bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A093: Deciphering acquired resistance to KRASG12D inhibition in a mouse model of pancreatic ductal adenocarcinoma
Authors: Dilly Julien , Abbassi Laleh , Hennessey Connor J. , Uribe Giselle A. , Parent Brendan , Yang Annan , Kapner Kevin S. , Li Ziyue , Dasgupta Shatavisha , Jordan Alexander , Hoffman Megan T. , Qiang Li , Hambitzer Felix P. , Chugh Seema , Shalek Alex K. , Dougan Stephanie K. , Wolpin Brian M. , Nowak Jonathan A. , Raghavan Srivatsan , Winter Peter S. , Aguirre Andrew J. 
Published: January 2024

Abstract
KRAS is a major oncogenic driver in pancreatic ductal adenocarcinoma (PDAC) and is mutationally activated in approximately 90% of cases, with the glycine-to-aspartic acid substitution at position 12 (p.G12D) being the most prevalent alteration. Mutations in this oncogene have been associated with more aggressive disease and poorer outcomes and have remained “undruggable” for more than three decades. However, the recent development of mutant-specific small molecule inhibitors of KRAS has given hope for the treatment of this highly lethal and treatment-refractory malignancy. Here we evaluated the genomic and transcriptional mechanisms of resistance to MRTX1133, a first-in-class inhibitor of KRASG12D, in an autochthonous mouse model of PDAC. We leveraged single-nucleus RNA sequencing and whole-exome sequencing on 16 samples from KPC mouse specimens (LSL-KrasG12D/+; LSL-Trp53R172H/+; p48-Cre) that were treated with either MRTX1133 or the vehicle, including 6 samples from mice that developed resistance to KRASG12D inhibition. Our analysis has uncovered that resistance is multifaceted and characterized by both emergent genomic and transcriptional features. Genetically, resistant tumors harbored clonal and subclonal amplifications in the HIPPO pathway, cell cycle regulators, and ABC transporters. Transcriptionally, we employed non-negative matrix factorization and identified recurrent gene expression programs in resistant and vehicle samples. Using this approach, we uncovered the existence of an intermediate phenotype between classical and mesenchymal cell states that is enriched in tumors with evolved resistance to MRTX1133. In summary, our study provides a high resolution genomic and transcriptional landscape of resistance to KRAS targeting in a preclinical in vivo model of PDAC, highlighting the complexity of treatment resistance and identifying various pathways and effectors that may serve as potential new targets for combination therapy.
Citation Format: Julien Dilly, Laleh Abbassi, Connor J. Hennessey, Giselle A. Uribe, Brendan Parent, Annan Yang, Kevin S. Kapner, Ziyue Li, Shatavisha Dasgupta, Alexander Jordan, Megan T. Hoffman, Li Qiang, Felix P. Hambitzer, Seema Chugh, Alex K. Shalek, Stephanie K. Dougan, Brian M. Wolpin, Jonathan A. Nowak, Srivatsan Raghavan, Peter S. Winter, Andrew J. Aguirre. Deciphering acquired resistance to KRASG12D inhibition in a mouse model of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A093.
Abstract A096: PIKfyve as a potential therapeutic target in pancreatic cancer
Authors: Grenier Shea , Galapate Cheska , Zhang Yijuan , Arora Gurpreet , Olson Steven , Emerling Brooke , Commisso Cosimo 
Published: January 2024

Abstract
A lack of effective treatments beyond surgical resection and chemotherapy contributes to the 12% five-year survival rate of pancreatic ductal adenocarcinoma (PDAC), underscoring the need to identify novel therapeutic approaches. Pharmacological inhibition of phosphatidylinositol 3-phosphate 5-kinase (PIKfyve) with small molecules has been demonstrated to have therapeutic effects in tauopathies, viral infection, and cancer; however, these compounds have not been evaluated in PDAC. The PIKfyve lipid kinase generates PI5P and/or PI(3,5)P2 from phosphoinositol (PI) or PI3P, respectively, and is associated with cellular signaling, membrane homeostasis, and vesicular trafficking. Evidence suggests that PIKfyve inhibitors exhibit anti-cancer effects through autophagy inhibition and lysosomal impairment in non-Hodgkin’s B cell lymphoma, multiple myeloma, and prostate cancer, among other cancer types. Here, we report that the treatment of PDAC cells with apilimod, a PIKfyve-specific inhibitor, results in increased cytoplasmic vacuolization, a characteristic phenotype, increased expression of transcription factor EB (TFEB), and antiproliferative effects in vitro. We also demonstrate that apilimod is a novel inhibitor of macropinocytosis, an endocytic mechanism of nutrient uptake in PDAC. YM201636, another PIKfyve inhibitor, exhibits similar vacuolization and cytostatic effects in PDAC cells. Importantly, preliminary data suggests that genetic knockdown of PIKfyve phenocopies the observed pharmacological effects in vitro. Future experiments will assess the mechanistic underpinnings of PIKfyve function using agonists and endosomal inhibitors and will investigate the in vivo therapeutic potential of targeting PIKfyve in PDAC. Combined, this study will assess PIKfyve as a potential target in the treatment of PDAC for which novel therapeutics are urgently needed.
Citation Format: Shea Grenier, Cheska Galapate, Yijuan Zhang, Gurpreet Arora, Steven Olson, Brooke Emerling, Cosimo Commisso. PIKfyve as a potential therapeutic target in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A096.
Abstract A118: Chromatin accessibility profiling of human pancreatic tumors reveals epigenetic features of malignancy and rapid recurrence
Authors: MacPherson Kevin , Link Jason M. , Worth Patrick , Sheppard Brett , Fields Andrew , Daniel Colin , Nishida Andrew , Pelz Carl , Waugh Trent , Agritelle Ethan , Muschler John , Adey Andrew , Sears Rosalie 
Published: January 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) disease progression involves complex cell state transitions in both malignant and non-malignant populations within the tumor microenvironment. To uncover PDAC cell states and epigenetic features associated with clinical outcome, we studied 42 PDAC samples (35 primary tumors and 7 metastases) from 41 patients with single cell ATAC-seq, along with 10 sample-matched single cell RNA-seq profiles. Our work uncovered thousands of chromatin regions with altered accessibility in malignant cells relative to normal ductal and acinar cells. Numerous epigenetic changes were universal to all PDAC clusters regardless of patient-of-origin and occurred proximal to genes involved in glycolysis, regulation of MYC, hypoxic response, extracellular matrix remodeling, and repression of transposable elements. Topic modeling of high dimensional chromatin data revealed networks of co-accessible cis-regulatory regions active in malignant cells, as well as networks specific to basal-like and classical PDAC molecular subtypes. Furthermore, our epigenomic data also suggest alternate paths of lineage infidelity across the classical-basal continuum: while basal-like PDAC cells acquire chromatin accessibility mimicking that of skin or mammary epithelial tissue, several classical subtype tumors featured a subpopulation of malignant cells with increased accessibility of neural-associated chromatin regions genome-wide. Within the immune compartment, we also identified a cis-regulatory network with increased activity in T-cells sampled from rapidly recurring PDAC tumors. Motif analysis of this network revealed enrichment for SMAD and FOXP1 motifs, suggesting widespread modification of T-cells by TGF-β. To our knowledge, our work is the largest single-cell resolution study of chromatin state in human PDAC to date, revealing key epigenetic features associated with PDAC subtype and clinical outcome.
Citation Format: Kevin MacPherson, Jason M. Link, Patrick Worth, Brett Sheppard, Andrew Fields, Colin Daniel, Andrew Nishida, Carl Pelz, Trent Waugh, Ethan Agritelle, John Muschler, Andrew Adey, Rosalie Sears. Chromatin accessibility profiling of human pancreatic tumors reveals epigenetic features of malignancy and rapid recurrence [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A118.
Abstract B007: Early detection and risk stratification of pancreatic cancer using apolipoprotein A2-isoforms as a blood biomarker
Authors: Honda Kazufumi , Kashiro Ayumi H. , Kobayashi Michimoto , Takeuchi Keiko , Shizume Yuya , Oh Takanori , Morizane Chigusa , Hijioka Susumu , Nara Satoshi 
Published: January 2024

Abstract
To reduce the mortality rate of pancreatic cancer, there is an urgent need to develop a biomarker that can efficiently screen for pancreatic cancer in blood tests. We had identified the unique processing of C-terminal amino acids of apolipoprotein A2 homodimers, we named it apolipoprotein A2-isoforms (apoA2-i). ApoA2-i consists of three isoforms with different C-terminal amino acids. Especially, we had reported that apoA2-ATQ/AT, known as the intermediate isoform, was significantly reduced in the bloodstream of pancreatic adenocarcinoma (PDAC) patients compared to healthy controls. However, previous reports were investigated using a research use only (RUO) reagent, which could not be used in clinical settings. We generated a novel ELISA for measuring apoA2-i under the Japanese medical device Quality Management System requirements, and measured the concentration of apoA2-i in 2,732 of plasma samples. The clinical equivariance and significance of apoA2i were evaluated by pre-specified endpoints. The point estimate of the area under the curve to distinguish between PDAC and healthy controls was higher for apoA2-ATQ/AT [0.879, 95% confidence interval (CI): 0.832–0.925] than for CA19-9 (0.849, 95%CI: 0.793–0.905) and achieved the primary endpoint. The cut-off apoA2-ATQ/AT of 59.5 μg/mL was defined based on 95% specificity in 2,000 healthy samples. The sensitivity of apoA2-ATQ/AT for detecting both stage I (47.4%) and I/II (50%) of PDAC was higher than that of CA19-9 (36.8% and 46.7%, respectively). The combination of apoA2-ATQ/AT (cut-off, 59.5 μg/mL) and CA19-9 (37 U/mL) increased the sensitivity for pancreatic cancer to 87.7% compared with 69.8% for CA19-9 alone. ApoA2-ATQ/AT has equivalent or better clinical performance to CA19-9 as a blood biomarker.
Citation Format: Kazufumi Honda, Ayumi H. Kashiro, Michimoto Kobayashi, Keiko Takeuchi, Yuya Shizume, Takanori Oh, Chigusa Morizane, Susumu Hijioka, Satoshi Nara. Early detection and risk stratification of pancreatic cancer using apolipoprotein A2-isoforms as a blood biomarker [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B007.
Abstract B008: Secretome labeling identifies gelsolin as a potential pro-tumorigenic PDAC biomarker
Authors: Kastan Jonathan P. , Standring Oliver , Cifani Paolo , Gaeth Victoria , Jensen Amanda , Park Youngkyu , Tuveson David 
Published: January 2024

Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is a highly lethal malignancy with a 5-year survival rate around 10% due to late detection and therapeutic resistance. Thus, new methods to detect PDAC earlier in high-risk and general populations are greatly needed. Early detection tests have historically relied on circulating nucleic acids or proteins that have been identified as enriched in patients with PDAC by large-scale studies, but they often lack a firm basic biological context that would bolster the sensitivity and specificity of these tests. To this end, we have introduced a construct into PDAC organoid and 2D lines that enables the labeling of PDAC-secreted proteins with biotin (Sec61-BioID) in vitro and in vivo. With this system, we can specifically isolate the PDAC secretome and identify the proteins via mass spectrometry. From this approach, we have identified Gelsolin (GSN), an enzyme that regulates actin dynamics, as a highly secreted protein by a panel of PDAC cell lines in vitro and in vivo. We have explored the biological role of secreted GSN in PDAC tumorigenesis via CRISPR knockout. GSN knockout abrogated the growth of PDAC tumors in NSG mice, and we are delineating the potential mechanisms that explain this defect via histological analysis and in vitro cell proliferation and invasion assays. Additionally, we have analyzed purified secreted GSN from PDAC lines by mass spectrometry to identify potential post-translational modifications that may differentiate PDAC-derived GSN from other GSN molecules, secreted by healthy tissue, in circulation. We are currently utilizing biochemical approaches to validate these putative modifications and define their specificity in PDAC patient blood as compared to healthy age-matched controls.
Citation Format: Jonathan P. Kastan, Oliver Standring, Paolo Cifani, Victoria Gaeth, Amanda Jensen, Youngkyu Park, David Tuveson. Secretome labeling identifies gelsolin as a potential pro-tumorigenic PDAC biomarker [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B008.
Abstract B023: Hypoxia supports CAF-mediated epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma
Authors: Kowalewski Karl , Lazzara Matthew 
Published: January 2024

Abstract
The pancreatic ductal adenocarcinoma (PDAC) microenvironment is populated by distinct subtypes of cancer-associated fibroblasts (CAFs), including myofibroblastic CAFs (myCAFs) that synthesize and remodel the stromal matrix and inflammatory CAFs (iCAFs) that secrete cytokines and growth factors. Subpopulations of CAFs reside in regions of tumor hypoxia, which may play a role in determining CAF behaviors. We tested the hypothesis that iCAFs preferentially drive ductal cell epithelial-mesenchymal transition (EMT), which promotes PDAC chemoresistance, and that hypoxia promotes the iCAF phenotype. Cell-cell communication analysis using publicly available single-cell RNA sequencing (scRNA-seq) data of human tumors indicated that iCAFs secrete growth factors predicted to promote ductal cell EMT. This inference was confirmed in experiments showing that PDAC cells exhibit stronger EMT in response to conditioned medium from iCAFs than from myCAFs. Publicly available scRNA-seq data further indicated a correlation between hypoxia and the iCAF phenotype. qRT-PCR and immunofluorescence microscopy confirmed that hypoxia promotes the iCAF phenotype, and conditioned medium experiments demonstrated the preferential ability of hypoxic CAFs to utilize an NFκB-dependent pathway to secrete cytokines that promote EMT. A screen of 430 kinase inhibitors nominated specific growth factors that we validated to be EMT-inducing and generated by hypoxic CAFs. Finally, iterative indirect immunofluorescence imaging (4i) of tumor sections from KrasLSL-G12D/+; Trp53LSL-R172H/+, Pdx1-Cre; Rosa26YFP/YFP (KPCY) mice and quantitative image analysis demonstrated a spatial correlation in PDAC tumors between mesenchymal neoplastic cells and hypoxic CAFs. Our results raise the intriguing possibility that hypoxia cooperates with CAFs to promote EMT in PDAC and identify drug targets whose antagonism may interfere with a PDAC-stromal signaling process that promotes chemoresistance.
Citation Format: Karl Kowalewski, Matthew Lazzara. Hypoxia supports CAF-mediated epithelial-mesenchymal transition in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B023.
Abstract B056: Selective epithelial activation of KRAS G12D mutation drives ductal pancreatic neoplasia in pigs
Authors: Jara Carlos P. , Al-Gahmi Al-Murtadha , Le Binh , Carlson Mark A. 
Published: January 2024

Abstract
An innovative approach in pancreatic cancer (PC) research is to utilize large animal models which (i) would be useful for development of technologies that require a human-sized platform and (ii) would produce data that could have greater clinical relevance and accuracy compared to data produced by murine models. To this end, our group has been developing porcine PC models and has reliably induced PC in the KRAS G12D/p53 R167H Oncopig model. The objective of the present study was to generate a slower-growing, early-stage PC model with intraductal injection of adenoviral vector with a Keratin 8 promoter driving the expression of the Cre-Recombinase protein (Ad5mK8-nlsCre) in oncopigs which, we hypothesized, would produce pancreatic neoplasia restricted to the epithelium. Results We first confirmed with scRNA-seq and immunohistochemistry that Keratin-8 expression in the porcine pancreas was restricted to ductal and acinar cells. Using an ex vivo infection assay with the Ad5mK8-nlsCre vector in wild-type porcine pancreas, we then demonstrated that expression of Cre-recombinase was confined to epithelial cells. We then performed a dose-response study of ductal injection (laparotomy) of Ad5mK8-nlsCre (10(7)-10(10) pfu) in Oncopigs. At the planned 2-month endpoint, all Ad5mK8-nlsCre concentrations produced microscopic evidence of ductal hyperplasia, metaplasia, and nuclear atypia, with KRAS-G12D expression by immunohistochemistry. At the higher Ad5mK8-nlsCre concentration, there was increased ductal mucin production. Using an epithelial-specific AdCre vector, we produced microscopic epithelial neoplasia within the pancreas of the Oncopig. Conclusion While further follow-up and characterization is needed, this induction technique may yield a porcine model of early-stage PC, which could be useful to (i) study early tumor biology and progression and (ii) develop diagnostic and interventional technologies for early tumor management.
Citation Format: Carlos P. Jara, Al-Murtadha Al-Gahmi, Binh Le, Mark A. Carlson. Selective epithelial activation of KRAS G12D mutation drives ductal pancreatic neoplasia in pigs [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B056.
Abstract B076: Development of novel gemcitabine-modified miRNA mimics for pancreatic ductal adenocarcinoma
Authors: Ju Jingfang 
Published: January 2024

Abstract
Pancreatic cancer, including its most common subtype, pancreatic adenocarcinoma (PDAC), has the lowest five-year survival rate among patients with PDAC in the United States. Despite advancements in anticancer treatment, the overall median survival for patients with PDAC has not dramatically improved. Therefore, there is an urgent need to develop new strategies of treatment to address this issue. Non-coding RNAs, including microRNAs (miRNAs), have been found to have major roles in carcinogenesis and the subsequent treatment of various cancer types like PDAC. In this study, we developed a new treatment strategy by modifying tumor suppressor miRNAs, hsa-miRNA-15a (miR-15a) with the nucleoside analog chemotherapeutic gemcitabine (Gem) to create Gem-modified mimics of miR-15a (Gem-miR-15a). In a panel of PDAC cell lines, we found that Gem-miR-15a induces cell cycle arrest and apoptosis, and these mimics are potent inhibitors with single digit nM IC50 up to several hundred fold less than their native counterparts or Gem alone. Furthermore, we found that Gem-miR-15a retained miRNA function by downregulating the expression of several key targets including WEE1, CHK1, BMI1, and YAP1 for Gem-miR-15a. Compared to Gem, we also found that our Gem-modified miRNA mimics exhibit enhanced efficacy by over several hundred fold less than Gem in patient-derived PDAC organoids. Gem-miR-15a was able to eliminate Gem resistant PDAC cells and organoids. In addition, Gem-miR-15a was able to be delivered to PDAC cells without the aid of delivery vehicle, a major advancement in nucleic acid based medicine. Furthermore, we observed that Gem-miR-15a significantly inhibits PDAC tumor growth in vivo without observing any noticeable signs of toxicity. Overall, our results demonstrate the therapeutic potential of muti-targeted Gem-modified miRNAs as a novel treatment strategy for PDAC.
Citation Format: Jingfang Ju. Development of novel gemcitabine-modified miRNA mimics for pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B076.
Abstract B078: A complex of NF1 and SPRED2 non-canonically behave as tumor promoters in pancreatic cancer
Authors: Kim Sun , Ting Hsiu-Chi , Deschenes Astrid , Kastan Jonathan , Park Youngkyu , Tuveson David 
Published: January 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with poor prognosis due to late detection and lack of effective therapeutic options. &gt;90% of PDAC tumors are driven by activating mutations in the KRAS oncogene, making it an appealing subject for further investigation into understanding PDAC biology and offering a potential genetic vulnerability to target in patients. Our laboratory has previously reported a mutant-KRAS-proximal complex at the plasma membrane that consists of tumor-suppressor Neurofibromatosis type 1 (NF1), Sprouty Related EVH1 Domain Containing 2 (SPRED2), and Ribosomal S6 Kinase 1 (RSK1). This complex mechanistically suppresses WT KRAS signaling via RSK1, a suppression which is then relieved upon mutant KRAS inhibition, ultimately promoting adaptive resistance for PDAC cells under these conditions. We find that both knockout of either NF1 or SPRED2 in PDAC organoids induces a substantial growth defect in vivo. Our preliminary data suggests that NF1 and SPRED2 support KRAS activity in mouse pancreatic cancer in vivo. Moreover, both SPRED2 and NF1 KO show decreased proliferation, invasion, and attachment on collagen family members in vitro. Given NF1's well-established role as a tumor-suppressor, our observations of decreased tumorigenic properties upon NF1 deletion are unexpected. We hypothesize that NF1 and SPRED2 promote tumorigenesis via recruitment of RSK1 to the plasma membrane, inducing the phosphorylation of putative substrates to stimulate a pro-migratory cellular behavior. Our work suggests the existence of a unique RSK1 program localized at the plasma membrane by mutant KRAS, providing a new facet of oncogenesis to investigate for fundamental understanding and potential therapeutic opportunities.
Citation Format: Sun Kim, Hsiu-Chi Ting, Astrid Deschenes, Jonathan Kastan, Youngkyu Park, David Tuveson. A complex of NF1 and SPRED2 non-canonically behave as tumor promoters in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B078.