bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B060: Enhancing models of pancreatic cancer: Integrating patient-derived models with tissue engineering to investigate clinical responses to therapy
Authors: Smith Alexander C. , Muschler John , Munks Mike , Sears Rosalie C. , Brody Jonathan 
Published: January 2024

Abstract
Cancer modeling systems can be advantageous in enabling personalized medicine through rapid testing of therapeutic responsiveness. However, modeling systems often fail in these efforts due to 1) inadequately replicating unique patient genetics, 2) inadequately modeling the patient tumor microenvironment (TME), and 3) lack of internal validation references when isolated from clinical drug response data. We have developed a patient-derived models of cancer (PDMC) program for pancreatic cancer that addresses these challenges. By integrating patient cancer modeling and tissue engineering efforts with clinical trial protocols that perform serial tissue biopsies and analyses during treatment, we can make direct assessments of how different modeling systems replicate actual patient outcomes. Clinical trial protocols include tissue biopsies pre- and post- treatment using targeted therapeutics including MEK and PARP inhibitors. The modeling program, meanwhile, includes collecting metadata from pre- and post- treatment biopsies, the banking of patient tissues, cell line and xenograft generation from each biopsy, multiomic comparisons of models to patient tissue, comparisons of therapeutic responsiveness in models, and ultimately tissue re-engineering through bioprinting of tumor cells along with TME components. Whole exome sequencing is used to confirm that genetic alterations are preserved in each model, and we have established models representing a range of human PDAC genomic profiles. This includes common KRAS and TP53 mutations, as well as rare BRCA mutations and KRAS-wild-type tumors with BRAF mutations. Many cancer-associated fibroblast (CAF) lines have also been established through this program. Including patient derived cell lines, CAD lines, endothelial cells, and PBMCs into 3D bioprinted tumors allows us to better model the TME. Assays performed upon bioprinted tissues can then be directly compared to the same assays performed on the patient tumor to assess similarities as well as further obstacles. Ongoing efforts include building a resource of precise and validated PDMCs for diverse pancreatic cancers, and establishing a path forward for improved cancer modeling for the actualization of personalized medicine in PDAC treatment.
Citation Format: Alexander C. Smith, John Muschler, Mike Munks, Rosalie C. Sears, Jonathan Brody. Enhancing models of pancreatic cancer: Integrating patient-derived models with tissue engineering to investigate clinical responses to therapy [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 B060.
Abstract B070: Histone deacetylation inhibition promotes bi-directional subtype switch in pancreatic cancer
Authors: Klein Lukas , Tu Mengyu , Schmitt Eva K. , Penz Frederike , Mizi Athanasia , Küffer Stefan , Hessmann Elisabeth , Papantonis Argyris , Ellenrieder Volker , Singh Shiv K. 
Published: January 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with 5-year survival of just 11%. Recent large-scale transcriptomic studies have identified two prognostically relevant neoplastic tumor subtypes, i.e. the well-differentiated classical (CLA) subtype with better prognosis, characterized by epithelial gene expression, as well as the dedifferentiated, invasive basal-like (BL) subtype, which displays mesenchymal stemness-related gene signatures. These subtypes have shown to be highly plastic and responsive to extrinsic signals, e.g. from the microenvironment or treatment-induced. Here, we investigate master transcription factor networks governing lineage determination in the different subtypes and the role of histone deacetylation (HDAC) co-regulators in their maintenance. We utilized established, subtype-defined PDAC cell lines in vitro and in orthotopic transplantation models to determine subtype plasticity in response to HDAC inhibition by the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). By integration of RNA-seq, ATAC-seq as well as HiChIP for the activating mark histone 3 lysine 27 acetylation (H3K27ac), we show that the subtype-dependent chromatin organization and regulatory networks can be influenced by pharmacological inhibition of chromatin remodelers, in turn promoting changes in transcription of lineage-determining factors. Targeting these transcription factor networks by HDAC inhibition can lead both to a favorable switch from BL to CLA identity, as well as a detrimental CLA to BL switch. Functional assay such as trans-well invasion further supported the changes in subtype identity following SAHA treatment. This bi-directional subtype switch was additionally validated in patient-derived xenograft cell lines. Together, our findings highlight the importance of understanding the underlying transcriptional and epigenetic mechanisms of the pancreatic cancer subtypes, as they may exhibit opposing responses to targeted therapies.
Citation Format: Lukas Klein, Mengyu Tu, Eva K. Schmitt, Frederike Penz, Athanasia Mizi, Stefan Küffer, Elisabeth Hessmann, Argyris Papantonis, Volker Ellenrieder, Shiv K. Singh. Histone deacetylation inhibition promotes bi-directional subtype switch 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 B070.
Abstract B071: Tumor Treating Fields (TTFields) together with PARP inhibitors for treatment of pancreatic cancer cells
Authors: Martinez-Conde Antonia , Ene Hila , Ben-Meir Kerem , Dor-On Eyal , Lamichhane Puru , Haber Adi , Giladi Moshe , Palti Yoram 
Published: January 2024

Abstract
Purpose/Objectives: Pancreatic cancer remains a leading cause of cancer-related death, with limited treatment options available for the advanced stage. PARP inhibitors (PARPi) are effective treatment options in patients with germline BRCA mutations. Recently, TTFields – electric fields that disrupt cellular processes critical for cancer cell viability – have been shown to induce a state of BRCAness in various cancer types. The objective of this study was to examine possible sensitization of BRCA wild type pancreatic cancer cell lines to PARP inhibition by the application of TTFields. Materials/Methods: BxPC3 and AsPC1 BRCA wild type, human pancreatic cancer cells were treated for 48 and 72 h, respectively, with TTFields (intensity of 1 and 0.7 V/cm RMS, respectively) at a frequency of 150 kHz using the inovitro device. TTFields were applied to the cells alone or together with various concentrations of the PARP inhibitors niraparib or olaparib. Cell count, colony formation, and apoptosis were measured at treatment end. Results: Applying TTFields to pancreatic cell lines resulted in cytotoxicity, anti-clonogenic effect, and induction of apoptosis. PARP inhibitors also demonstrated such effects, in a dose-dependent fashion. Co-application of TTFields enhanced the effects of PARP inhibitors. Conclusions: The results show a benefit for concomitant application of TTFields and PARPi in pancreatic cancer, potentially due to the BRCAness state induced by TTFields. The data suggest TTFields may enhance PARP inhibition efficacy in the absence of background BRCA mutations.
Citation Format: Antonia Martinez-Conde, Hila Ene, Kerem Ben-Meir, Eyal Dor-On, Puru Lamichhane, Adi Haber, Moshe Giladi, Yoram Palti. Tumor Treating Fields (TTFields) together with PARP inhibitors for treatment of pancreatic cancer cells [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 B071.
Abstract B088: The macropinosome: Uncovering the molecular anatomy of an oncogene-driven organelle
Authors: Manceau Ambroise , Galenkamp Koen M.O. , Galapate Cheska M. , Commisso Cosimo 
Published: January 2024

Abstract
As an integral aspect of the metabolic reprogramming that occurs in cancer, oncogenic KRAS mutations drive the stimulation of macropinocytosis, a type of endocytosis that mediates nonselective fluid-phase uptake. Using KRAS-driven models of pancreatic ductal adenocarcinoma (PDAC), we were the first to demonstrate that macropinocytosis functions in tumor cells as a nutrient acquisition pathway. Macropinocytosis triggers the internalization of extracellular proteins via discrete endocytic vesicles called macropinosomes. The incoming protein cargo is targeted for lysosome-dependent degradation, causing the intracellular release of amino acids. These protein-derived amino acids support metabolic fitness by contributing to the intracellular amino acid pools, as well as to the biosynthesis of central carbon metabolites. In this way, macropinocytosis represents a novel amino acid supply route that tumor cells use to survive the nutrient-poor conditions of the tumor microenvironment. While the tenets of the signal transduction events that drive macropinocytosis in cancer have emerged, a detailed picture of the macropinosome itself is not yet available. With the aid of nanotechnology, we have developed a methodology to isolate a pure fraction of macropinosomes from PDAC cells. Using a large-scale proteomic approach, we have been able to generate a list of proteins that reside in macropinosomes. The specificity of this approach was confirmed through the identification and validation of proteins known to specifically localize to these organelles in different contexts, such as Rab5 or SDC1. Thanks to this innovative method, we have demonstrated the involvement of two calcium channels, ATP2B1 and ATP2B4, in the formation of macropinosomes. By elucidating the molecular anatomy of KRAS-driven macropinosomes, we will gain further insight into the regulation and function of macropinocytosis in cancer. Moreover, having a clearer picture of the macropinosome will make us better positioned to exploit this pathway therapeutically and deliver breakthroughs to patients.
Citation Format: Ambroise Manceau, Koen M.O. Galenkamp, Cheska M. Galapate, Cosimo Commisso. The macropinosome: Uncovering the molecular anatomy of an oncogene-driven organelle [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 B088.
Abstract B094: The role of paraspeckles and splicing regulation in driving basal-like pancreatic cancer
Authors: Soares Zamira G. , Berry Emily , Esgdaille Dakarai , Twardowski Jennifer , Mello Stephano S. 
Published: January 2024

Abstract
The basal-like pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive type of mesenchymal PDAC that resists treatment and has a poor prognosis. Understanding the mechanisms driving basal-like PDAC biology will be essential for development of treatment strategies for this aggressive tumor. We have previously shown that loss of the tumor-suppressive non-coding RNA Neat1 recapitulate the phenotype of Arid1a-deficient mice (a component of the SWI/SNF chromatin remodeling complex) in a mouse model for PDAC, with loss of exocrine pancreatic identity and development of acinar- and ductal-derived lesions (Mello et al., 2017), suggesting that Neat1 and Arid1a may share a common molecular mechanism. We now demonstrate that the loss of these two divergent genes induce the emergence of basal-like PDAC. This provides an opportunity to probe for shared features specific to Neat1- and Arid1a-deficient PDAC, as compared to PDAC in which both genes are functional. Notably, our data indicate that both Neat1- and Arid1a-deficient pancreatic cells fail to form nuclear paraspeckles, i.e. structures implicated in the retention of RNA splicing factors. Consistent with this idea, we also find significantly increased exon-skipping, including a sub-set of such events shared between Neat1- and Arid1a-deficient PDAC. In addition, nucleotide sequence motifs associated with exon-skipping locations suggest involvement of RNA splicing factors known to accumulate in paraspeckles, such as Srsf1, Srsf2, Srsf10, Rbm38, Dazap1 and others. We also show that, upon genetic or pharmacological attenuation of splicing regulator function, basal-like PDAC develop epithelial features, reminiscent of mesenchymal-epithelial transition, reduce both their proliferation and migration potential and undergo cell death. Our findings provide an important opportunity to elucidate the molecular pathways that link aberrant RNA splicing and paraspeckle deficiency to basal-like PDAC, providing new insight for the development of mechanism-based novel PDAC treatment strategies to improve patient outcome.
Citation Format: Zamira G. Soares, Emily Berry, Dakarai Esgdaille, Jennifer Twardowski, Stephano S. Mello. The role of paraspeckles and splicing regulation in driving basal-like 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 B094.
Abstract B095: Leukemia inhibitory factor fosters tumor growth in KRAS-driven pancreatic ductal adenocarcinoma
Authors: Miller-Phillips Lisa , Hanafi Imene Boukhalfa , Umetsu Sarah , Olshen Adam , Roy Ritu , Kiemen Ashley , Wang Man-Tzu , Collisson Eric 
Published: January 2024

Abstract
While inflammation is a known and well-validated risk factor for developing pancreatic ductal adenocarcinoma (PDA), it remains unclear how Leukemia inhibitory factor (LIF), a cytokine of the IL-6 class family, influences tumor initiation and progression in PDA. LIF is highly upregulated in PDA when compared to the normal healthy pancreas. Using a human single-cell RNAseq PDA data set, we identified pancreatic cancer cells as the main source of LIF, followed by fibroblasts and stellate cells. After confirming that Pdx1-expressing cells represent the majority of Lif-expressing cells in the pancreas, we crossed our newly developed Lif flox/flox allele into the well-established KrasLSL-G12D/+, Trp53flox/flox, Pdx1-Cre (KPC) mouse model. Lif flox/flox, Pdx1-Cre (LC) mice present with normal pancreas histology, mouse weight, and mouse size at 12 months, indicating that Lif is dispensable for mouse pancreas development and function. Lif flox/flox, Trp53flox/flox, Pdx1-Cre (LPC) mice also showed no differences in pancreas histology when compared to normal Lif-expressing PC mice. Lif flox/floxKPC (LKPC) mice develop PDA tumors. Cell lines from LKPC tumors (n=4) presented with undetectable Lif expression and no LIF protein secretion. Control KPC tumor cell lines (n=4) showed Lif expression and LIF secretion, confirming the successful deletion of Lif in our newly developed mouse model. LKPC mice (n=21) showed a significant increase in disease-specific overall survival at 72 days when compared to control KPC mice (n=26) at 62 days (p&lt;0.05). When mice reached endpoint, LKPC mice presented with significantly smaller tumors with an average tumor weight of 0.7g compared to KPC control animals with an average tumor weight of 1.3g (p&lt;0.05). In summary, we find that cancer-cell expressed LIF augments tumor growth and shortens disease-specific overall survival, nominating leukemia inhibitory factor depletion as a promising therapeutic target in KRAS-driven pancreatic cancer.
Citation Format: Lisa Miller-Phillips, Imene Boukhalfa Hanafi, Sarah Umetsu, Adam Olshen, Ritu Roy, Ashley Kiemen, Man-Tzu Wang, Eric Collisson. Leukemia inhibitory factor fosters tumor growth in KRAS-driven 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 B095.
Abstract B098: Oncogenic KRAS relies on β1 integrin expression to drive pancreatic neoplasia and PDAC development
Authors: Muschler John L. , Huang Ge , Smith Alexander C. , Sears Rosalie C. 
Published: January 2024

Abstract
Oncogenic Kras drives cancer progression through cooperation with multiple cellular factors, many of which are yet to be determined. The β1 integrins, a family of extracellular matrix receptors, are strong candidates; they are implicated in many aspects of cancer progression including cell growth and survival signaling, cell migration and metastasis. Additionally, multiple studies have identified β1 integrins within the interactome of oncogenic Kras. We are investigating the potential cooperation if β1 integrins in Kras-mediated oncogenesis using genetic perturbations within the tamoxifen-inducible and conditional Ptf1a-CreERTM; LSL- KrasG12D (p48-KCER) model of pancreatic cancer. Conditional deletion of the β1 integrins from the adult pancreas produced minimal tissue abnormalities; there were no obvious tissue defects at 6 months post induction, although there was some evidence of pancreatitis at 1 year post induction. However, deletion of the β1 integrins within the KCER model of pancreatic cancer (KCER-Δβ1) resulted in a profound suppression of pancreatic disease progression. There was no detectable neoplasias at 3 months post-induction and minimally detectable neoplasias at 6 months post-induction, compared to prominent neoplasia development and stromal expansion in the control KCER mice at these time-points. Moderate stromal expansion was observed in KCER-Δβ1 mice at 6 months post-induction despite the lack of neoplasia development. To investigate the mechanisms of this integrin-KRAS cooperation, we conditionally deleted the expression of two canonical integrin signaling molecules, the integrin-linked kinase (ILK) and the focal adhesion kinase (FAK). Neither the ILK knockout (KCER-ΔILK) nor the FAK knockout (KCER-ΔFAK) phenocopied the KCER-Δβ1 mice, as both developed neoplasias and stromal expansion at 3 months post-induction and beyond. To explore the role of integrin activation, we next deleted expression of the integrin-cytoskeleton linker molecule Talin-1 in the KCER model. Surprisingly, even though Talin-1 is key to integrin activation, the KCER-ΔTalin-1 mice also failed to phenocopy the KCER-Δβ1, showing ample neoplasia development at 3 and 6 months post-induction, and trending towards faster disease progression at later stages. These combined results demonstrate crucial cooperation between oncogenic Kras and β1 integrins to drive pancreatic cancer progression, and point to non-canonical β1 integrin functions in mediating this cooperation.
Citation Format: John L. Muschler, Ge Huang, Alexander C. Smith, Rosalie C. Sears. Oncogenic KRAS relies on β1 integrin expression to drive pancreatic neoplasia and PDAC development [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 B098.
Abstract B101: Tumor-selective inhibition of active RAS in pancreatic ductal adenocarcinoma
Authors: Wasko Urszula N. , Jiang Jingjing , Tomassoni Lorenzo , Wang Yingyun , Lee Bianca , Orlen Margo , Drizyte-Miller Kristina , Menard Marie , Dilly Julien , Sastra Steven A. , Palermo Carmine F. , Chang Stephanie , Aguirre Andrew J. , Der Channing J. , Vonderheide Robert H. , Stanger Ben Z. , Califano Andrea , Singh Mallika , Olive Kenneth P. 
Published: January 2024

Abstract
RM-042 is a broad-spectrum inhibitor of the active (GTP-bound) form of KRAS, HRAS, and NRAS, with affinity for both mutant and wild type (WT) variants (RASMULTI(ON)). Given that more than 90% of human pancreatic ductal adenocarcinoma (PDAC) cases are driven by activating mutations in KRAS, we assessed the therapeutic potential of RM-042 in a comprehensive range of PDAC models, including human and murine cell lines, human patient-derived organoids, human PDAC explants, subcutaneous and orthotopic cell-line or patient derived xenografts, syngeneic allografts, and genetically engineered mouse models. We observed broad and remarkable anti-tumor activity across these models following direct RAS inhibition by RM-042 at doses and concentrations that were tolerable in vivo. Analyses of tumor and normal tissues following RM-042 treatment revealed divergent cellular responses to RAS inhibition. While we observed anti-proliferative effects in both normal and tumor tissues, RAS-dependent tumors alone exhibited a susceptibility to cell death via apoptosis within hours of dosing. Finally, using single cell regulatory network analysis, we found that different subtypes of PDAC malignant epithelial cells responded in distinct ways to RAS inhibition by RM-042, resulting in an enrichment of the more differentiated gastro-intestinal lineage state (GLS) cellular subtype. Together, these data have significant implications for the clinical development of RAS inhibitors in the setting of PDAC. A related inhibitor, RMC-6236, is currently in early clinical evaluation (NCT05379985).
Citation Format: Urszula N. Wasko, Jingjing Jiang, Lorenzo Tomassoni, Yingyun Wang, Bianca Lee, Margo Orlen, Kristina Drizyte-Miller, Marie Menard, Julien Dilly, Steven A. Sastra, Carmine F. Palermo, Stephanie Chang, Andrew J. Aguirre, Channing J. Der, Robert H. Vonderheide, Ben Z. Stanger, Andrea Califano, Mallika Singh, Kenneth P. Olive. Tumor-selective inhibition of active RAS 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 B101.