Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a 5-year survival rate of approximately 9%. An improved understanding of PDAC initiation and progression is paramount for discovering strategies to better detect and combat this disease. Although transcriptomic analyses have uncovered distinct molecular subtypes of human PDAC, the factors that influence subtype development remain unclear. Here, we interrogate the impact of cell of origin and different Trp53 alleles on tumor evolution, using a panel of tractable genetically engineered mouse models. Oncogenic KRAS expression, coupled with Trp53 deletion or point mutation, drives PDAC from both acinar and ductal cells. Gene-expression analysis reveals further that ductal cell–derived and acinar cell–derived tumor signatures are enriched in basal-like and classical subtypes of human PDAC, respectively. These findings highlight cell of origin as one factor that influences PDAC molecular subtypes and provide insight into the fundamental impact that the very earliest events in carcinogenesis can have on cancer evolution. Significance: Although human PDAC has been classified into different molecular subtypes, the etiology of these distinct subtypes remains unclear. Using mouse genetics, we reveal that cell of origin is an important determinant of PDAC molecular subtype. Deciphering the biology underlying pancreatic cancer subtypes may reveal meaningful distinctions that could improve clinical intervention. This article is highlighted in the In This Issue feature, p. 521

Study Design Retrospective cohort study. Objectives (1) To compare the risk of Spinal Epidural Hematoma (SEH) associated with specific pre-operative and post-operative anticoagulation (AC) and antiplatelet medications (APM). (2) To define the incidence of SEH and identify risk factors for SEH in our population. Methods Thoracolumbar surgeries between October 2009 and March 2020 were collected. Patients who underwent incision and drainage of a symptomatic SEH were identified. AC and APM was recorded 14 days pre-operatively and post-operatively. Demographics and intra-operative factors were recorded. Relative risk with 95% confidence interval was used, with Bonferroni-corrected P-values <.05 used for significance. Results 9307 surgeries were identified. 177 (1.9%) patients returned to the OR within 30 days, 37 of whom (.39%) returned due to SEH. Seven patients were on either AC or APM pre-op, and sixteen post-op. Five were on aspirin pre-operatively (RR 3.2, 95% CI 1.25–8.22, P = .015). Risk was not increased in patients on multiple agents. No AC or APM demonstrated increased risk of hematoma post-operatively, despite trends toward significance with multiple agents. The use of a drain and complicated hypertension were associated with increased risk of SEH. Conclusions Pre-operative aspirin is associated with increased risk of SEH, even when appropriately discontinued. Appropriately dosed post-operative anticoagulation does not increase the risk of SEH, though being on multiple agents trends toward statistical significance and should be better studied. Surgeons should be vigilant and carefully monitor patients on pre-operative antiplatelet medications for spinal epidural hematoma.

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The vast majority of human pancreatic ductal adenocarcinomas (PDACs) harbor TP53 mutations, underscoring p53’s critical role in PDAC suppression. PDAC can arise when pancreatic acinar cells undergo acinar-to-ductal metaplasia (ADM), giving rise to premalignant pancreatic intraepithelial neoplasias (PanINs), which finally progress to PDAC. The occurrence of TP53 mutations in late-stage PanINs has led to the idea that p53 acts to suppress malignant transformation of PanINs to PDAC. However, the cellular basis for p53 action during PDAC development has not been explored in detail. Here, we leverage a hyperactive p53 variant—p53 53,54 —which we previously showed is a more robust PDAC suppressor than wild-type p53, to elucidate how p53 acts at the cellular level to dampen PDAC development. Using both inflammation-induced and KRAS G12D -driven PDAC models, we find that p53 53,54 both limits ADM accumulation and suppresses PanIN cell proliferation and does so more effectively than wild-type p53. Moreover, p53 53,54 suppresses KRAS signaling in PanINs and limits effects on the extracellular matrix (ECM) remodeling. While p53 53,54 has highlighted these functions, we find that pancreata in wild-type p53 mice similarly show less ADM, as well as reduced PanIN cell proliferation, KRAS signaling, and ECM remodeling relative to Trp53 -null mice. We find further that p53 enhances chromatin accessibility at sites controlled by acinar cell identity transcription factors. These findings reveal that p53 acts at multiple stages to suppress PDAC, both by limiting metaplastic transformation of acini and by dampening KRAS signaling in PanINs, thus providing key new understanding of p53 function in PDAC.

<p>Acinar and ductal cell-derived tumor gene expression analysis</p>