bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C044: Macropinocytic stress reprograms cancer-associated fibroblasts and enhances therapeutic responses in pancreatic cancer
Authors: Zhang Yijuan , Maganti Swetha , Hope Jennifer , Ling Li , Galapate Cheska Marie , Carrette Florent , Bradley Linda , Commisso Cosimo 
Published: January 2024

Abstract
Macropinocytosis is a fundamental metabolic pathway that has been demonstrated to support the survival and function of tumor cells and cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinoma (PDAC) through in vitro studies and xenograft mouse models. However, the impact of macropinocytosis on the PDAC tumor microenvironment in an immune-competent setting remains poorly understood. In this study, we utilized the selective inhibitor 5-(N-ethyl-N-isopropyl)-amiloride (EIPA) to block macropinocytosis in both tumor cells and CAFs in syngeneic PDAC mouse models. We observed that EIPA treatment inhibited PDAC tumor growth, which was accompanied by reduced tumor proliferation and increased cell apoptosis. Moreover, EIPA treatment decreased the presence of myofibroblastic CAFs and collagen deposition within PDAC tumors, while also promoting the expansion of tumor vasculature. By modifying the tumor stroma, EIPA priming enhanced drug delivery and improved the effectiveness of PDAC chemotherapy. Interestingly, immune profiling of PDAC tumors revealed that EIPA administration specifically increased the infiltration of CD8+ and CD4+ T cells. We discovered that EIPA induced changes in the cytokine/chemokine landscape within tumors by triggering an inflammatory CAF (iCAF)-like phenotype. Mechanistically, we discerned that inhibition of macropinocytosis triggers metabolic stress that in turn activates stress-responsive transcription factors and promotes the expression of early-phase proinflammatory cytokines and chemokines in mouse CAFs. Notably, combination treatment with EIPA and immune checkpoint blockade (ICB) reduced PDAC tumor burden and significantly inhibited tumor metastasis. Overall, our findings establish that macropinocytosis functions to support the barrier function of the stroma by maintaining fibroblastic identity and provide further evidence that inhibition of macropinocytosis represents a promising therapeutic modality in PDAC.
Citation Format: Yijuan Zhang, Swetha Maganti, Jennifer Hope, Li Ling, Cheska Marie Galapate, Florent Carrette, Linda Bradley, Cosimo Commisso. Macropinocytic stress reprograms cancer-associated fibroblasts and enhances therapeutic responses 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 C044.
Abstract C059: Hub gene analysis identifies CAD as a potential mediator for drug resistance in pancreatic cancer
Authors: Vyas Foram , Grünwald Barbara , Aliar Kazeera , Jang Gun Ho , O'Kane Grainne , Kislinger Thomas , Gallinger Steven , Haibe-Kains Benjamin , Khokha Rama 
Published: January 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a complex disease pathobiology and poor treatment options, emphasizing the need for novel therapeutic targets. Hub genes have high connectivity (i.e., exceptionally many interaction partners), for example, certain proteases with numerous interaction partners. Thereby, hub genes are often central biological regulators and dysregulated proteolysis is indeed a key trait of malignant tissues. Here, we aimed to identify novel protease-related hub genes with potential involvement in pancreatic cancer. We applied an integrative computational approach to compartment-specific multiOMIC profiles of laser-capture micro-dissected human PDAC tissues (n = 32) and queried associations of identified candidate genes with clinical outcomes in early (n = 186) and advanced PDAC patients (n = 253). This identified 20 protease-related genes with ≥ 10 physically verified interaction partners in pancreatic cancer. Among these, the pyrimidine biosynthesis regulator gene CAD emerged as a potentially druggable target in pancreatic cancer. CAD expression was nearly restricted to the malignant PDAC epithelium. Furthermore, higher CAD expression was associated with significantly worse overall survival in patients with advanced but not resectable disease, suggesting a role in treatment response rather than disease progression. Moreover, patients with higher CAD expression specifically demonstrated poor response to mFFX but not Gemcitabine-nab-Paclitaxel treatment, which is in line with previous reports on CAD expression being protective against 5-Fluouracil, a component of FFX. Moving forward, we will interrogate the role of CAD in PDAC tissue biology and scrutinize its involvement in FFX resistance, using patient-derived organoids.
Citation Format: Foram Vyas, Barbara Grünwald, Kazeera Aliar, Gun Ho Jang, Grainne O'Kane, Thomas Kislinger, Steven Gallinger, Benjamin Haibe-Kains, Rama Khokha. Hub gene analysis identifies CAD as a potential mediator for drug resistance 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 C059.
Abstract C060: Characterization of a collection of patient-derived xenograft models for pancreatic ductal adenocarcinoma translational research
Authors: Yáñez Mariana , Arenas Enrique Javier , Macarulla Teresa , Tian Tian , Arribas Joaquín , Llorente Sofía , Fabregat Carles , Escorihuela Marta , Castet Florian , Querol Jessica , Salcedo Maria Teresa 
Published: January 2024

Abstract
To conduct successful translational research for pancreatic ductal adenocarcinoma (PDAC), it is imperative to have preclinical models that accurately reflect the intricate molecular, genomic, and histological features of the disease. Patient-derived xenografts (PDXs) have emerged as invaluable platforms for studying tumor biology and personalized therapeutic intervention. Here we present a collection of 32 PDAC PDX models established and fully characterized in our institution. This PDAC PDX collection was generated with tissue from both primary and metastatic lesions, comprehensively representing the disease spectrum. Genomic profiling using next-generation sequencing revealed a remarkable concordance between the PDX samples and their original patient tumor tissue. Notably, identifying common driver mutations associated with PDAC further validates the clinical relevance of this PDX collection. Moreover, histopathologic examination confirmed the similarity between PDX tumor samples and their original patient tissue samples. Interestingly, we also optimized a protocol to generate tumoroids from PDAC PDXs. Leveraging the broad spectrum of disease represented in our collection will facilitate addressing critical research questions, identifying novel therapeutic targets, and ultimately improving patient outcomes of PDAC.
Citation Format: Mariana Yáñez, Enrique Javier Arenas, Teresa Macarulla, Tian Tian, Joaquín Arribas, Sofía Llorente, Carles Fabregat, Marta Escorihuela, Florian Castet, Jessica Querol, Maria Teresa Salcedo. Characterization of a collection of patient-derived xenograft models for pancreatic ductal adenocarcinoma translational research [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 C060.
Abstract C065: Base excision repair pathway regulates transcription-replication conflicts in pancreatic ductal adenocarcinoma
Authors: Meng Fan , Singh Anup K. , Li Tiane , Attiyeh Marc , Kohram Fatemeh , Williams Terence , Liu Yilun , Raoof Mustafa 
Published: January 2024

Abstract
Oncogenic mutations (such as in KRAS) can dysregulate transcription and replication leading to transcription conflicts (TRCs). Unresolved TRCs can cause lethal DNA damage. Here, we sought to investigate the causal role of oncogenic mutations in regulating TRCs in pancreatic ductal adenocarcinoma (PDAC). Further, we characterize the adaptive pathways that mitigate TRCs for PDAC survival. Human PDAC demonstrated 30-120-fold higher levels of TRC genomic signature compared to breast, colon and lung cancer (p&lt;0.001). Gene expression analysis demonstrated high levels of known TRC resolution factors in human tumors compared to normal tissues. TRCs as measured by RNAPII-PCNA proximity ligation assay were significantly enriched in human PDAC cells (Panc-1, BxPC3, MiaPaca2) compared to immortalized normal HPNE cells (p&lt;0.001). Similarly transcriptomic complexes were enriched in nascent DNA immunoprecipitates from Panc1 cells but not HPNE cells. Ectopic expression of oncogenic KRAS(G12D) in human pancreatic ductal epithelial (HPNE) cells enhanced TRCs, and TRC-related DNA:RNA hybrids (R-loops). Inhibition of KRAS or downstream effectors abrogated TRCs in Panc1 and MiaPaca2 cells. An siRNA screen identified several factors in the base-excision repair (BER) pathway as regulators of TRCs. Sub-lethal exposure to hydrogen peroxide enhanced TRCs, whereas N-acetyl cysteine abrogated TRCs. These findings were validated by a pharmacologic approach using inhibitors of APE1 endonuclease in BER pathway (Methoxyamine and CRT). Mechanistic studies revealed that BER pathway inhibition severely altered RNA polymerase II dynamics at nascent DNA; causing RNAPII trapping and contributing to enhanced TRCs. The ensuing DNA damage activated Chk2-ATR pathway but not Chk1-ATM pathway. Co-treatment with ATR inhibitor (VX970, 10-80nM) and BER inhibitor (methoxyamine, 6-12mM) at clinically relevant doses, synergistically enhanced DNA damage and reduced clonogenic survival in PDAC cells. The study uncovers a novel role of BER pathway defects and oxidative DNA damage in promoting TRCs. Our studies provide mechanistic insights into the regulation of TRCs in PDAC which has implications for genome instability and therapy in PDAC.
Citation Format: Fan Meng, Anup K. Singh, Tiane Li, Marc Attiyeh, Fatemeh Kohram, Terence Williams, Yilun Liu, Mustafa Raoof. Base excision repair pathway regulates transcription-replication conflicts 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 C065.
Abstract C086: Investigating resistance to RAS therapies in PDAC models
Authors: Ting Hsiu-Chi , Kim Sun , Park Youngkyu , Deschnes Astrid , Kastan Jonathan , Nigri Jeremy , Tuveson David 
Published: January 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) carries a significantly unfavorable prognosis due to delayed detection and limited therapeutic options, resulting in high mortality rates. The majority of PDAC tumors (&gt;90%) harbor activating mutations in the KRAS oncogene, making KRAS an attractive target for investigating the complex biology of PDAC and identifying potential genetic vulnerabilities that can be exploited for patient treatment. Although small molecules targeting Kras have shown promising results in preclinical and clinical studies of PDAC, the responses have not been durable, and understanding the mechanisms of resistance is a current challenge for the field. To overcome these challenges, we employed two genetic models to mimic Kras inhibition by small molecules. Firstly, using the FPC mouse model, we deleted an endogenous oncogenic KrasG12V allele in mice with measurable PDAC. Secondly, we utilized Auxin-inducible degron 2 (mAID-Auxin) technology to induce acute degradation of Kras proteins, enabling us to evaluate the efficacy of Kras degradation both in vitro and in vivo. Both models led to acute tumor regressions followed by eventual relapse, providing another approach for modeling response and resistance. Acute Kras degradation resulted in a rapid decrease in p-ERK signaling and tumor cell proliferation and alterations in multiple signaling pathways. Sustained degradation of KrasG12D resulted in tumor relapse that predominantly exhibited a mesenchymal phenotype. Intriguingly, we observed several epithelial foci within the relapsed tumors, which displayed reactivated p-ERK signaling. In summary, our study presents an acute ablation model of oncogenic Kras in PDAC, effectively recapitulating the response observed in Kras inhibition both in vitro and in vivo. Furthermore, our model provides insights into the survival mechanism following Kras loss and the mechanisms underlying tumor relapse upon long-term Kras inhibition in PDAC. These findings contribute to our understanding of PDAC biology and offer potential avenues for alternative therapeutic interventions.
Citation Format: Hsiu-Chi Ting, Sun Kim, Youngkyu Park, Astrid Deschnes, Jonathan Kastan, Jeremy Nigri, David Tuveson. Investigating resistance to RAS therapies in PDAC models [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 C086.
Abstract C093: Dysregulated spliceosomal components promote pancreatic cancer progression
Authors: Wan Ledong , Lin Kuan-Ting , Rahman Mohammad A. , Ishigami Yuma , Kral Alexander J. , Voss Dillon , Wang Zhikai , Jensen Mads A. , Wilkinson John E. , Park Youngkyu , Tuveson David A. , Krainer Adrian R. 
Published: January 2024

Abstract
Dysregulated RNA splicing factors have been widely reported in tumorigenesis, but their involvement in pancreatic ductal adenocarcinoma (PDAC) is not well understood. We found that two proteins involved in different stages of spliceosome assembly contribute to PDAC tumorigenesis by regulating alternative splicing, either through direct or indirect interaction with RNA. First, we showed that the splicing factor SRSF1—an RNA-binding protein involved in early spliceosome assembly—can induce pancreatitis and accelerate KRASG12D-mediated PDAC by activating the MAPK pathway. Moreover, the expression of SRSF1 decreased in morphologically normal pancreatic cells expressing KRASG12D to maintain cellular homeostasis. Second, we found that breast cancer amplified sequence 2 (BCAS2, also known as SPF27)—a spliceosome scaffold protein associated with conformational changes—also contributes to PDAC progression. Although BCAS2 does not bind RNA directly, it can regulate alternative splicing events in a sequence-specific manner by promoting the usage of specific 5’ splice sites. BCAS2 promotes the inclusion of exon 21, which has a weak 5' splice site, in the SOS Ras/Rac Guanine Nucleotide Exchange Factor 1 (SOS1) pre-mRNA, resulting in a more oncogenic isoform. These studies not only improve our understanding of the oncogenic role of aberrant alternative splicing, but also provide insights into the mechanisms of alternative-splicing regulation at different stages of spliceosome assembly.
Citation Format: Ledong Wan, Kuan-Ting Lin, Mohammad A. Rahman, Yuma Ishigami, Alexander J. Kral, Dillon Voss, Zhikai Wang, Mads A. Jensen, John E. Wilkinson, Youngkyu Park, David A. Tuveson, Adrian R. Krainer. Dysregulated spliceosomal components promote pancreatic cancer progression [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 C093.
Abstract C105: Functional dissection of the basal cell state in pancreatic cancer
Authors: Singhal Anupriya , Styers Hannah , Yan Yan , Joost Simon , Pitter Kenneth , Grbovic-Huezo Olivera , Sahin Hulya , Basturk Olca , Tammela Tuomas 
Published: January 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a treatment-refractory malignancy with a dismal prognosis. Cancer cell plasticity – the capacity to differentiate and adapt to cell-extrinsic pressure via non-genetic mechanisms – promotes PDAC progression and drives resistance to treatment. Thus, targeting plasticity is a promising therapeutic strategy yet plasticity drivers in PDAC remain poorly understood. Using genetically engineered mouse models driven by oncogenic KrasG12D and loss of p53 (“KPC” model), we profiled primary PDAC tumors using single-cell RNA sequencing and single cell ATAC sequencing. We identified a cancer cell differentiation state that co-expresses both epithelial and mesenchymal programs and has a distinct epigenetic landscape with accessible chromatin across gene sets that mark cancer cell states with divergent phenotypes, suggesting that this cell state is primed for cell state switching. Notably, this high-plasticity cell state (HPCS) signature aligns with a "basal" signature in human PDAC, which associates with poor prognosis and resistance to chemotherapy. To functionally interrogate the HPCS in PDAC progression, we developed a novel lineage-tracing and ablation system allowing (1) visualization of cells in a specific state; (2) timed introduction of a heritable mark allowing us to track cell state progeny; and (3) timed cell state killing via a suicide gene. Lineage-tracing experiments revealed that the HPCS has a robust capacity for differentiation into epithelial/”classical” and mesenchymal states, indicating that the HPCS is functionally plastic and acts as a source of fixed malignant states. Strikingly, targeted elimination of the HPCS over short time periods resulted in tumor collapse, underscoring a critical role in tumor maintenance. Taken together, our data indicates that PDAC harbors a striking dependency on the HPCS, which drives malignant cell state transitions, promotes intra-tumoral diversity, and is critical for tumor maintenance. Our results strongly encourage therapeutic approaches aimed at eradicating this critical subset of cancer cells to improve outcomes in PDAC.
Citation Format: Anupriya Singhal, Hannah Styers, Yan Yan, Simon Joost, Kenneth Pitter, Olivera Grbovic-Huezo, Hulya Sahin, Olca Basturk, Tuomas Tammela. Functional dissection of the basal cell state 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 C105.
Abstract C114: Engrailed-1 promotes pancreatic cancer metastasis
Authors: Xu Jihao , Roe Jae-Seok , Lee EunJung , Tonelli Claudia , Somervile Tim , Yao Melissa , Milazzo Joseph , Tiriac Herve , Kolarzyk Anna , Lee Esak , Grem Jeam , Lazenby Audrey , Grunkemeyer James , Hollingsworth Michael , Grandgenett Paul , Borowsky Alexander , Park Youngkyu , Vakoc Christopher , Tuveson David , Hwang Chang-il 
Published: January 2024

Abstract
Engrailed-1 (EN1) is a critical homeodomain transcription factor (TF) required for neuronal survival, and EN1 expression has been shown to promote aggressive forms of triple negative breast cancer. Here, we report that EN1 is aberrantly expressed in a subset of pancreatic ductal adenocarcinoma (PDA) patients with poor outcomes. EN1 predominantly repressed its target genes through direct binding to gene enhancers and promoters, implicating a role in the acquisition of mesenchymal cell properties. Gain- and loss-of-function experiments demonstrated that EN1 promoted PDA transformation and metastasis in vitro and in vivo. Our findings nominate the targeting of EN1 and downstream pathways in aggressive PDA.
Citation Format: Jihao Xu, Jae-Seok Roe, EunJung Lee, Claudia Tonelli, Tim Somervile, Melissa Yao, Joseph Milazzo, Herve Tiriac, Anna Kolarzyk, Esak Lee, Jeam Grem, Audrey Lazenby, James Grunkemeyer, Michael Hollingsworth, Paul Grandgenett, Alexander Borowsky, Youngkyu Park, Christopher Vakoc, David Tuveson, Chang-il Hwang. Engrailed-1 promotes pancreatic cancer metastasis [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 C114.
Abstract PR12: Targeting CDK7/9 in basal pancreatic cancer
Authors: Kugel Sita , Kartha Nithya , Gianopulos Jessica E. , Schrank Zach , Cavender Sarah M. , Dobersch Stephanie , Faiyaz Notta , Price David H. , Hsieh Andrew C. , Hingorani Sunil R. 
Published: January 2024

Abstract
Pancreatic ductal adenocarcinoma (PDA) is classified into two distinct subtypes, classical and basal, with the basal subtype predicting worse survival in patients. We hope that with a deeper understanding of the biology that drives these subtypes, we can identify novel subtype-specific therapies. We recently described a novel finding that basal PDAs are uniquely sensitive to transcriptional inhibition by targeting cyclin-dependent kinase 7 (CDK7) and CDK9. Additionally, we identified that Sirtuin 6 histone deacetylase (SIRT6) expression levels correlate with PDA subtype, showing that basal PDA is low in SIRT6 expression and classical PDA is high through analysis of hundreds of human PDA tumors. Furthermore, we uncovered an important mechanism by which SIRT6 regulation of the integrated stress response (ISR) can control sensitivity of PDA to CDK7/9 inhibitors. By using a variety of in vitro drug assays, genetic manipulation experiments, immunofluorescence, cycloheximide chase experiments, and in vivo drug studies in human patient-derived xenografts (PDXs) of PDA, we were able to show that SIRT6 regulates activating transcription factor 4 (ATF4) protein stability. Therefore, SIRT6 high/classical PDA has a constitutively active ISR, enabling it to recover and survive the stress of CDK7/9 transcriptional inhibition. On the other hand, basal PDA has low SIRT6 which promotes ATF4 protein instability and a nonfunctional ISR, therefore CDK7/9 transcription inhibition leads to apoptosis. Furthermore, we found that similar to intrinsic resistance, acquired resistance to CDK7/9 inhibitors occurs through the loss of basal state drivers and that restoration of these genes re-sensitizes cells to CDK7/9 inhibition. Importantly, this work highlights the role of chromatin modifiers in regulating PDA subtypes and sensitivity to CDK7/9 inhibitors. PDA subtypes have very distinct chromatin landscapes. We have found that classical PDA maintains its epithelial cell state through chromatin regulators like the SETDB1 heterochromatin complex and more specifically the KRAB-Zinc Finger protein ZNF274. Loss or gain of ZNF274 can induce a cell state change in which classical PDA loses its epithelial characteristics and becomes more mesenchymal in nature. Excitingly, this sensitizes cells to CDK7/9 inhibition. Thus, our work demonstrates the importance of cell state and subtype in therapeutic response to CDK7/9 inhibitors in pancreatic cancer.
Citation Format: Sita Kugel, Nithya Kartha, Jessica E. Gianopulos, Zach Schrank, Sarah M. Cavender, Stephanie Dobersch, Notta Faiyaz, David H. Price, Andrew C. Hsieh, Sunil R. Hingorani. Targeting CDK7/9 in basal 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 PR12.
Sesgo de género en las elites políticas de América Latina: claves interpretativas desde una encuesta comparada a académicos
Authors: Serna Miguel 
Published: January 2024

El objeto del artículo es presentar un análisis desde el mundo académico de la percepción de “techos de cristal” y obstáculos de las mujeres para el acceso a puestos jerárquicos e integración a las elites políticas de América Latina. El estudio tuvo como universo de investigación 2.877 académicos de las principales universidades de Argentina, Chile, Brasil, México y Uruguay. Se aplicó una encuesta de género on line conformada por una muestra de 313 expertos en la temática (economistas, contadores, sociólogos, politólogos y CCSS) entre 2019 y 2021. Los resultados aportan desde una mirada de género y comparada de países de académicos sobre la situación de las inequidades de género en la cúspide del poder político, los factores que inciden y el papel de las políticas públicas e instituciones en el reclutamiento discriminado de las elites.