bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A082: Defining the lysosome proteome during pancreatic cancer tumor evolution and metastasis
Authors: Nguyen Thuy T.P , Hernandez Grace A. , Rademaker Gilles , Luy Matthew , Li Alexander , Qiu Longhui , Paulo Joao A. , Perera Rushika M. , Mancias Joseph D. 
Published: September 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a five-year survival rate of only 13%, characterized by rapid proliferation, high metastatic potential, and resistance to conventional therapies. PDAC tumors are heavily reliant on nutrient-scavenging pathways such as autophagy and the lysosome – a degradative organelle that plays an essential role in the digestion and recycling of diverse cellular material. Despite their importance, the specific function of lysosomes over the course of tumor evolution and metastasis in PDAC tumors remains poorly understood. To understand the function of the lysosome in PDAC, we utilize a biochemical method known as LysoIP-based proteomics, which isolates intact lysosomes for subsequent analysis using mass spectrometry-based proteomics. This approach allows for a comprehensive analysis of lysosomal composition that can uncover unique features and functions of PDAC lysosomes that promote cellular adaptation to stress in support of tumor growth. A limitation of lysosome isolation from 2D cultured cells is that it does not recapitulate lysosomal features associated with tumors growing in vivo. To address this limitation, we generated a genetically engineered mouse model of PDAC incorporating conditional expression of ‘LysoTag’ (TMEM192-mRFP-3xHA) that enables capture and profiling of lysosomes at different stages of tumor evolution, including early-stage, late-stage, and metastatic disease. Employing this strategy, we successfully captured lysosomal proteins from primary tumors (pancreas), as well as lung and liver metastases. Our preliminary analysis revealed an enrichment of resident lysosomal membrane and luminal proteins in the datasets, confirming the successful isolation of intact lysosomes from these complex tissues. Additionally, we identified non-resident lysosomal proteins (termed cargo) that are enriched and co-evolved with advancing tumor stages. Notably, our results reveal distinct differences in the lysosomal proteome of tumor cells across different tissues. These findings emphasize the critical role of lysosomal function in tumor progression and suggest that targeting lysosomal components could be a promising therapeutic strategy for treating metastatic PDAC.
Citation Format: Thuy T.P Nguyen, Grace A. Hernandez, Gilles Rademaker, Matthew Luy, Alexander Li, Longhui Qiu, Joao A. Paulo, Rushika M. Perera, Joseph D. Mancias. Defining the lysosome proteome during pancreatic cancer tumor evolution and metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A082.
Abstract A083: Genomic Analysis of Structural Variations in Pancreatic Cancer Using Long-Read Sequencing
Authors: Du Yongxing , Zheng Xiaohao , Duan Yunjie , Wang Chengfeng 
Published: September 2024

Abstract
Objective: Structural variations (SVs) constitute the greatest source of genomic alterations leading to the oncogenesis of many cancers, including the deadliest pancreatic cancer (PC). However, SVs in PC remain largely undefined due to technological limitations of the traditional short-read sequencing. This study aims to establish a comprehensive signature of genomic SVs in PC. Methods: PacBio whole genome long-read sequencing was employed to investigate the genomic landscape of SVs in eight tissues from four pancreatic cancer patients. A variety of SVs callers, including pbsv, Sniffles, cuteSV, and svim, were comprehensively adopted to improve the accuracy of SVs detection. Many undefined characteristics of germline and somatic SVs were revealed by comparing with multiple previously published databases. Besides, the impacts of structural variations on 3D chromatin organization were analyzed by integrating multi-omics data including Hi-C, RNA seq and ChIP seq. Results: A total of 26,844 and 27,028 non-redundant SVs were identified in human pancreatic cancer and matched para-cancerous tissues, respectively. Notably, among these SVs, 23.97% were novel and had not been previously reported. Germline SVs were further characterized and found enriched in 25 well-known susceptible genes, such as TP63, PVT1, and ABO. Additionally, we proposed a panel of germline SVs with predicted highest pathogenicity, involving STOX1, DSPP, and WRN. Totally, 616 somatic SVs were identified and presented high burdens in patients with lymph node metastasis. We observed that somatic DELs and INSs were significantly more prevalent in repetitive regions than in non-repetitive regions. Interestingly, DELs showed a decrease in the proportion occurring in simple repeat regions but an increase in the proportion occurring in LINE and SINE regions compared to INSs. Moreover, it was observed that deletions within topologically associated domains were associated with local enhanced interactions and disrupted chromatin loops, which might influence H3K27ac modification of histone contributing to enhancer or silencer hijacking. Conclusion: This study provides insights into the genomic signature of SVs in human pancreatic cancer. These findings might shed new light on the complexity of SVs and their pathogenesis by interplaying with chromatin organization.
Citation Format: Yongxing Du, Xiaohao Zheng, Yunjie Duan, Chengfeng Wang. Genomic Analysis of Structural Variations in Pancreatic Cancer Using Long-Read Sequencing [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A083.
Abstract A084: CDK12 inhibition drives mitotic catastrophe, triggering genome instability and innate immune response in pancreatic cancer
Authors: Iwadate Dosuke , Yamamoto Keisuke , Kato Hiroyuki , Tateishi Keisuke , Fujishiro Mitsuhiro 
Published: September 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited therapies. In our screening using patient-derived organoids, we identified cyclin-dependent kinase 12 (CDK12) as a promising target in a subset of PDAC. Both pharmacological and genetic inhibition of CDK12 exerted potent antitumor activity in vitro and in vivo, inducing double-strand DNA breaks and apoptosis. CDK12 is a member of cyclin-dependent kinases that is involved in gene expression regulations at multiple levels. Recently, CDK12 has gained attention as a therapeutic target in several types of cancers including triple-negative breast cancer and Ewing sarcoma. However, little is known about the impact and possibility of CDK12 inhibition in pancreatic cancer treatment. As the lack of specific inhibitors that selectively target CDK12, studying CDK12 has long been challenging. To overcome this, we used CRISPR-Cas9 mediated genome editing to generate FKBP12F36V (dTAG) knock-in PDAC cell lines, enabling rapid elimination of endogenous CDK12 using a degrader against dTAG (dTAG-13). Quantitative-image-based cytometry and time lapse imaging showed that CDK12 ablation induces mitotic arrest, DNA damage and apoptosis (mitotic catastrophe). Specifically, loss of CDK12 kinase activity in the S phase was sufficient to slow DNA replication speed, leading to spindle assembly checkpoint activation and mitotic catastrophe. Importantly, cells that escaped mitotic death accumulate micronuclei, triggering immune response signaling that is mediated by the cGAS-STING-type I interferon pathway. Our results suggest that CDK12 is a promising target in a subset of PDAC patients, where CDK12 inhibition exerts antitumor activity both in cell autonomous and non-cell autonomous ways through inducing mitotic catastrophe as well as triggering immune response.
Citation Format: Dosuke Iwadate, Keisuke Yamamoto, Hiroyuki Kato, Keisuke Tateishi, Mitsuhiro Fujishiro. CDK12 inhibition drives mitotic catastrophe, triggering genome instability and innate immune response in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A084.
Abstract B002: Tumor-secreted PTHrP facilitates pancreatic cancer cachexia by regulation of de novo lipogenesis pathway
Authors: Bhalerao Nikita , Peura Jessica , Ogoti Yamini , Johnson Calvin , Chen Qingbo , Korobkina Ekaterina , Keller Faith , Wengyn Maximillan , Norgard Robert , Kremmer Richard , Watson Emma , Ruscetti Marcus , Guertin David , Pitarresi Jason R 
Published: September 2024

Abstract
Pancreatic cancer is associated with one of the highest and most severe forms of cancer- associated cachexia amongst solid tumors. In an effort to further our understanding of the molecular etiology of pancreatic cancer-associated cachexia, we have developed mouse models to study adipose tissue wasting during Pancreatic Ductal Adenocarcinoma (PDAC) progression. In these pursuits, we have identified a pro-cachectic factor, PTHrP, that is produced and secreted by PDAC tumor cells and directly signals to adipocytes to facilitate wasting. Genetic deletion and pharmacological inhibition of PTHrP significantly extended the survival of tumor-bearing animals and dramatically reduced cachectic phenotypes in these animals, manifesting as decreased adipose and muscle tissue wasting. Mechanistic studies have shown crosstalk between tumor-cell derived PTHrP and adipose tissue PTH1R that drives the cachectic phenotype. Finally, bulk RNA sequencing analysis in PTHrP-driven cachectic models point towards a role for reduced de novo lipogenesis and adipogenesis in cachectic adipose depots, suggesting potential rewiring of the metabolic profile of white adipose tissue in tumor-bearing mice with higher PTHrP expression.
Citation Format: Nikita Bhalerao, Jessica Peura, Yamini Ogoti, Calvin Johnson, Qingbo Chen, Ekaterina Korobkina, Faith Keller, Maximillan Wengyn, Robert Norgard, Richard Kremmer, Emma Watson, Marcus Ruscetti, David Guertin, Jason R Pitarresi. Tumor-secreted PTHrP facilitates pancreatic cancer cachexia by regulation of de novo lipogenesis pathway [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B002.
Abstract B007: Optimization of an Orthotopic Mouse Model of Pancreatic Cancer to Simulate Liver Metastasis and Cancer Cachexia
Authors: Wang David J , Spadafora Victoria , Pryce Benjamin R , Oles Alexander , Talbert Erin E , Ostrowski Micheal C , Guttridge Denis C 
Published: September 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with a poor prognosis due to two key features. The first is metastasis at presentation, occurring in approximately 80% of PDAC patients, with 90% of these metastases occurring in the liver. The second is cachexia, which compromises treatment tolerance and reduces the quality of life for patients. Although various mouse models of PDAC exist, recapitulating both metastatic and cachectic features have been challenging. In this study, we optimized an orthotopic mouse model of PDAC by altering implantation sites, subcloning parental murine PDAC cells, adjusting the number of transplanted cells, and varying the age of recipient mice to study liver metastasis and cancer cachexia. These modifications significantly increased the latency of tumor development and the time course of the disease, concurrently increasing the rate of liver metastasis to approximately 70%. Furthermore, reliable cachexia endpoints were also achieved in both PDAC mice with and without metastases, mirroring the condition in patients. We also found that cachectic muscles from PDAC mice with metastasis exhibit a similar transcriptional profile to muscles derived from mice and patients without metastasis. Together, this model is likely to be advantageous in both advancing our understanding of the mechanisms of PDAC cachexia and in evaluating novel therapeutics.
Citation Format: David J Wang, Victoria Spadafora, Benjamin R Pryce, Alexander Oles, Erin E Talbert, Micheal C Ostrowski, Denis C Guttridge. Optimization of an Orthotopic Mouse Model of Pancreatic Cancer to Simulate Liver Metastasis and Cancer Cachexia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B007.
Abstract B008: Twist1 drives pancreatic ductal adenocarcinoma-mediated muscle cachexia
Authors: Parajuli Parash , Atfi Azeddine 
Published: September 2024

Abstract
Cancer cachexia is a debilitating syndrome that affects the survival and quality of life of cancer patients. Up to 95% of pancreatic ductal adenocarcinoma (PDAC) patients experience muscle cachexia, yet the underlying mechanisms remain poorly understood. The transcription factor Twist1 plays essential roles in mesenchymal stem cell fate determination, and its deregulation contributes to cancer progression and metastasis. In this study, we report on the serendipitous finding that Twist1 functions in PDAC to drive muscle cachexia. We found that conditional overexpression of Twist1 in the pancreatic epithelium (pTwist1) during early development resulted in severe growth retardation, which was mainly characterized by muscle hypotrophy. This intriguing observation prompted us to inquire whether pTwist1 could function in the pancreatic epithelium to regulate muscle mass, and if so, whether this has any implication as it relates to PDAC-mediated muscle cachexia. We found that enforced expression of pTwist1 in healthy adult animals was sufficient to elicit the cardinal features of muscle cachexia, including progressive decline in body weight, physical activity, muscle force, and muscle mass. In the context of PDAC, enforced expression of pTwist1 in a KrasG12D background led to a dramatic acceleration of tumor progression, and this was associated with severe muscle cachexia. To the best of our knowledge, these findings provide the first evidence that the pro-malignant transcription factor Twist1 functions in PDAC to drive muscle cachexia, thus revealing new insights into the underlying mechanisms of muscle that could be harnessed to curb this debilitating syndrome.
Citation Format: Parash Parajuli, Azeddine Atfi. Twist1 drives pancreatic ductal adenocarcinoma-mediated muscle cachexia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B008.
Abstract B014: NF-kB Regulates Innate Immunity in the Muscle Microenvironment to Control Distinct States of Wasting in Pancreatic Cancer-Induced Cachexia
Authors: Guttridge Denis C , Pryce Benjamin R , Oles Alexander , Talbert Erin E , Morgan Katherine A , Mahvi David A , Ostrowski Michael C , Zimmers Teresa A , Tidball James G , Wang David J 
Published: September 2024

Abstract
Cancer cachexia is a debilitating syndrome characterized by unintentional weight loss largely due to the depletion of adipose and skeletal muscle mass. Cachexia occurs in at least half of all patients with cancer, with increasing incidences in more advanced cases, and is estimated to be responsible for greater than 20% of all cancer related deaths. In pancreatic ductal adenocarcinoma (PDAC), which has a 5-year survival rate of 13%, the incidence of cachexia can be as high as 80% and is associated with poor disease outcomes. Mitigating the effects of cachexia has the potential to increase both quality of life and survival for patients with PDAC. However, there are currently no effective means of treating cachexia, thereby underscoring the need to further understand the pathology of this disease. Although cancer cachexia is classically characterized as a systemic inflammatory disorder, emerging evidence indicates that weight loss also associates with local tissue inflammation. We queried the regulation of this inflammation and its causality to cachexia by exploring skeletal muscle, whose atrophy strongly associates with poor outcomes. Using both a genetically engineered mouse model of PDAC- induced cachexia named KPP and patient samples, we show that cachectic muscle is marked by enhanced innate immunity. Accumulation of macrophages is regulated by an NF-kB activity that localizes to multiple cells within the muscle microenvironment. In addition, this accumulation of macrophages derives from an equal contribution of infiltrating monocytes and resident cells. Moreover, NF-kB activated cells and macrophages undergo a crosstalk; whereas NF-kB+ cells signal and recruit macrophages to inhibit muscle regeneration and promote atrophy, but interestingly at the same time can also protect myofibers, macrophages signal back to NF-kB+ cells to sustain an innate immune response in a feed-forward loop. Together, we propose that NF-kB functions in multiple cells in the muscle microenvironment to regulate innate immunity that both promotes and protects against muscle wasting in cancer.
Citation Format: Denis C Guttridge, Benjamin R Pryce, Alexander Oles, Erin E Talbert, Katherine A Morgan, David A Mahvi, Michael C Ostrowski, Teresa A Zimmers, James G Tidball, David J Wang. NF-kB Regulates Innate Immunity in the Muscle Microenvironment to Control Distinct States of Wasting in Pancreatic Cancer-Induced Cachexia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B014.
Abstract B015: Duodenal aspiration biopsy in diagnosis of pancreatic neoplasms
Authors: Kashintsev Aleksei , Proutski Vitali 
Published: September 2024

Abstract
Introduction Intraductal papillary mucinous neoplasms (IPMNs) are a subset of lesions with elevated malignant potential, warranting their inclusion in screening standards. Despite endoscopic ultrasound (EUS) with fine-needle aspiration biopsy (FNAB) serving as the standard for verification, the occurrence of erroneous conclusions remains significant. Consequently, analysis of pancreatic juice is considered as a potential adjunctive diagnostic method. However, the absence of methods for obtaining pancreatic juice in adequate volume and quality poses a barrier to the widespread adoption of this approach.Materials and MethodsA method of duodenal aspiration biopsy (DAB) was developed involving active aspiration from the lumen of duodenum, yielding large volume of the mix of pancreatic juice and bile uncontaminated by gastric juice. Patients diagnosed with pancreatic neoplasms utilizing EUS with FNAB, were enrolled and ALB was implemented as an adjunctive diagnostic procedure. Cytological analysis of the material obtained was performed along with measuring the level of carcinoembryonic antigen (CEA). The level &gt;192 ng/mL was considered significant, according to the Fukuoka 2017 guidelines.ResultsIn patients with cystic neoplasms of the pancreas undergoing DAB, results of cytological examination were non-informative in certain cases. However, analysis of CEA levels in the pancreatic juice and bile mixture always demonstrated strong concordance with the degree of dysplasia. In some instances, elevated CEA values facilitated the adoption of a more aggressive treatment strategy, leading to the detection of carcinoma. Conversely, low CEA levels prompted the decision to opt for observation rather than radical surgery in other cases.ConclusionDiagnosing precancerous transformations of the pancreas remains a challenging task, characterized by a notable rate of false-positive or false-negative conclusions. The DAB method offers a promising solution, seamlessly integrating into routine clinical practice and offering supplementary data to enhance the verification of pancreatic cancer.
Citation Format: Aleksei Kashintsev, Vitali Proutski. Duodenal aspiration biopsy in diagnosis of pancreatic neoplasms [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B015.
Abstract B021: Development of an ultrasensitive sequencing platform for blood-based mutation profiling of pancreas cancer patients
Authors: Ramaker Ryne , Abbruzzese James , Counter Chris 
Published: September 2024

Abstract
Introduction: One barrier to improving Pancreatic Ductal Adenocarcinoma (PDAC) patient outcomes is the absence of effective, non-invasive biomarkers for disease screening, treatment monitoring, and identification of therapeutic targets. While sequencing-based approaches to detect mutant circulating tumor DNA (ctDNA) in blood have transformed clinical management in several cancer types, use of these ‘liquid biopsies’ has lagged behind in PDAC due to low shedding of PDAC tumor cells. Nevertheless, intact circulating tumor cells have been documented in even the earliest stages of PDAC and precede the limits of disease detection on imaging or gross histology in mouse models. This suggests that circulating tumor cells could server as a PDAC biomarker if the sensitivity of sequencing could be increased. Methods: Point mutations in the gene KRAS are found in up to 95% of PDAC patients and hence represent a potential biomarker target for this cancer. To detect these pathogenic mutations in KRAS, we will adapt Maximum Depth Sequencing (MDS) for exon 2 of this gene by testing various primers and reaction conditions. The sensitivity of the K-MDS assay was optimized for blood by spiking PDAC cells with known KRAS mutations into healthy control blood at various dilutions. Finally, to evaluate the clinical sensitivity, we have collected paired blood draws from 200 advanced PDAC patients in prospective fashion, one to be tested with a commercial ctDNA test and one by K-MDS. Results: We optimized MDS to sequence exon 2 of KRAS and successfully detected a single mutant template in &gt;107recovered independently barcoded templates (e.g. 107 individual KRAS alleles). We then optimized the assay for human blood and demonstrated that K-MDS could reproducibly detect a KRAS mutation corresponding to PDAC cells spiked into healthy control whole blood at the lowest dilution tested, namely one cell per ml of blood. This corresponds to a sensitivity of one mutated fragment per one million KRAS fragments, or 1000x more sensitive than currently available commercial assays. We are currently performing K-MDS on prospective PDAC cohort, with completion of this study expected this fall. Conclusions: We developed a highly sensitive sequencing assay cable of detecting PDAC ctDNA in whole blood. With successful validation in PDAC blood samples, this assay could provide a powerful tool for non-invasive PDAC mutation profiling and disease monitoring.
Citation Format: Ryne Ramaker, James Abbruzzese, Chris Counter. Development of an ultrasensitive sequencing platform for blood-based mutation profiling of pancreas cancer patients [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B021.