Michelle A Anderson’s research while affiliated with University of Michigan and other places

Purpose Pancreatic ductal adenocarcinoma (PDAC) is generally divided in two subtypes, classical and basal. Recently, single-cell RNA sequencing has uncovered the coexistence of basal and classical cancer cells, as well as intermediary cancer cells, in individual tumors. The latter remains poorly understood; here, we sought to characterize them using a multimodal approach. Experimental Design We performed subtyping on a single-cell RNA sequencing dataset containing 18 human PDAC samples to identify multiple intermediary subtypes. We generated patient-derived PDAC organoids for functional studies. We compared single-cell profiling of matched blood and tumor samples to measure changes in the local and systemic immune microenvironment. We then leveraged longitudinally patient-matched blood to follow individual patients over the course of chemotherapy. Results We identified a cluster of KRT17-high intermediary cancer cells that uniquely express high levels of CXCL8 and other cytokines. The proportion of KRT17high/CXCL8⁺ cells in patient tumors correlated with intratumoral myeloid abundance, and, interestingly, high protumor peripheral blood granulocytes, implicating local and systemic roles. Patient-derived organoids maintained KRT17high/CXCL8⁺ cells and induced myeloid cell migration in a CXCL8-dependent manner. In our longitudinal studies, plasma CXCL8 decreased following chemotherapy in responsive patients, while CXCL8 persistence portended worse prognosis. Conclusions Through single-cell analysis of PDAC samples, we identified KRT17high/CXCL8⁺ cancer cells as an intermediary subtype, marked by a unique cytokine profile and capable of influencing myeloid cells in the tumor microenvironment and systemically. The abundance of this cell population should be considered for patient stratification in precision immunotherapy. See related commentary by Faraoni and McAllister, p. 2297

Introduction The mechanistic definition of chronic pancreatitis (CP) identifies acute pancreatitis (AP) as a precursor stage. We hypothesized that clinical AP frequently precedes the diagnosis of CP and is associated with patient- and disease-related factors. We describe the prevalence, temporal relationship and associations of AP in a well-defined North American cohort. Methods We evaluated data from 883 patients with CP prospectively enrolled in the North American Pancreatitis Studies across 27 US centers between 2000 and 2014. We determined how often patients had one or more episodes of AP and its occurrence in relationship to the diagnosis of CP. We used multivariable logistic regression to determine associations for prior AP. Results There were 624/883 (70.7%) patients with prior AP, among whom 161 (25.8%) had AP within 2 years, 115 (18.4%) within 3–5 years, and 348 (55.8%) >5 years prior to CP diagnosis. Among 504 AP patients with available information, 436 (86.5%) had >1 episode. On multivariable analyses, factors associated with increased odds of having prior AP were a younger age at CP diagnosis, white race, abdominal pain, pseudocyst(s) and pancreatic duct dilatation/stricture, while factors associated with a lower odds of having prior AP were exocrine insufficiency and pancreatic atrophy. When compared with patients with 1 episode, those with >1 AP episode were diagnosed with CP an average of 5 years earlier. Conclusions Nearly three-quarters of patients were diagnosed with AP prior to CP diagnosis. Identifying which AP patients are at-risk for future progression to CP may provide opportunities for primary and secondary prevention.

Background: Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related death in the US. A key hallmark of this disease is that, while tumors initially show susceptibility to standard chemotherapeutic agents, most patients eventually develop resistance, leading to poor survival. While the mechanisms of chemoresistance are unclear, murine studies have implicated the myeloid compartment of the tumor immune microenvironment. Correlative data in human tumors supports this notion, however, mechanistic studies are lacking, thus impairing translation to the clinic. The study of human pancreatic cancer has historically been challenging due to difficulty of fresh biospecimen acquisition, patient heterogeneity, and a diverse tumor microenvironment. Moreover, the vast majority of pancreatic cancer patients do not qualify for surgical resection, further limiting tissue availability. We have overcome these difficulties by developing a pipeline to analyze human tumor samples and matched blood using high-fidelity techniques including single-cell RNA sequencing (scRNAseq) and mass cytometry (CyTOF), together with establishment of organoids from the same tumors. Notably, in this pipeline we can use small amounts of tissue from endoscopic fine needle biopsies, thus allowing us to sample tumors from patients at any disease stage. Results: We performed CyTOF on longitudinally-matched peripheral blood mononuclear cells (PBMCs) from 30 patients and single-cell RNA sequencing on 6 patients in the treatment naïve and on-treatment (FOLFIRINOX) state. CyTOF revealed distinct alterations in the myeloid population, with a shift toward CXCR2hiPD-L1hi granulocytes with FOLFIRINOX treatment over time. Analysis of PBMCs from scRNAseq showed a distinct myeloid gene signature with FOLFIRINOX and in particular highlighted interleukin-8 (IL8), a chemokine involved in myeloid cell chemotaxis that is associated with poor prognosis in pancreatic cancer. Further mapping of IL8 in tumor tissue by scRNAseq showed that it is highly expressed in subpopulations of tumor epithelial cells and tumor-infiltrating granulocytes. IL8-high tumor-infiltrating granulocytes also highly expressed VEGF and CXCR4, suggesting immunosuppressive and angiogenic roles. IL8-high tumor epithelial cells were found to have a basal-like phenotype and also expressed a network of other chemokines including CXCL1, CXCL3, CXCL5, which are known to recruit immunosuppressive myeloid cells. Conclusions: Through longitudinal and multimodal mapping using PDAC patient blood and tumor biospecimens, we have identified IL8 as a potential mediator of epithelial-myeloid crosstalk in PDAC chemoresistance and tumor aggression. Validation studies using an all-human co-culture system of PDAC patient-derived organoids and myeloid cells are currently underway. Citation Format: Eileen S. Carpenter, Samantha Kemp, Padma Kadiyala, Nina Steele, Ahmed Elhossiny, Stephanie The, Valerie Gunchick, Rémy Nicolle, Michelle Anderson, Wenting Du, Carlos Espinoza, Richard Kwon, Erik-Jan Wamsteker, Anoop Prabhu, Allison Schulman, Vaibhav Sahai, Timothy Frankel, Filip Bednar, Marina Pasca di Magliano. Longitudinal profiling of pancreatic cancer patients identifies interleukin-8 as a mediator of myeloid-epithelial crosstalk [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-098.

Healthcare organizations have recognized the value of physician leaders in change management and achieving institutional goals. Physicians leaders are now at all levels from individual clinics to the very top of large, multi-hospital organizations. Most endoscopy units have medical directors and organizations with multiple or large, complex units often have a “Chief of Endoscopy” (CoE) or the equivalent of this to oversee and lead the teams and decisions pertaining to these units. The following review will discuss the process to become a CoE, the importance of aligning personal values and skills with organizational purpose and will give suggestions for relevant metrics to success. It will also explore the challenges faced by women in endoscopy leadership positions and will give advice to women leaders and those who support her as mentors, colleagues, or partners. Although much of the discussion is intentionally focused on high-level endoscopy leadership, the information and messages have pertinence to any organizational leadership position and to leaders at any point in their leadership pathway.

Background and study aims Women remain underrepresented in gastroenterology, especially advanced endoscopy. Women represent 30 % of general gastroenterology fellows; yet in 2019, only 12.8 % of fellows who matched into advanced endoscopy fellowship (AEF) programs were women. Methods We administered a web-based survey to the program directors (PDs) of AEF programs that participated in the 2018–2019 American Society for Gastroenterology (ASGE) match. We assessed PD and program characteristics, in addition to perceived barriers and facilitators (scale 1–5, 5 = most important) influencing women pursuing AEF training. Results We received 38 (59.3 %) responses from 64 PDs. 15.8 % (6/38) of AEF PDs and 13.2 % (5/38) of endoscopy chiefs were women. By program, women represented 14.8 % (mean) ± 17.0 % (SD) of AEF faculty and 12.0 % (mean) ± 11.1 % (SD) of AEF trainees over the past 10 years. 47.4 % (18/38) programs reported no female advanced endoscopy faculty and 31.6 % (12/38) of programs have never had a female fellow. Percentage of female fellows was strongly associated with percentage of female AEF faculty (ß = 0.43, P < 0.001). Inflexible hours and call (mean rank 3.3 ± 1.1), exposure to fluoroscopy (2.9 ± 1.1), lack of women endoscopists at national conferences/courses (2.9 ± 1.1) and lack of female mentorship (2.9 ± 1.0) were cited as the most important barriers to recruitment. Conclusion We utilized a survey of AEF PDs participating in the ASGE match to determine program characteristics and identify contributors to gender disparity. Women represent a minority of AEF PDs, endoscopy chiefs, advanced endoscopy faculty and AEF trainees. Our study highlights perceived barriers and facilitators to recruitment, and emphasizes the importance of having female representation in faculty, and leadership positions in endoscopy.

Purpose Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease characterized by an extensive fibroinflammatory stroma, which includes abundant cancer-associated fibroblast (CAF) populations. PDAC CAFs are heterogeneous, but the nature of this heterogeneity is incompletely understood. The Hedgehog pathway functions in PDAC in a paracrine manner, with ligands secreted by cancer cells signaling to stromal cells in the microenvironment. Previous reports investigating the role of Hedgehog signaling in PDAC have been contradictory, with Hedgehog signaling alternately proposed to promote or restrict tumor growth. In light of the newly discovered CAF heterogeneity, we investigated how Hedgehog pathway inhibition reprograms the PDAC microenvironment. Experimental Design We used a combination of pharmacologic inhibition, gain- and loss-of-function genetic experiments, cytometry by time-of-flight, and single-cell RNA sequencing to study the roles of Hedgehog signaling in PDAC. Results We found that Hedgehog signaling is uniquely activated in fibroblasts and differentially elevated in myofibroblastic CAFs (myCAF) compared with inflammatory CAFs (iCAF). Sonic Hedgehog overexpression promotes tumor growth, while Hedgehog pathway inhibition with the smoothened antagonist, LDE225, impairs tumor growth. Furthermore, Hedgehog pathway inhibition reduces myCAF numbers and increases iCAF numbers, which correlates with a decrease in cytotoxic T cells and an expansion in regulatory T cells, consistent with increased immunosuppression. Conclusions Hedgehog pathway inhibition alters fibroblast composition and immune infiltration in the pancreatic cancer microenvironment.