bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A018: Exercise stimulates anti-tumoral immunity in metastatic PDAC
Authors: Riachi Mansour E. , Hirsch Carolina G. Alcantara , Ma Erica , Shapiro Beny , Javed Ammar , Wolfgang Christopher L. , Bar-Sagi Dafna 
Published: January 2024

Abstract
The majority of pancreatic ductal adenocarcinoma (PDAC) patients are metastatic at presentation with limited treatment options and a poor overall 5-year survival of 3%. The liver is the predominant site of distant metastasis in PDAC. Our group has previously shown that aerobic exercise can inhibit tumorigenesis in a primary PDAC mouse model by promoting anti-tumor immunity, however, the effects of exercise in the metastatic setting have not been explored. As such, we developed a model of PDAC liver metastasis by isolating primary pancreatic and liver metastatic cell lines from 18–20-week-old LSL-KRasG12D/+; LSL-Trp53R172H/+; p48Cre; Rosa26LSL-tdTomato/+ (KPCTpancreas or KPCTliver, respectively) mice. KPCTpancreas cells were surgically implanted into the pancreata of syngeneic wild-type mice. One week after pancreatic implantation, KPCTliver cells were implanted into the liver either by direct injection into the parenchyma or via the portal vein. The portal vein method enables us to account for the extravasation step of the metastatic cascade, while the direct parenchymal injection offers a less invasive surgery. Both models preserve the spleen, which is the largest secondary lymphoid organ and essential to the immune response. Treadmill running was initiated in the aerobic exercise cohort 5 days per week for 2 weeks or mice were allowed to rest. Endpoint analysis revealed that aerobic exercise treatment decreased tumor burden in both primary tumors and liver metastasis as measured by tumor weights and tdTomato fluorescence imaging when compared to the rested controls. Immune profiling of the liver metastases revealed elevated IL-15Rɑ+ CD8+ T cells as well as CD19+ B cells in the exercise cohort. While identification of IL-15Rɑ+ CD8+ T cells is consistent with the immune changes we have previously reported in the primary pancreatic tumor of exercised mice, the latter changes reveal organ specific immune cell recruitment not observed in the primary pancreatic tumor of exercised mice. The combined immune profiling and phenotypic changes suggest that aerobic exercise reduces PDAC metastatic growth by modulating systemic and intra-tumoral immunity. The induction of an anti-tumorigenic immune response by aerobic exercise could open avenues for potential pharmacological intervention in downstream pathways to aid in the treatment of metastatic PDAC.
Citation Format: Mansour E. Riachi, Carolina G. Alcantara Hirsch, Erica Ma, Beny Shapiro, Ammar Javed, Christopher L. Wolfgang, Dafna Bar-Sagi. Exercise stimulates anti-tumoral immunity in metastatic PDAC [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 A018.
Abstract A043: The tumor-intrinsic RNA binding protein HuR is essential for anti-tumor immunity in PDAC
Authors: Guo Yifei , Finan Jennifer M. , Hedberg Madeline D. , Brody Jonathan R. , Eil Robert 
Published: January 2024

Abstract
Immunotherapies have shown limited effectiveness in pancreatic ductal adenocarcinoma (PDAC), despite successes in many other cancers. The RNA-binding protein HuR is known to play a critical role in the oncogenesis of PDAC through regulating key mRNA transcripts. Our lab has showed that tumor-intrinsic HuR is overexpressed in PDAC and regulates the tumor microenvironment composition and alters multiple tumor cytokine release. Thus, we hypothesized that HuR plays a role in immune evasion of PDAC. We disrupted the locus encoding HuR (Elavl1), using CRISPR Cas9 in Kras-p53 mutant-driven (KPC) murine PDAC to assess its function in tumor immune evasion. Here, we report that HuR, a known pro-survival factor for PDAC, has a role in tumor immune evasion by suppressing T cell infiltration and T cell activation. Specifically, HuR-knockout (KO) KPC tumors grew slower compared to KPC wildtype (WT) tumors in an orthotopically implantation model (p-value&lt;0.0001), even though they grew at the same rate in vitro (in a non-compromised environment). Accordingly, HuR-KO tumors had more T cell infiltration and activated T cells comparing to HuR-WT tumors (p-value=0.0047). Furthermore, T cell depletion partially rescued the size of HuR-KO tumors. Collectively, these data support the hypothesis that HuR suppresses T cell activation and prevents T cells from infiltrating the PDAC microenvironment, which therefore leads to PDAC immune evasion. Ongoing experiments will transduce KPC cell lines with ovalbumin (OVA) antigen, which will selectively active CD8+ OT-I T cells through their transgenic TCR, to measure the ability of KPC HuR-WT or HuR-KO OVA cells in directly activating CD8+ OT-I T cells. We will also rescue HuR in HuR-KO cells to validate HuR’s role in immune evasion. These findings support the concept that HuR plays an important pro-survival role of PDAC in vivo, and that targeting strategies against HuR being developed (e.g., siHuR nanotherapies and small molecule inhibitors) could potentially enhance PDAC sensitivity to immune-based anti-cancer therapies such as checkpoint blockade and T cell transfer.
Citation Format: Yifei Guo, Jennifer M. Finan, Madeline D. Hedberg, Jonathan R. Brody, Robert Eil. The tumor-intrinsic RNA binding protein HuR is essential for anti-tumor immunity in PDAC [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 A043.
Abstract A066: A novel approach for exocrine pancreas transcriptomics reveals the cellular landscape of the pancreas
Authors: Aney Katherine J. , Jeong Woo-Jeong , Vallejo Andres F. , Chen Ethan , Wang Austin , Dougan Stephanie K. , Wise Kellie , Jensen Kirk , Martelotto Luciano , Nissim Sahar 
Published: January 2024

Abstract
Pancreatic acinar cells are responsible for producing large amounts of digestive enzymes, which are essential for nutrient breakdown but make it difficult to capture the transcriptome of individual cells. To address this challenge, we use a reversible fixative that is compatible with 10X Genomics, thereby preserving the acinar transcriptome and capturing cell composition more faithful to histology. Using this method, we transcriptionally characterize all cell types in the healthy mouse pancreas, and track how these populations change during acute pancreatitis and subsequent recovery. We identify immune cells in the healthy and inflamed pancreas at a level of detail previously unappreciated, characterizing T cell subsets including Th2, γδT, and regulatory T cells. Pancreatitis elicits an influx of neutrophils along with activation and proliferation of macrophages and dendritic cells. Observing significant transcriptional changes in acinar cells after pancreatitis, we define an Acinar to Ductal Metaplasia Index (ADMI), a gene signature that can be used to measure deviation from normal acinar identity in bulk or single cell RNA datasets. We corroborate ADMI using orthogonal GeoMx data, and validate its utility in independent published datasets. We are now expanding our study to perform transcriptomics using our fixation method on pancreatic cancer precursor lesions. Together, we aim to characterize cell types in the mouse pancreas under healthy, inflamed, and precursor conditions to establish a reference atlas for future research on the exocrine pancreas in healthy and diseased states.
Citation Format: Katherine J. Aney, Woo-Jeong Jeong, Andres F. Vallejo, Ethan Chen, Austin Wang, Stephanie K. Dougan, Kellie Wise, Kirk Jensen, Luciano Martelotto, Sahar Nissim. A novel approach for exocrine pancreas transcriptomics reveals the cellular landscape of the pancreas [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 A066.
Abstract A067: A single sample classifier of Bailey's molecular subtype of PDAC
Authors: Baba Taisuke , Sunagawa Masaki , Yamaguchi Junpei , Kokuryo Toshio , Ebata Tomoki 
Published: January 2024

Abstract
&lt;Background&gt; Transcriptomic molecular subtype of pancreatic cancer (PDAC) is expected to be an important part of future personalized medicine. However, most classifier methods are based on the relative expression patterns in the dataset. Batch correction methods are still under development, thus no one can know if the subtyping of their own dataset is accurate, which has made many researchers hesitant to perform studies involving molecular subtyping. PurIST is a robust classifier of Moffitt tumor subtype invented by Rashid et al. It calculates a score based on the expression pattern within a sample and predicts a specific subtype. Unlike traditional cluster-based subtyping, the predicted subtype never changes. Because these types of methods are independent of the cohort composition and the prediction can be made for even a single sample, these methods are called single sample classifiers (SSCs). The approaches of most SSCs to absorb the batch differences are to make the information fuzzy, thus sacrificing the predictive ability. In this study, we invented a single sample classifier called inverse pair boosting (IPB). Our approach does not lose information, instead, magnifies the differences between subtypes and relatively reduces the differences between batches to a negligible level. &lt;Methods and Results&gt; Considering Moffitt's tumor classification, classical tumors have high classical gene expressions and low basal-like gene expressions, whereas, the gene expression patterns of basal-like tumors are the other way around. This kind of one side up and the other side down relationship is widely observed in the gene expression pattern. We used this to enhance the subtyping difference and overcome the batch differences. We developed a machine learning model with IPB method based on the Bailey's original RNA-seq data (PACA-AU RNA-seq), and tested its robustness with PACA-AU microarray data. Although there is a huge gap between RNA-seq data and microarray data due to their different modalities, the accuracy of the Bailey's subtype prediction on microarray data was 0.86, which was much higher than other SSCs (accuracy = 0.60 - 0.67). &lt;Conclusion&gt; We developed a single sample classifier of Bailey's molecular subtype of PDAC using novel approach called IPB. Our AI model can make a significant contribution to the development of research on molecular subtypes of PDAC.
Citation Format: Taisuke Baba, Masaki Sunagawa, Junpei Yamaguchi, Toshio Kokuryo, Tomoki Ebata. A single sample classifier of Bailey's molecular subtype of PDAC [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 A067.
Abstract A076: Spatial genomic expression profiling reveals metastatic gene markers in mucinous cystic carcinoma of the pancreas and regional lymph nodes
Authors: Gopinath Chirag S. , Ghodrati Arshia , Demirkhanyan Lusine , Gnanamony Manu , Norton Joseph A. , Orcutt Sonia T. , Gondi Christopher S. 
Published: January 2024

Abstract
Pancreatic cancer is a highly lethal disease characterized by low detectability in its early stages, leading to limited treatment options in advanced stages. Mucinous cystic carcinoma (MCC) is a rare subtype of pancreatic cancer that produces mucin. In this study, we investigated the genetic characteristics of MCC and its metastatic potential. Using spatial genomic analysis, we observed the upregulation of several genes in MCC, including CPA1 and CPB1, which encode carboxypeptidases produced by the pancreas. These genes were highly expressed in both the pancreatic tumor and regional lymph nodes, suggesting their potential as gene markers for the metastatic potential of MCC. Moreover, we observed co-localization and upregulation of genes encoding chymotrypsin-like-elastase in both the pancreatic tissue and lymph nodes, indicating their potential involvement in metastasis. Furthermore, we observed significant elevation in the expression of pancreatic enzymes encoded by PRSS1, PRSSA, CLPS, and PLAG2GA in both the pancreatic tissue and lymph nodes. The presence of PRSS1 and PRSSA in the lymph node suggests the presence of cancer cells in the lymphatic system, which in turn promotes tumor growth, invasion, and metastasis. Additionally, elevated expression of CLPS in the lymph nodes may be associated with altered lipid metabolism and the breakdown of fat molecules in the tumor microenvironment. This upregulation was accompanied by increased levels of SPARC, an extracellular matrix protein, in both tissues, emphasizing the correlation between metastatic potential and tumorigenesis. Notably, commonly observed tumor markers for pancreatic cancer, such as SMAD4, did not exhibit upregulation in our MCC case, indicating alternative mechanisms of tumor development in this particular subtype. Additionally, we noted heightened expression of the CA 19-9 antigen, a valuable marker for monitoring the progression of pancreatic cancer. In conclusion, our findings reveal the upregulation of several gene markers in this rare subtype of pancreatic cancer and regional lymph nodes. Understanding the expression patterns of these markers can aid in identifying potential therapeutic targets and detecting metastatic potential at an early stage for MCC.
Citation Format: Chirag S. Gopinath, Arshia Ghodrati, Lusine Demirkhanyan, Manu Gnanamony, Joseph A. Norton, Sonia T. Orcutt, Christopher S. Gondi. Spatial genomic expression profiling reveals metastatic gene markers in mucinous cystic carcinoma of the pancreas and regional lymph nodes [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 A076.
Abstract A077: The EZH2 epigenetic factor orchestrates oncogenic properties in ATM-deficient pancreatic cancer
Authors: Roger Elodie , Härle Anna , Gout Johann , Perkhofer Lukas , Hessmann Elisabeth , Kleger Alexander 
Published: January 2024

Abstract
Despite decades of extensive basic and translational research improving our understanding of pancreatic ductal adenocarcinoma (PDAC), its complex biology remains a significant challenge and limits overcoming its dismal prognosis. Due to its resistance to conventional therapies and heterogeneous mutational landscape, molecular stratification and the development of targeted therapeutic options are essential for improving survival of PDAC patients. Previous work from our group investigated loss-of-function mouse models for the serine/threonine kinase ATM causing homologous recombination deficiency (HRD) in PDAC. Specifically, ATM loss caused certain oncogenic features in the arising tumors, including the acquisition of an invasive phenotype along with the emergence of a prominent desmoplastic reaction, but also sensitizes toward platinum-based therapies and PARP1 inhibition (Russell, Nat Commun; Perkhofer, Cancer Res; Gout, Gut). However, the mechanisms orchestrating these oncogenic features remain unclear. Here, we identified the histone-methyltransferase EZH2 as a direct ATM substrate to operate as an epithelial-mesenchymal gatekeeper. In detail, ATM-deficient tumors accumulated EZH2, suggesting that ATM status contributes to rewiring the epigenetic landscape of pancreatic tumors, subsequently supporting oncogenic features. To investigate whether and how EZH2 impacts ATM-deficient PDAC pathogenesis, we generated conditional double ATM and EZH2-knockout in the KrasG12D/+; Ptf1aCre/+ mice. Double-null mice showed extended mouse survival, reduced metastasis burden, and decreased undifferentiated malignant cell features. Interestingly, both in vivo and in vitro investigations revealed that ATM status significantly impacts EZH2 activity via a post-translational regulation axis. Specifically, the ATM kinase activity was critical to promote Culin1 E3-ubiquitin ligase recruitment and subsequent EZH2 ubiquitination and degradation. Finally, we demonstrated that a combinatorial therapy involving a potent EZH2 inhibitor promotes genomic instability and exacerbates the cytotoxic effects of PARP interference in ATM-deficient HRD PDAC. Overall, our study demonstrates that ATM deficiency significantly impacts EZH2 epigenetic functions and pinpoints the molecular stratification according to ATM status prior to pharmacological EZH2 interference in PDAC therapies as a valuable approach to target ATM-deficient HRD tumors.
Citation Format: Elodie Roger, Anna Härle, Johann Gout, Lukas Perkhofer, Elisabeth Hessmann, Alexander Kleger. The EZH2 epigenetic factor orchestrates oncogenic properties in ATM-deficient 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 A077.
Abstract A086: TFEB protects pancreatic cancer cells against nucleolar stress
Authors: Duff Florence Mc , Bessy Laure , Marchand Benoit , Boucher Marie-Josee 
Published: January 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate among cancers. Despite its limited efficacy, gemcitabine is widely used in PDAC regimens. Chemoresistance to gemcitabine is likely a contributor to its poor effectiveness. Our previous research has shown that gemcitabine induces a cytoprotective autophagy and lysosomal response in pancreatic cancer cells. Further understanding of the mechanisms behind this autophagy and lysosomal response could lead to new therapeutic opportunities. It is known that gemcitabine can cause DNA replication arrest, double-strand breaks, and possibly nucleolar stress. Herein, we aim to specifically determine whether gemcitabine induces nucleolar stress and if this nucleolar stress triggers a cytoprotective response. Indicative of nucleolar stress, we demonstrate nucleoplasmic localization of nucleolin and nucleolar morphological changes upon gemcitabine treatment. Treatment of cells with the nucleolar stress inducer CX-5461 leads to an autophagy and lysosomal response as monitored by increased LC3 and LAMP1 puncta, and mature cathepsin B levels. Furthermore, enriched nuclear localization of the master regulator of autophagy and lysosomal function, TFEB, is observed in CX5461-treated cells (as detected by immunofluorescence and subcellular fractionation). This nuclear enrichment of TFEB correlates with the enrichment of faster migrating forms of TFEB (indicative of post-translational modification changes) as detected by immunoblotting. Through clonogenic assays, PDAC cells with reduced TFEB function (PDAC-shTFEB) demonstrate higher sensitivity than control cells to CX-5461. Furthermore, PDAC-shTFEB cells express higher levels of apoptotic markers upon CX-5461 treatment. Overall, our data provide the first evidence that nucleolar stress induces a TFEB-dependent protective response. Given that our work was performed in cells without functional wild-type p53 signaling, TFEB could act as a sensor of nucleolar stress relaying a protective response and assisting cells to engage in timely and coordinated action to cope with stress. Therefore, our results provide further support for the involvement of TFEB in the chemoresistance of PDAC cells.
Citation Format: Florence Mc Duff, Laure Bessy, Benoit Marchand, Marie-Josee Boucher. TFEB protects pancreatic cancer cells against nucleolar stress [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 A086.
Abstract A105: Wild-type IDH1 inhibition enhances chemotherapy response in pancreatic cancer
Authors: Zarei Mehrdad , Hajihassani Omid , Hue Jonathan J. , Graor Hallie J. , Loftus Alexander W. , Rothermel Luke D. , Winter Jordan M. 
Published: January 2024

Abstract
Background and Aims: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive forms of cancer, with a five-year overall survival rate of 12% among all-comers. Current systemic therapeutic options are limited to cytotoxic chemotherapies which have limited clinical efficacy and are often associated with the rapid development of drug resistance. We examined mechanistic and therapeutic implications of combining anti-wild-type IDH1 therapy with conventional chemotherapeutics to treat PDAC. Methods: Therapeutic responses were tested in vivo and in vitro through survival studies, testing for the effects of ivosidenib (an allosteric IDH1 inhibitor) and PDAC chemotherapeutics. Usage of ivosidenib is based on pre-clinical work showing anti-wild-type IDH1 activity under tumor associated conditions. Results: Chemotherapy treatment of PDAC cells induced the production of reactive oxygen species and increased TCA cycle activity. Treatment also resulted in the rapid induction of wild-type IDH1 expression, which served as a key resistance factor. The enzyme is protective under chemotherapy-associated stress by supporting antioxidant defense and mitochondrial function, through the generation of NADPH and alpha-ketoglutarate, respectively. Pharmacologic suppression of wild-type IDH1 was synergistic with conventional chemotherapeutics in vitro, and potentiated sub-therapeutic doses of these drugs in murine PDAC models. Conclusions: Pharmacologic wild-type IDH1 inhibition with ivosidenib proved to be cooperative with conventional PDAC chemotherapeutics in diverse models. This promising new treatment approach is easily translatable, and provides the basis of an ongoing clinical trial (NCT05209074).
Citation Format: Mehrdad Zarei, Omid Hajihassani, Jonathan J. Hue, Hallie J. Graor, Alexander W. Loftus, Luke D. Rothermel, Jordan M. Winter. Wild-type IDH1 inhibition enhances chemotherapy response 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 A105.