor (INSR) signaling in KrasG12D carrying pancreatic acinar cells. We generated Ptf1aCreER;LSL-KrasG12D;nTnG mice with an Insrwt/wt, Insrwt/f, or Insrf/f genotype to reduce insulin receptor mRNA by 0%, 50%, or 100% in acinar cells. Loss of insulin receptors from acinar cells did not significantly influence body weight, fasting glucose, or insulin levels. Compared to mice with wild-type INSR expression in acinar cells, mice lacking INSR had a 2.7-fold and 5.3-fold significant reduction in PanIN plus tumor area in males and females, respectively. Collectively, these results indicate that hyperinsulinemia and INSR signaling in acinar cells are important for the early stages of pancreatic cancer. Insulin-lowering interventions such as lifestyle management and therapies targeting insulin receptor signaling may be beneficial in preventing and/or treating pancreatic cancer.

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Master's Student Supervision

Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.

Cellular origin influences the immune microenvironment in a pancreatic cancer mouse model with loss of Pten and activation of KRAS (2022)

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with an overall 5-year survival rate of merely 10%. Mouse studies in the past decade have made progress towards a better understanding of how PDAC cellular origin affects tumorigenesis. However, there is little study done on the immune microenvironment differences between acinar and ductal cell-derived precursor lesions and PDAC. Following our previous study that showed loss of Pten with oncogenic KrasG12D mutations in the ductal cells (KPtenΔDuct/+) resulted the formation of intraductal papillary mucinous neoplasias (IPMN) as the precursor lesion in mice, we further found similar mutations in the acinar cells (KPtenΔAcinar/+) formed pancreatic intraepithelial neoplasia (PanIN) instead. I subsequently used the KPtenΔDuct/+and KPtenΔAcinar/+ models to elucidate the effect of cellular origin on the immune microenvironment by performing immunohistochemistry. I focused on immune cell infiltration densities in precursor lesions and PDAC derived from KPtenΔDuct/+ and KPtenΔAcinar/+ mice and found that immune cell population and its changes throughout tumorigenesis are different starting at a precursor lesion stage between these two models. Additionally, macrophages polarized by conditioned media derived from KPtenΔDuct PDAC cells were polarized in less magnitude compared with macrophages polarized by KPtenΔAcinar PDAC cells. This difference in polarization was at least partially due to the lower expression of GM-CSF in KPtenΔDuct PDAC cells. Our study is the first to directly compare immune cell population between acinar- and ductal-derived PDAC with the same genetic background. Our study suggests cellular origin could influence PDAC immune heterogeneity.

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Cell of origin can change the transcriptome profile of tumors arising from distinct pancreatic cell types (2019)

Both acinar and ductal cells can give rise to PDAC in murine models. However, the gene expression profiles of these tumors, as well as their role in tumor heterogeneity remain unknown. The objective of this study was to understand whether the cellular origin of PDAC could cause functional or molecular heterogeneity. We created PDAC cell lines from mouse models (Sox9CreER;KrasLSL-G12D;Trp53f/f mice a.k.a. Duct:Kras-p53 mice and Ptf1aCreER;KrasLSL-G12D;Trp53f/f a.k.a. Acinar:Kras-p53 mice), which developed tumors originating from ductal or acinar cells, respectively. Duct:Kras-p53 mice formed high grade PanINs, developed PDAC much faster, and had a shorter lifespan compared to Acinar:Kras-p53 mice. In contrast, Acinar:Kras-p53 mice formed abundant of low grade PanINs with mucinous characteristics and PDAC initiation was delayed. I performed differential gene expression analysis between 12 acinar- and 13 ductal-cell-derived tumors using a specific R programming language package called DESeq2. I found 827 differentially expressed genes between tumors of different cellular origin (p-value
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Cell of origin in pancreatic ductal adenocarcinoma (2017)

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a ductal morphology. Prior research has identified both pancreatic acinar and ductal cells as possible cells of origin for histologically similar PDAC. However, because different mutations were induced in acinar and ductal cells, apt comparisons could not be made to address whether the tumor cell of origin influences PDAC initiation, development, and other tumor differences. To address this open question, I induced oncogenic Ras expression (KrasG¹²D) with concomitant homozgyous Trp53 deletion at 4 weeks of age in a ductal cell specific (Sox9CreER; KrasLSL-G12D; Trp53flox/flox (“Duct:KPcKO”)) and an acinar cell specific (Ptf1aCreER; KrasLSL-G12D; Trp53flox/flox (“Acinar:KPcKO”)) mouse model. I found that Duct:KPcKO mice met their humane endpoints earlier (82 days post injection, p.i.) than the Acinar:KPcKO mice (128 days p.i.), for reasons associated with differences in the timing of PDAC onset. While tumors from both cells of origin were similarly proliferative and shared many physical characteristics, Duct:KPcKO mice developed tumors much earlier than Acinar:KPcKO mice and this was further associated with a difference in precursor lesion initiation. Specifically, ductal cells only formed high-grade lesions while acinar cells formed precursor lesions of all grades. These findings suggest that cell type intrinsic differences may allow ductal cells to rapidly form PDAC under genetically favorable conditions. In comparison, acinar cells likely require additional steps to alter cell identity and become duct-like – thus delaying PDAC initiation and extending survival. Taken together, I have demonstrated, by using cell type specific mouse models, that cell of origin can alter disease initiation, progression and impact PDAC phenotype.

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