tbuckley/cabot-search huggingface dataset:
Abstract B024: Hypoxia at 3D organoid establishment selects essential subclone within heterogenous pancreatic cancer
Authors: Koichiro Kumano, Hiromitsu Nakahashi, Pakavarin Louphrasitthiphol, Yukihito Kuroda, Yoshihiro Miyazaki, Osamu Shimomura, Shinji Hashimoto, Yoshimasa Akashi, Bryan James Mathis, Jaejeong Kim, Yohei Owada, Tatsuya Oda
Journal: Cancer Research (2024)

Abstract Hypoxia is a key microenvironment associated with malignant traits, including epithelial-mesenchymal transition (EMT) and chemotherapy resistance. Pancreatic ductal adenocarcinoma (PDAC) is extremely hypoxic due to hypovascularity and abundant stromal proliferation. This severe condition accelerates the emergence of hypoxia-adapted cells, which contaminate PDAC as a heterogeneous population. Thus, analyzing hypoxia-adapted cells should be prioritized in analyzing/developing PDAC therapeutic strategies. Recently, 3D organoid culture has been widely used to simulate various organ cancers, featuring precise control with respect to cellular selection through diverse culture conditions. However, as the technology of single-cell analysis has revealed more details of the heterogeneity, the current 3D organoid culture system was also known to have limitation that the system has some potential selection bias. Although several selection biases have been identified, very few reports have focused on oxygen concentrations as a selection bias, leaving room for intervention. To overcome the potential selection bias, we focused on oxygen concentration during the establishment of 3D organoids. We subjected identical PDAC surgical samples to normoxia (O2 20%) or hypoxia (O2 1%) from primary culture, yielding glandular and solid organoid morphology, respectively. Pancreatic cancer organoids established under hypoxia displayed higher expression of EMT-related proteins, a Moffitt basil-like subtype transcriptome, and higher 5-FU resistance in contrast to established organoids under normoxia. We suggest that hypoxia during organoid establishment efficiently selects for hypoxia-adapted cells possibly responsible for PDAC malignant traits, facilitating a fundamental source for elucidating and developing new treatment strategies against recalcitrant PDAC. Citation Format: Koichiro Kumano, Hiromitsu Nakahashi, Pakavarin Louphrasitthiphol, Yukihito Kuroda, Yoshihiro Miyazaki, Osamu Shimomura, Shinji Hashimoto, Yoshimasa Akashi, Bryan James Mathis, Jaejeong Kim, Yohei Owada, Tatsuya Oda. Hypoxia at 3D organoid establishment selects essential subclone within heterogenous 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 B024.
Abstract B009: Identifying of a novel diagnostic markers for pancreatic neuroendocrine tumors by proteomics with patient blood
Authors: Eun-Young Koh, Ji Hye Jeong, Hee-Sung Ahn, Kyunggon Kim, Eunsung Jun
Journal: Cancer Research (2024)

Abstract Neuroendocrine tumors are tumors originating from endocrine cells in various organs, and present very heterogeneous characteristics, and the incidence rate is gradually increasing. Among them, neuroendocrine tumors originating from pancreas are divided into functional tumors and non-functional tumors according to the presence hormone secretion function. Since non-functional tumors are often asymptomatic, early diagnosis is not easy, and differential diagnosis from pancreas ductal adenocarcinoma (PDAC) is difficult, making it difficult to determine the direction of treatment. Therefore, we aimed to find protein biomarkers for the diagnosis and differential diagnosis of pancreatic neuroendocrine tumors (PNET) through proteomic analysis of human blood. First, a total of 60 human plasma samples were obtained from 17 PNETs, 23 PDACs, and 20 Healthy donors (HD), and liquid chromatography-mass spectrometry (LC-MS) proteomics analysis was performed. For 60 cases of raw data obtained through LC-MS analysis, identification and label-free quantification were performed through the Human swissprot protein sequence database. Through pre-processing and normalization, an average of 549 protein lists for each sample were obtained. And through quantitative evaluation, the proteomes that were increased or decreased for each disease were analyzed and classified, and ACTR3, CD163, and LECT2, which were increased in PNET, were selected as diagnostic biomarker candidates. The diagnostic AUC for distinguishing PNET from HD was 0.706 for ACTR3, 0.971 for CD163, and 0.541 for LECT2. The diagnostic AUC to distinguish PNET from PDAC was 0.821 for ACTR3, 0.870 for CD163, and 0.783 for LECT2. We selected three candidates, ACTR3, CD163, and LECT2, as blood biomarkers for the accurate diagnosis of PNET. And through the combination of markers, it is expected that the sensitivity and accuracy of the diagnosis can be further increased. In the future, we will study the function as a marker that can simultaneously predict diagnosis and treatment response by identifying the molecular biological mechanism for the generation and progression of PNET through these three markers. Citation Format: Eun-Young Koh, Ji Hye Jeong, Hee-Sung Ahn, Kyunggon Kim, Eunsung Jun. Identifying of a novel diagnostic markers for pancreatic neuroendocrine tumors by proteomics with patient blood [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 B009.
Abstract B108: Integrated <i>in vivo</i> dissection of metastatic phenotypes and molecular programs in pancreatic ductal adenocarcinoma
Authors: Saswati Karmakar, Anastasia Lyulina, Xiaochen Xiong, Yuning J. Tang, Steven Lopez, Nicolas William Hughes, Laura Attardi, Dmitri A. Petrov, Monte M. Winslow
Journal: Cancer Research (2024)

Abstract The ability of pancreatic ductal adenocarcinoma (PDAC) cells to form tissue destructive metastases remains a critical impediment to therapy. Metastasis is a complex multistep process that is poorly understood and the molecular events and cellular states that enable cancer cells to overcome each step of the metastatic cascade remain elusive. To investigate the regulators of PDAC metastasis, we accrued and characterized a panel of 31 cell lines generated from mouse models of PDAC. Initial experiments indicated that these cell lines have an ~40-fold difference in their ability to form lung metastases after transplantation into immunocompetent recipient mice. To more accurately quantify the relationship between metastatic seeding, growth, organ tropism, and immune evasion across all cell lines in parallel, we tagged each cell line with a barcode that provides both cell line-level and subclonal-level resolution. We pooled all 31 barcoded cell lines, transplanted them to seed metastases in different organs, and performed barcode sequencing on DNA from the metastasis-bearing tissues after short (seeding) and long (expansion) time periods. Neither seeding nor metastatic outgrowth correlated with growth in culture. Metastatic seeding did not directly correlate with overall metastatic burden, indicating that these processes depend on distinct biological processes. Transplantation into syngeneic immune-competent and immune-deficient recipient mice quantified the impact of immune responses towards each cell line. Bulk and single cell RNA-sequencing uncovered unexpected intra- and inter-cell line heterogeneity. Future experiments will integrate the data on metastatic phenotypes with molecular information to uncover drivers and inhibitors of each step of the metastatic cascade. Broad-scale molecular profiling coupled with quantitative in vivo analysis of metastatic phenotypes will uncover the relationships between metastatic phenotypes, create a resource for the community, and reveal novel pathways that govern PDAC metastasis, which could have implications for developing novel therapeutic strategies. Citation Format: Saswati Karmakar, Anastasia Lyulina, Xiaochen Xiong, Yuning J. Tang, Steven Lopez, Nicolas William Hughes, Laura Attardi, Dmitri A. Petrov, Monte M. Winslow. Integrated in vivo dissection of metastatic phenotypes and molecular programs 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 B108.
Abstract B025: IL-1 blockade prevents cardiac toxicity and improves immunotherapy efficacy in mouse models of pancreatic cancer
Authors: Nilesh P. Talele, Heena Kumra, Igor L. Gomes-Santos, Sylvie Roberge, William W. Ho, Patrick Andersson, Sampurna Chatterjee, Marie Siwicki, Dan G. Duda, Mikael J. Pittet, Dai Fukumura, Rakesh K. Jain
Journal: Cancer Research (2024)

Abstract Background: Immune checkpoint blockers (ICBs) have revolutionized cancer treatment, but they are often associated with severe immune related adverse events (irAEs). These severe irAEs are more often seen in patients with obesity or concomitantly treated with cytotoxic therapies. Methods: We aimed to understand the mechanisms of ICB-induced irAEs, in the context of obesity and ICB/chemotherapy combinations. We developed a mouse model of cardiac irAEs, which is the most fatal type of irAE in ICB-treated cancer patients, with clinically relevant features: (i) an ICB-resistant cancer (pancreatic ductal adenocarcinoma or PDAC), (ii) obesity induced with high-fat diets, and (iii) a combination treatment of ICB (α-PD1 + α-CTLA4) and chemotherapy (FOLFIRINOX). Results: Our FDA and single institution retrospective analyses indicate that patients treated with ICB had greater relative risk of developing myocarditis as compared to other anti-cancer therapies. Mice with orthotopic PDAC and obesity developed irAEs after treatment with ICB and chemotherapy as compared to chow diet. These irAEs recapitulated those observed in patients with cancer and obesity, including cardiac dysfunction consistent with myocarditis, cardiac fibrosis, and increased circulating levels of interleukin-1 beta (IL-1b). IL-1β blockade prevented myocarditis and reduced cardiac fibrosis after immunotherapy. Importantly, IL-1β blockade also enhanced the anti-tumor effects of ICB + FOLFIRINOX combination therapy, and increased mouse survival. Conclusions: We developed a translationally relevant 'triple hit' mouse model and discovered that IL-1β mediates ICB-induced cardiotoxicity. In addition, we found that IL-1β blockers, which are already used in the clinic for cardiology indications, both reduce adverse events and simultaneously enhance the antitumor effects triggered by immunotherapy. Citation Format: Nilesh P. Talele, Heena Kumra, Igor L. Gomes-Santos, Sylvie Roberge, William W. Ho, Patrick Andersson, Sampurna Chatterjee, Marie Siwicki, Dan G. Duda, Mikael J. Pittet, Dai Fukumura, Rakesh K. Jain. IL-1 blockade prevents cardiac toxicity and improves immunotherapy efficacy in mouse models of 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 B025.
Abstract C060: Characterization of a collection of patient-derived xenograft models for pancreatic ductal adenocarcinoma translational research
Authors: Mariana Yáñez, Enrique Javier Arenas, Teresa Macarulla, Tian Tian, Joaquín Arribas, Sofía Llorente, Carles Fabregat, Marta Escorihuela, Florian Castet, Jessica Querol, Maria Teresa Salcedo
Journal: Cancer Research (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 A076: Spatial genomic expression profiling reveals metastatic gene markers in mucinous cystic carcinoma of the pancreas and regional lymph nodes
Authors: Chirag S. Gopinath, Arshia Ghodrati, Lusine Demirkhanyan, Manu Gnanamony, Joseph A. Norton, Sonia T. Orcutt, Christopher S. Gondi
Journal: Cancer Research (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 A066: A novel approach for exocrine pancreas transcriptomics reveals the cellular landscape of the pancreas
Authors: Katherine J. Aney, Woo-Jeong Jeong, Andres F. Vallejo, Ethan Chen, Austin Wang, Stephanie K. Dougan, Kellie Wise, Kirk Jensen, Luciano Martelotto, Sahar Nissim
Journal: Cancer Research (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 A080: Target genes in pancreatic cancer cells of the pan-quadruplex clinical candidate compound QN-302 revealed by comparative transcriptome profiling
Authors: Ahmed Ahmed, Tariq Arshad, Maria Roman-Escorza, Dan M. Neidle, Stephen Neidle
Journal: Cancer Research (2024)

Abstract QN-302 is a tetra-substituted naphthalene derivative designed to have high affinity to quadruplexes in cancer-related genes, which have multiple quadruplex occurrence in their promoter sequences. QN-302 has ca 1 nM in vitro activity against a panel of pancreatic ductal adenocarcinoma (PDAC) cell lines and shows high activity against four distinct PDAC in vivo models, including the KPC genetic model. QN-302 is currently being developed for clinical trials in solid tumors including PDAC. It has also recently been granted orphan drug drug (ODD) status by the FDA. We have previously reported on whole-genome transcriptome studies for QN-302, which show that it selectively targets quadruplex-rich genes in PDAC-related pathways, and thus acts as a pan-quadruplex agent. We have recently extended our analysis to include two closely related analogs of QN-302 as well as data from a gemcitabine-resistant line. QN-302 is consistently ca 10-fold more potent in PDAC cells and in vivo than the second-best analog. RNA-seq whole-cell and comparative bioinformatics analyses have been used to probe these differences. This has resulted in the identification of those target genes that the naphthalene diimide family have in common, many of which are involved in PDAC pathways such as hedgehog, axon guidance, WNT/β-catenin and hippo. It has also been possible to identify a small number of quadruplex target genes that are highly and selectively down-regulated by QN-302, and which are also highly up-regulated in human PDAC. We suggest that these contribute to the exceptional in vivo potency of this compound. Citation Format: Ahmed Ahmed, Tariq Arshad, Maria Roman-Escorza, Dan M. Neidle, Stephen Neidle. Target genes in pancreatic cancer cells of the pan-quadruplex clinical candidate compound QN-302 revealed by comparative transcriptome profiling [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 A080.
Abstract A096: PIKfyve as a potential therapeutic target in pancreatic cancer
Authors: Shea Grenier, Cheska Galapate, Yijuan Zhang, Gurpreet Arora, Steven Olson, Brooke Emerling, Cosimo Commisso
Journal: Cancer Research (2024)

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