bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A11: Combined Src and EGFR inhibition targets STAT3 to induce stromal remodeling and increase drug delivery to improve survival in a mouse model of pancreatic cancer
Authors: Dosch Austin R. , Dai Xizi , Reyzer Michelle L. , Kwon Deukwoo , Caprioli Richard , Merchant Nipun B. , Nagathihalli Nagaraj S. 
Published: March 2020

Abstract
Lack of durable response to cytotoxic chemotherapy is a major contributor to the dismal outcomes seen in pancreatic ductal adenocarcinoma (PDAC). Extensive tumor desmoplasia and poor vascular supply are two predominant characteristics that hinder the delivery of chemotherapeutic drugs into PDAC tumors and mediate resistance to therapy. Previously, we have shown that STAT3 is a key biomarker of therapeutic resistance to gemcitabine treatment in PDAC, which can be overcome by combined inhibition of the Src kinase and epidermal growth factor receptor (EGFR) pathways. Although it is well established that concurrent EGFR and Src inhibition exert these anti-eoplastic properties through inhibiting mitogenic pathways in tumor cells directly, the influence of this combined therapy on stromal constituents in PDAC tumors remains unknown. In the present study, we demonstrate in both orthotopic tumor xenografts and Ptf1acre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) mouse models that concurrent EGFR and Src inhibition abrogates STAT3 activation, resulting in stromal remodeling through the depletion of tumor collagen content, increasing microvessel density, and preventing tissue fibrosis in vivo. Furthermore, these stromal changes resulting from combined pathway inhibition produce a direct increase in intratumoral gemcitabine levels as determined by MALDI-IMS and improve overall survival in PKT mice treated with combined EGFR and Src inhibition with gemcitabine. As a phase 1 clinical trial utilizing concurrent EGFR and Src inhibition in combination with gemcitabine has recently concluded, these data provide translational insight into the novel mechanism of action of this regimen and expand our understanding into the phenomenon of stromal-mediated therapeutic resistance.
Citation Format: Austin R. Dosch, Xizi Dai, Michelle L. Reyzer, Deukwoo Kwon, Richard Caprioli, Nipun B. Merchant, Nagaraj S. Nagathihalli. Combined Src and EGFR inhibition targets STAT3 to induce stromal remodeling and increase drug delivery to improve survival in a mouse model of pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A11.
Abstract A34: Suppression of dystroglycan function is a hallmark of acinar-to-ductal metaplasia and favors the development of neoplasias and PDAC
Authors: Huang Ge , Lanciault Christian , Sears Rosalie , Muschler John 
Published: March 2020

Abstract
The basement membrane (BM) is a predominant microenvironmental factor of the precancerous exocrine pancreas, and evidence suggests that the BM functions not only as a barrier to tumor cell invasion but also as an active tumor-suppressing signaling substrate. However, the molecular underpinnings of such a mechanism have not been resolved. Here we explore the expression and function of the prominent BM receptor dystroglycan (DG) in the normal pancreas and pancreatic disease. We show that DG is highly expressed in the acinar compartment of the normal pancreas; however, there is a strong suppression of DG expression with acinar-to-ductal metaplasia (ADM) in chronic pancreatitis and in all stages of pancreatic cancer evolution, from ADM to neoplasias to adenocarcinoma. The conditional knockout of DG in the murine pancreas produced no evidence of developmental or functional deficiency. However, deletion of DG expression in the context of oncogenic Kras expression (p48-Cre;KrasG12D) led to a clear acceleration of disease, including accelerated PanIN formation and an increased incidence of adenocarcinoma and metastases. Disease acceleration was accompanied by neoplasias with a strongly cystic morphology. These data establish DG as a potent suppressor of pancreatic neoplasias and cancers, and one that is muted in chronic pancreatitis and at the earliest stages of oncogenic transformation. We conclude that DG is a key mediator of the tumor-suppressing functions of the normal BM, and that maintenance or restoration of DG function is a potential target for the delay or prevention of pancreatic cancer evolution.
Citation Format: Ge Huang, Christian Lanciault, Rosalie Sears, John Muschler. Suppression of dystroglycan function is a hallmark of acinar-to-ductal metaplasia and favors the development of neoplasias and PDAC [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A34.
Abstract A41: Cancer-associated fibroblast (CAF) specific biomarkers in pancreatic ductal adenocarcinoma (PDAC): Transcriptomic and molecular insight
Authors: Putri Jayarani F. , Kumagai Yutaro , Miyazaki Yoshihiro , Oda T. , Kida Yasuyuki S. 
Published: March 2020

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of malignancy-related death with poor prognosis. The late diagnosis due to nonspecific symptoms, highly aggressive nature, intrinsic resistance to chemotherapeutic, and the lack of effective therapeutic are the main causes of poor prognosis in PDAC. This cancer type comprises up to 90% cellular component of desmoplastic stroma that holds a major role in drug resistance and malignancy. The complexity of the genome is another leading cause of molecular alteration in PDAC. Hence, the urge to find the prognosis marker for PDAC is extremely needed for the new therapeutic regimens. In this study we performed RNA-seq analysis from MSC in single and co-cultured conditions (in vitro), MSC and Xeno-MSC (in vivo), and patient-derived CAF. Read alignment and junction mapping was accomplished using HISAT2 and cufflinks respectively and followed by map reads using UCSC hg38 reference genome annotation. Data were expressed as fragments per kilobase of exon per million fragments mapped (FPKM). Three out of eight clusters on heatmap were selected based on their expression pattern across all the samples. Approximately 900 transcripts from selected clusters were classified into three major protein classes: transcription factors, kinases, and membrane proteins. Remarkably, several genes on selected clusters have been studied in CAF, giving proof of the fidelity of our data analysis. Prompted to get more specific CAF-related genes, we put more parameters such us: unexpressed in normal pancreatic, relatively low expression in pancreatic cancer, ≥2 folds increase of CAF mRNA expression to normal or pancreatic cancer, and have not studied in PDAC. We found 16 transmembrane protein-coding genes that are potentially involved in CAF remodeling. To gain a better understanding of tumor-CAF interaction from these candidate genes, immunostaining using paraffin sections from tumor-bearing mice model together with αSMA/IL6 and protein analysis was carried out. We sought the downstream pathways as well to discover novel regulatory networks and causal relationship between CAF and pancreatic cancer. Our study addresses the extent to which factor(s) can reset stromal alteration and elucidate the role of transmembrane protein during CAF reprogramming.
Citation Format: Jayarani F. Putri, Yutaro Kumagai, Yoshihiro Miyazaki, T. Oda, Yasuyuki S. Kida. Cancer-associated fibroblast (CAF) specific biomarkers in pancreatic ductal adenocarcinoma (PDAC): Transcriptomic and molecular insight [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A41.
Abstract A53: Meflin-positive cancer-associated fibroblasts inhibit pancreatic carcinogenesis
Authors: Mizutani Yasuyuki , Kobayashi Hiroki , Enomoto Atsushi , Takahashi Masahide 
Published: March 2020

Abstract
Cancer-associated fibroblasts (CAFs) constitute a major component of the tumor microenvironment. Recent observations in genetically engineered mouse models and clinical studies have suggested that there may exist at least two functionally different populations of CAFs, i.e., cancer-promoting CAFs (pCAFs) and cancer-restraining CAFs (rCAFs). Although various pCAF markers have been identified, the identity of rCAFs remains unknown because of the lack of rCAF-specific marker(s). In the present study, we found that Meflin, a glycosylphosphatidylinositol-anchored protein that is a marker of mesenchymal stromal/stem cells and maintains their undifferentiated state, is expressed by pancreatic stellate cells that are a source of CAFs in pancreatic ductal adenocarcinoma (PDAC). Analysis of human PDAC tissues revealed that the infiltration of Meflin-positive CAFs correlated with favorable patient outcome. Consistent herewith, Meflin deficiency led to significant tumor progression with poorly differentiated histology in a PDAC mouse model. Similarly, genetic ablation of Meflin-positive CAFs resulted in poor differentiation of tumors in a syngeneic transplantation model. Conversely, delivery of a Meflin-expressing lentivirus into the tumor stroma or overexpression of Meflin in CAFs suppressed the growth of xenograft tumors. Lineage tracing revealed that Meflin-positive cells gave rise to α-smooth muscle actin-positive CAFs that are positive or negative for Meflin, suggesting a mechanism for generating CAF heterogeneity. Mechanistically, Meflin interacts with lysyl oxidase to inhibit its collagen crosslinking activity, and Meflin deficiency resulted in straightened and wide stromal collagen fibers that represent a signature for aggressive tumors. Together, the data suggest that Meflin is a marker of rCAFs that suppress PDAC progression.
Citation Format: Yasuyuki Mizutani, Hiroki Kobayashi, Atsushi Enomoto, Masahide Takahashi. Meflin-positive cancer-associated fibroblasts inhibit pancreatic carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A53.
Abstract B23: Bioadhesive nanoparticles as a delivery vehicle in pancreatic cancer epithelial cells and pancreatic fibroblasts
Authors: Hasan Nesrin M. , Suh Hee Won , Saltzman Mark , Ahuja Nita 
Published: March 2020

Abstract
Pancreatic cancer, referred to as pancreatic ductal adenocarcinoma (PDAC), is characterized by high lethality and limited treatment options. PDAC is generally diagnosed at a later stage and is resistant to chemotherapy and radiation therapy. Therefore, there is an urgent unmet need for novel treatment options to improve the survival of patients. PDAC is characterized by dense solid tumors that hinder drug penetration, and novel treatment technologies should be utilized to improve drug access to cancer cells. Nanoparticle-based compounds have been shown to improve site specific targeting, intracellular penetration, and circulation time and therefore can be used for therapeutic delivery to solid tumors. In our study, we performed in vitro characterization studies of non-bioadhesive nanoparticles (NNPs) and bioadhesive nanoparticles (BNPs) in pancreatic cancer epithelial cells and pancreatic fibroblasts. NNPs are polylactic acid-hyperbranched polyglycerol (PLA-HPG) nanoparticles and BNPs are obtained through conversion of HPG to an aldehyde-rich corona, which increases the bioadhesive property through formation of linkages with proteins. The aim of our study was to characterize the internalization of nanoparticles in vitro in different pancreatic cell lines. We incubated pancreatic cancer epithelial cells (PANC-1 and MIA PaCa-2) and pancreatic fibroblasts with fluorescent DiO-loaded NNPs and BNPs to assess internalization. Both DiO-NNPs and DiO-BNPs were internalized by PANC-1, MIA PaCa-2, and pancreatic fibroblasts as determined by both flow cytometry and fluorescence microscopy. The nanoparticles were internalized in a dose- and treatment time-dependent manner. Although both nanoparticles were internalized, due to their increased bioadhesive properties BNPs had 1.7-fold higher internalization compared to NNPs. Viability of the cells following DiO-NNPs and DiO-BNPs treatment was assessed through both acridine orange staining and flow cytometry analysis. DiO-NNPs and DiO-BNPs treatments did not affect the viability of the cells. Similar results were obtained with DiI-loaded nanoparticles. In summary, our study shows that nanoparticles can be internalized by pancreatic cancer epithelial cells and pancreatic fibroblasts and do not cause any loss of viability. Our results demonstrate the potential applicability of nanoparticles, especially bioadhesive nanoparticles, for synergistic therapeutic targeting of different cell types in pancreatic cancer to improve treatment outcomes.
Citation Format: Nesrin M. Hasan, Hee Won Suh, Mark Saltzman, Nita Ahuja. Bioadhesive nanoparticles as a delivery vehicle in pancreatic cancer epithelial cells and pancreatic fibroblasts [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B23.
Abstract B44: Clinical utility of semiquantitative evaluation of progesterone receptor immunohistochemistry in neuroendocrine tumors of the pancreas
Authors: Purushothaman Sonya , Michele Simona De , Low Dorothy , Remotti Helen E. 
Published: March 2020

Abstract
Purpose: Progesterone receptor (PR) is expressed strongly in a subset of neuroendocrine cells in the pancreas. Tamoxifen has long been used in adjuvant endocrine therapy of steroid hormone receptor–positive breast cancer, and currently clinical trials are assessing its use in pancreatic neuroendocrine tumors (NET) that show variable PR expression. Prior studies have reported receptor status as “positive” or “negative,” using 1% or 10% positive nuclei as a cutoff. In this study, we assessed PR immunohistochemical expression in a cohort of NET and other pancreatic nonexocrine carcinomas. Theoretically, tumors with highest PR expression are more likely to respond to adjuvant tamoxifen.
Experimental Design: Immunohistochemical staining for PR was performed on tissue microarrays of 54 well-differentiated neuroendocrine tumors of the pancreas and 8 poorly differentiated carcinomas of the pancreas, including 4 acinar cell carcinomas, 2 neuroendocrine carcinomas, and 2 small-cell neuroendocrine carcinomas. A minimum of 4 separate 2-mm tumor cores were sampled on each case.
Results: PR expression in non-neoplastic pancreatic islets was used for positive control. PR staining was evaluated using a semiquantitative H-score method. Positive PR staining (defined as greater than 1%) was identified in 61% (33 of 54 cases) of well-differentiated NET (mean H-score 100) and 0% (0 of 8 cases) of poorly differentiated carcinomas of the pancreas. Of the 33 PR positive cases of well-differentiated NET, 3 cases had less than 10% nuclear staining (mean H-score 7), 8 cases had 10% to less than 50% nuclear staining (mean H-score 44), and 22 cases had 50% or greater nuclear staining (mean H-score 229).
Conclusions: Based on these findings, we suggest analysis of NET tumor PR expression should include a quantitative or semiquantitative score rather than dichotomized immunohistochemical evaluation of hormone receptors, particularly in the evaluation of patients’ response to clinical trials with tamoxifen. High-grade endocrine and acinar carcinomas showed no PR expression and are less likely to derive benefit from adjuvant endocrine therapy.
Citation Format: Sonya Purushothaman, Simona De Michele, Dorothy Low, Helen E. Remotti. Clinical utility of semiquantitative evaluation of progesterone receptor immunohistochemistry in neuroendocrine tumors of the pancreas [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B44.
Abstract C28: KMT2D mediates TGF-β-induced epithelial-to-mesenchymal transition to promote more aggressive pancreatic cancer
Authors: Kim Hong S. , Lu Shuang , Cao Yubo , Yi Zhujun , Jeyarajan Sivakumar , Zhao Lili , Bedi Karan , Narayanan Ishwarya V. , Paulsen Michelle T. , Ljungman Mats , Shi Jiaqi 
Published: March 2020

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is predicted to be the second leading cause of cancer-related death in the United States by 2030. Surgery is the only potential curative treatment for patients with PDAC. However, less than 20% of patients are operable due to early metastasis. The mechanism of metastasis in PDAC is not fully understood. Recent studies failed to find metastasis-specific genetic mutations in PDAC, suggesting that aberrant epigenetic regulation may be one of the crucial mechanisms. Lysine-specific histone methyltransferase 2D (KMT2D) is one of the most frequently mutated epigenetic genes in human cancers, including PDAC. TCGA database analysis showed that KMT2D mutation is associated with poor survival in PDAC patients. However, the role of KMT2D in PDAC development remains elusive. Using human pancreatic tissue microarray containing both primary and metastatic PDAC tissues, we have found that the expression of KMT2D is specifically and significantly suppressed in metastatic PDAC, suggesting an important role of KMT2D in metastasis. Furthermore, treating PDAC cells with TGF-β resulted in decrease in KMT2D expression. In order to investigate the role of KMT2D in PDAC, we knocked out KMT2D (KMT2D KO) expression using CRISPR/Cas9 system in PDAC cell lines. We performed a novel Bru-seq analysis to investigate the effect of KMT2D on global nascent RNA transcript profile. Interestingly, epithelial-to-mesenchymal transition (EMT) pathway was one of the pathways that were highly upregulated upon KMT2D loss. RNA and protein assays confirmed that KMT2D KO cells had decreased epithelial marker, E-cadherin, and increased mesenchymal markers, vimentin and Snail. KMT2D KO cells also displayed enhanced ability to migrate and invade. Orthotopic xenograft mouse model using KMT2D KO cells showed less differentiated and more mesenchymal tumor cell morphology and larger primary and metastatic tumors compared to control cells. Taken together, loss of KMT2D in PDAC cells mediates TGF-β-induced EMT and enhances tumor growth and metastatic ability. These findings link epigenetic regulation to TGF-β signaling in PDAC and lay the foundation for designing novel therapeutic strategies.
Citation Format: Hong S. Kim, Shuang Lu, Yubo Cao, Zhujun Yi, Sivakumar Jeyarajan, Lili Zhao, Karan Bedi, Ishwarya V. Narayanan, Michelle T. Paulsen, Mats Ljungman, Jiaqi Shi. KMT2D mediates TGF-β-induced epithelial-to-mesenchymal transition to promote more aggressive pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C28.
Abstract C65: Identifying mechanisms of macrophage-mediated metastasis and therapy resistance in PDAC
Authors: Wu Tony J. , Cast Oliver , Memon Danish , Jimenez-Sanchez Alejandro , Machel Anne , Kehrloesser Sebastian , Gill Michael B. , Miller Martin L. 
Published: March 2020

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by desmoplasia, with macrophages as one of the most abundant, multifunctional immune cell populations in the tumor microenvironment (TME) and a major component of the immune infiltrate. To best improve clinical outcomes, consideration must be placed on targeted therapeutics that blunt heterotypic interactions between tumor cells and supporting cells within the TME. Here, we provide new insight into the dichotomous relationship between epithelial and mesenchymal phenotypes of PDAC cells in 3D culture. We report the ability of PDAC mesenchymal cells to form vascular mimicry-like structures in a 3D in vitro assay of invasion. Additionally, we demonstrate that macrophages have the ability to impart a proinvasive phenotype to PDAC cells when co-cultured in 3D, irrespective of EMT (epithelial-to-mesenchymal transition) status. To elucidate a mechanism for this macrophage-mediated proinvasive phenotype, we employed an unbiased, multi-omics approach. First, PDAC cell lines and primary macrophages were CTAP (cell-type specific labeling using amino acid precursors) labeled and admixed together for a prolonged period of time. To identify cell of origin of novel RNA and proteins, these mixed co-cultures were FACS sorted for downstream RNA-sequencing analysis or harvested in bulk for downstream proteome and secretome analysis. Preliminary integration of cell culture transcriptomes with CTAP-TMT (tandem mass tag) proteomes and secretomes implicates several key epithelial- and macrophage-derived signaling molecules as principal instructing signals for mediating the observed proinvasive phenotype. Blockade of this signaling axis, by inhibition of the signaling molecules or their receptors, disrupted the crosstalk between the two cell types and impaired the ability of macrophages to impart a proinvasive phenotype to PDAC cells. These preliminary preclinical data, recapitulated in vivo, suggest that targeting the TME of patients by using a staging regimen of chemokine inhibitor to disrupt tumor-macrophage cell interactions, followed with therapeutic modalities such as gemcitabine (and/or immunotherapy), would improve upon standard of care and inform future treatment options for PDAC in the clinic.
Citation Format: Tony J. Wu, Oliver Cast, Danish Memon, Alejandro Jimenez-Sanchez, Anne Machel, Sebastian Kehrloesser, Michael B. Gill, Martin L. Miller. Identifying mechanisms of macrophage-mediated metastasis and therapy resistance in PDAC [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C65.