Pancreatic Cancer Progression Research Articles

Abstract 4440: Topographical investigation of metabolites in excised squares (TIMES2): Comprehensive cross-sectional metabolite quantification of pancreatic cancer in vivo

Abstract Purpose: Pancreatic cancer is a lethal malignancy characterized by complex intratumoral metabolic reprogramming and intercellular nutrient sharing between cells in the tumor microenvironment (TME) that promote pancreatic cancer progression. However, this crosstalk, as well as regional variation in perfusion and oxygenation, can lead to metabolic heterogeneity that has not been appreciated by metabolomics of whole tumors. Here we quantify amino acids and tricarboxylic acid cycle (TCA) intermediates using a novel methodology that allows us to portray global tumor metabolite heterogeneity in a tumor. Methods: Human PaTu-8902 or murine HY19636 (from female KPC mice LSL-KrasG12D; p53 L/+, Ptf1a-Cre+) pancreatic cancer cell lines were orthotopically injected into pancreata of NCr nude mice (n=3) or C57BL/6 mice (n=2). Mice were euthanized after 3-5 weeks and tumors were harvested. Tumor slices were further sectioned into 1mm x 1mm x 1mm cubes using a custom-made multisectional slicing device and each cube location was recorded. Each cube was extracted using methanol, water, and chloroform with labelled amino acid standards, derivitized, and resolved using gas chromatography-mass spectrometry (DB-35MS column with Agilent 7890B gas chromatograph coupled to a single quadrupole 5977B mass spectrometer). 22 metabolites (15 amino acids, 5 TCA intermediates, lactate, and pyruvate) were identified by unique fragments and retention time compared to known standards. Peaks were picked using OpenChrom and analyzed using MATLAB. Data was analyzed using Graphpad Prism. Principal Component Analysis (PCA) was visualized using Python on a Jupyter notebook. Results: Both orthotopic human and murine pancreatic tumors demonstrated striking levels of intratumoral metabolite heterogeneity. Glycine, glutamine, and proline were the amino acids with the highest coefficient of variance, while leucine, isoleucine, and serine had the lowest coefficient of variance. α-ketoglutarate and succinate were the TCA intermediates with highest coefficient of variance. Lactate had the lowest coefficient of variance among all examined metabolites. Spatial mapping of each metabolite demonstrated distinct regions with varying abundance levels of metabolites. PCA demonstrated 75% of variance was carried by PC1 and 10% carried by PC2. Conclusions: This study reveals insights into the degree of intratumoral heterogeneity present in pancreatic tumors that illustrate the difficulty of in vivo metabolomics analysis and suggest that high-resolution (single cell) metabolomics techniques will be critical to study metabolism in the complex TME. Citation Format: Peter Yu, Robert Banh, Albert Sohn, Stephen Martis, Douglas Biancur, Keisuke Yamamoto, Elaine Lin, Alec Kimmelman. Topographical investigation of metabolites in excised squares (TIMES2): Comprehensive cross-sectional metabolite quantification of pancreatic cancer in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4440.

Abstract 1595: Persistence of fetal gene signatures along the mesenchymal lineage trajectory defines heterogeneity and function of pancreatic cancer associated fibroblasts

Abstract In pancreatic ductal adenocarcinoma (PDAC), cancer associated fibroblasts (CAFs) play critical and complex roles in the tumor microenvironment. CAFs are also a major cell type in the desmoplastic stroma in PDAC and may account for half of the entire tumor tissue. Here we aimed to investigate the origin, diversification, and function of CAFs. We constructed a dual-DNA-recombinase mouse genetic model carrying KrasG12D/+; Trp53frt/+; Pdx1Flpo/+; Isl1creER/+; R26Tomato/+ alleles, referred to as KPFIT. The DNA recombinase FlpO directs expression of an oncogene Kras (G12D mutation) and loss of a tumor suppressor p53 in pancreatic epithelial cells, while creER recombines the Tomato reporter in the splanchnic mesenchyme and its descendants. The splanchnic mesenchyme is a layer of fetal tissue surrounding the endoderm where the pancreatic epithelium arises. This approach capitalized on the independent functions of FlpO/Frt and CreER/LoxP systems, allowing us to lineage trace Tomato labeled splanchnic progenies (via IT) in a spontaneous pancreatic cancer model (via KPF) within the same mouse. Our study identified the splanchnic mesenchyme as the fetal origin of pancreatic fibroblasts during homeostasis and tumorigenesis. Notably, the other two postulated origins, bone marrow and epithelial cells, have minimal contributions to fibroblasts. Importantly, single cell transcriptomic analysis indicated persistent and dynamic gene expressions along the pancreatic mesenchymal trajectory during development, homeostasis, precancer lesion and cancer. Intriguingly, certain splanchnic factors are expressed in only subtypes of adult pancreatic fibroblasts in temporally and spatially distinct patterns. Furthermore, we constructed mouse genetic models to delete one of the splanchnic factors, Gata6, specifically in CAFs, which resulted in increased tumor burden in the pancreas. This suggests a non-cell autonomous function of GATA6 in CAFs to restrain pancreatic cancer progression. In summary, this study delineated a continuous cell trajectory of the mesenchymal lineage in the pancreas across different life stages. Moreover, persistent gene expressions along the mesenchymal trajectory contributes to pancreatic CAF heterogeneity. Importantly, such persistence may constitute an inherent mechanism to suppress pancreatic cancer. The enhancement of this mechanism could be explored further for therapeutic benefits. Citation Format: Lu Han, Tom Walter, Joseph Beaudet, Caroline Everett, Kun Fang, Michael Zimmermann, Angela Mathison, Raul Urrutia, Victor Jin, Gustavo Leone, Michael Ostrowski. Persistence of fetal gene signatures along the mesenchymal lineage trajectory defines heterogeneity and function of pancreatic cancer associated fibroblasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1595.

Abstract 4277: CREB-ROCK driven extracellular matrix remodeling exasperates pancreatic cancer progression

Abstract Background: Pancreatic Ductal Adenocarcinoma (PDAC) is characterized by a heightened oncogenic mutational burden, an immunosuppressive tumor microenvironment, and a dense desmoplastic stroma. During the tumor progression from in situ carcinoma to intraductal neoplasia, cancer cells manage to evade the stromal compartment and infiltrate into the ducts. This invasive tumor progression is often associated with the overexpression of extracellular matrix (ECM) modulating genes. Despite this correlation, there are currently no effective and specific inhibitors of ECM-altering pathways. By understanding the signaling mechanism, the ECM remodeling pathways may be intercepted to prevent invasive tumor progression. This study aims to elucidate the role of cAMP-response element binding protein 1 (CREB1) and its downstream effectors in regulating PDAC ECM remodeling. Methods: The Cancer Genome Atlas (TCGA) was quired for CREB1 expression and other ECM modulators in PDAC patients. In vitro, CRISPR/CAS9-based genomic editing was utilized to knockout CREB1 in the murine KPC cell line, on which RNA-seq analysis was performed. To investigate the effects of CREB in PDAC progression, a novel conditional CREB1 knockout (CREBfl/fl) was created in LSL-KrasG12D/+; Trp53 R172H/+; Pdx1Cre/+ (KPC) mice (KPCC-/-). Tumors were extracted and histologically evaluated. Immunoblotting and staining were conducted on both in vitro and in vivo samples. Chromatin immunoprecipitation sequencing (ChIP-seq) and qPCR were performed on the KPC CREBKO. Eukaryotic Promoter Database (EPD) and ENCODE databases were explored to evaluate the transcriptional role of CREB in regulating ECM genes. Results: Patient PDAC samples data from TCGA revealed elevated levels of CREB1, ROCK1, and ROCK2 compared to normal pancreatic tissues. When comparing high CREB expression to low CREB expression, upregulation of several ECM genes was noted, including ROCK1 and ROCK2 in patients with high CREB expression. In CREBKO, RNA-seq analysis revealed the downregulation of key ECM genes, including Mmp3, Mmp10, Lama3, and Fn1 compared to CREB wildtype. In our novel murine conditional knockout model, a substantial reduction in fibrosis was observed. In both in vitro and in vivo, immunoblot and staining demonstrated a marked reduction in the expression of ECM remodeling proteins upon CREB deletion. Through ChIP-seq, the direct involvement of CREB1 in the transcriptional regulation of Rock1 and Rock2 was established. EPD and ENCODE were utilized to confirm and validate our CREB regulation experimental findings. Conclusion: These findings demonstrate the role of CREB in PDAC progression, which may provide a potential target to intercept ECM remodeling via inhibition of the CREB-ROCK axis to suppress PDAC tumor progression and invasion. Citation Format: Sudhakar Jinka, Siddharth Mehra, Varunkumar Krishnamoorthy, Anna Bianchi, Karthik Rajkumar, Andrew Adams, Haleh Amirian, Samara Singh, Edmond W. Box, Erin Dickey, Nivelo L. Alberto, Ban Yuguang, Jashodeep Datta, Nipun Merchant, Nagaraj Nagathihalli. CREB-ROCK driven extracellular matrix remodeling exasperates pancreatic cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4277.

Abstract 2272: Unlocking the potential of miRNA sequencing for early detection and monitoring of pancreatic cancer progression and recurrence

Abstract Pancreatic cancer (PC) is an elusive and deadly disease. Many patients with PC are diagnosed with metastatic or locally advanced tumors, limiting surgical resection, and increasing the risk of relapse after treatment. Relapse is recorded to be as high as 75% in the first 2 years after clinical intervention, resulting in a mean 5-year survival of 12% in the US, and as low as 2% worldwide. It is vital to develop diagnostic and monitoring techniques for PC. MicroRNAs (miRNAs) are robustly expressed in patient tumors and provide a rich source of biomarkers for disease detection and status. miRNA are short nucleic acid strands that bind to catalytic proteins to guide the regulation of large RNAs within the cellular space. This system is altered in tumors, leading to abhorrent expression of miRNA. Due to significant advancements in sequencing technology, miRNA-seq has become more accurate and affordable in detecting profile changes. To identify biomarkers for PC progression, we developed from the Gemcitabine-sensitive MIA-PaCa-2 (MP2) cell line the Gemcitabine and FOLFIRINOX resistant MP2-GR cell line. MiRNA-seq was conducted on the parental MP2 and resistant MP2-GR cells to identify those miRNAs that were differentially expressed between the cell lines. These miRNAs were analyzed via pathway analysis and gene ontology to find predicted functions followed by annotations from the miRNA Enrichment Analysis and Annotation tool (miEAA) to identify differentially expressed miRNAs associated with PC progression. This comparison indicated several miRNAs related to PC resistance. This dataset was then compared to The Cancer Genome Atlas (TCGA), which contains data from over 300 PC patients. The miRNA set was used to predict both PC progression after treatment, and recurrence. We are currently refining this data set to increase its predictive sensitivity and widen our patient data set comparison to further elucidate this approach in a clinical setting. Citation Format: Ryan N. Fuller, Ann Morcos, Desirae Escalera, Nathan R. Wall. Unlocking the potential of miRNA sequencing for early detection and monitoring of pancreatic cancer progression and recurrence [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2272.

Unraveling the Connection: Pancreatic Cancer Cells and Schwann Cells.

Pancreatic ductal adenocarcinoma is one of the most lethal solid malignancies, characterized by its aggressiveness and metastatic potential, with a 5-year survival rate of only 13%. Progress in the management of metastatic disease has been modest. A robust connection between nervous system and tumor progression exists, with prominent neural alterations having been observed during pancreatic cancer's progression, including neural hypertrophy, neural density, and neural remodeling. The pancreatic tumor microenvironment includes s set of cells and structures that constantly dialogue with cancer cells, influencing its growth and behavior. The microglia is key cellular components of the tumor microenvironment, and Schwann cells are the principal glial cells in the peripheral neural system. Schwann cells can regulate changes in the tumor microenvironment and immune responses by secreting a variety of factors and can support a tumor's invasion of nerves and distant metastasis, with further pain exacerbation. Schwann cells secrete various pain-related molecules, such as the neural growth factor, to mediate the activation of primary sensory neurons, leading to pain induction. The binding of the neural growth factor to tropomyosin receptor kinase A is an important signaling mechanism for pain perception in humans. Consequently, directing efforts towards targeting neural invasion may provide an alternative strategy to improve the prognosis of and alleviate pain in patients with pancreatic cancer.

Deubiquitinase PSMD7 facilitates pancreatic cancer progression through activating Nocth1 pathway via modifying SOX2 degradation

BackgroundUbiquitination is a critical post-translational modification which can be reversed with an enzyme family known as deubiquitinating enzymes (DUBs). It has been reported that dysregulation of deubiquitination leads to carcinogenesis. As a member of the DUBs family, proteasome 26 S subunit non-ATPase 7 (PSMD7) serves as an underlying tumour-promoting factor in multiple cancers. However, the clinical significance and biological functions of PSMD7 in pancreatic cancer (PC) remain unclear.ResultsIn this study, we first reported frequent overexpression of PSMD7 in PC tissues, and high levels of PSMD7 were markedly linked to shorter survival and a malignant phenotype in PC patients. An array of in vitro and in vivo gain/loss-of-function tests revealed that PSMD7 facilitates the progression of PC cells. Additionally, we found that PSMD7 promotes PC cell progression by activating the Notch homolog 1 (Notch1) signalling. Interestingly, in PC cells, the inhibitory effect of PSMD7 knockdown on cellular processes was comparable to that observed upon Notch1 knockdown. Mechanistically, PSMD7 deubiquitinated and stabilised sex determining region Y (SRY)-box 2 (SOX2), a key mediator of Notch1 signalling. The stabilisation of SOX2, mediated by PSMD7, dramatically increased SOX2 protein levels, subsequently activating the Notch1 pathway. Finally, restoration of SOX2 expression abrogated the PSMD7-silenced antitumour effect.ConclusionsTaken together, our work identifies and validates PSMD7 as a promoter of PC progression through augmentation of the Notch1 signalling pathway mediated by SOX2. This finding suggests that PSMD7 holds promise as a potential therapeutic target for the management of this refractory disease.

The Role of Integrin Subunit Alpha 2 (ITGA2) in Pancreatic Cancer Progression

Background: Pancreatic cancer is a relatively uncommon type of cancer, although it is often very aggressive and highly metastases to other parts of the body. Investigating a potential gene marker or gene targeted therapy can improve the patient’s early prognosis and/or treatment. Objectives: In this study, we identify Integrin Subunit Alpha 2 (ITGA2) as a potential target in inhibiting pancreatic cancer progression. Materials and Methods: Cell cycle analysis, gene expression level, and cell proliferation assay are implanted in this study as investigational methods. Two-tailed student's t test is used to compare between the studied groups. Results: Cell cycle analysis for the transformed cell lines revealed increasing in G0/G1 phase and entering the cells the cell cycle arrest (quiescence) after knocking down ITGA2 expression. On the other hand, knocking down the ITGA2 effect, the mesenchymal to epithelial transition and the migration possibility of the cell lines by inhibiting the expression of metastatic marker vimentin. Furthermore, ITGA2 can manipulate the tumor microenvironment by downregulating extracellular matrix proteins (ECM-proteins) LAMB3, and LAMC2. Conclusion: ITGA2 downregulation reduces the cell proliferation, induces the cell cycle arrest, and reduce the possibility of metastasis in pancreatic cancer.

Morphology of the Dorsal Pancreatic Artery and Its Oncological Significance in Pancreatic Cancer.

Although the dorsal pancreatic artery (DPA) is an important artery that supplies the pancreas, its morphology has not been sufficiently studied. We investigated the morphology of the DPA and the progression of pancreatic cancer along this vessel. Overall, 142 patients with pancreatic cancer who underwent surgical resection at Kanazawa University Hospital between 2004 and 2015 were enrolled. We examined the morphology of the DPA using preoperative computed tomography and cancer progression along the DPA using resected specimens. We investigated the anatomical structures surrounding the DPA through cadaveric examination. The analysis of computed tomography images revealed the presence of the DPA in 141 patients. In typical cases, the DPA divides into a head and a body branch. Histopathological examination revealed cancer progression along the DPA in 32 patients. Cancer progression along the DPA was identified as a factor associated with a poor prognosis in pancreatic head or body cancer. Cadaveric examination showed the presence of abundant nerve and lymphatic tissues along the DPA. It is important to remove the soft tissue surrounding the DPA during surgery for pancreatic head or body cancer because it may serve as an important route for cancer progression.

Moracin D suppresses cell growth and induces apoptosis via targeting the XIAP/PARP1 axis in pancreatic cancer

BackgroundPancreatic cancer, a tumor with a high metastasis rate and poor prognosis, is among the deadliest human malignancies. Investigating effective drugs for their treatment is imperative. Moracin D, a natural benzofuran compound isolated from Morus alba L., shows anti-inflammation and anti-breast cancer properties and is effective against Alzheimer's disease. However, the effect and mechanism of Moracin D action in pancreatic cancer remain obscure. PurposeTo investigate the function and molecular mechanism of Moracin D action in repressing the malignant progression of pancreatic cancer. MethodsPancreatic cancer cells were treated with Moracin D, and cell proliferation was evaluated by cell counting kit-8 (CCK-8) and immunofluorescence assays. The clonogenicity of pancreatic cancer cells was assessed based on plate colony formation and soft agar assay. Flow cytometry was used to detect cell apoptosis. The expression of proteins related to the apoptosis pathway was determined by Western blot analysis. Moracin D and XIAP were subjected to docking by auto-dock molecular docking analysis. Ubiquitination levels of XIAP and the interaction of XIAP and PARP1 were assessed by co-immunoprecipitation analysis. Moracin D's effects on tumorigenicity were assessed by a tumor xenograft assay. ResultsMoracin D inhibited cell proliferation, induced cell apoptosis, and regulated the protein expression of molecules involved in caspase-dependent apoptosis pathways. Moracin D suppressed clonogenicity and tumorigenesis of pancreatic cancer cells. Mechanistically, XIAP could interact with PARP1 and stabilize PARP1 by controlling its ubiquitination levels. Moracin D diminished the stability of XIAP and decreased the expression of XIAP by promoting proteasome-dependent XIAP degradation, further blocking the XIAP/PARP1 axis and repressing the progression of pancreatic cancer. Moracin D could dramatically improve the chemosensitivity of gemcitabine in pancreatic cancer cells. ConclusionMoracin D repressed cell growth and tumorigenesis, induced cell apoptosis, and enhanced the chemosensitivity of gemcitabine through the XIAP/PARP1 axis in pancreatic cancer. Moracin D is a potential therapeutic agent or adjuvant for pancreatic cancer.

CCNI2 promotes pancreatic cancer through PI3K/AKT signaling pathway.

Globally, pancreatic cancer is recognized as one of the deadliest malignancies that lacks effective targeted therapies. This study aims to explore the role of cyclin I-like protein (CCNI2), a homolog of cyclin I (CCNI), in the progression of pancreatic cancer, thereby providing a theoretical basis for its treatment. Firstly, the expression of CCNI2 in pancreatic cancer tissues was determined through immunohistochemical staining. The biological role of CCNI2 in pancreatic cancer cells was further assessed using both in vitro and in vivo loss/gain-of-function assays. Our data revealed that CCNI2 expression was abnormally elevated in pancreatic cancer, and clinically, increased CCNI2 expression generally correlated with reduced overall survival. Functionally, CCNI2 contributed to the malignant progression of pancreatic cancer by promoting the proliferation and migration of tumor cells. Consistently, in vivo experiments verified that CCNI2 knockdown impaired the tumorigenic ability of pancreatic cancer cells. Moreover, the addition of phosphatidylinositol 3-kinase (PI3K) inhibitors could partially reverse the promoting effect of CCNI2 on the malignant phenotypes of pancreatic cancer cells. CCNI2 promoted pancreatic cancer through PI3K/protein kinase B (AKT) signaling pathway, indicating its potential as a prognostic marker and therapeutic target for pancreatic cancer.

Genetic Deletion of Galectin-3 Inhibits Pancreatic Cancer Progression and Enhances the Efficacy of Immunotherapy

BACKGROUND & AIMSPancreatic ductal adenocarcinoma (PDAC) has a desmoplastic tumor stroma and immunosuppressive microenvironment. Galectin-3 (GAL3) is enriched in PDAC, highly expressed by cancer cells and myeloid cells. However, the functional roles of GAL3 in the PDAC microenvironment remain elusive. METHODSWe generated a novel transgenic mouse model (KPPC;Lgals3-/-) that allows the genetic depletion of GAL3 from both cancer cells and myeloid cells in spontaneous PDAC formation. Single-cell RNA-sequencing analysis was used to identify the alterations in the tumor microenvironment upon GAL3 depletion. We investigated both the cancer cell-intrinsic function and immunosuppressive function of GAL3. We also evaluated the therapeutic efficacy of GAL3 inhibition in combination with immunotherapy. RESULTSGenetic deletion of GAL3 significantly inhibited the spontaneous pancreatic tumor progression and prolonged the survival of KPPC;Lgals3-/- mice. Single-cell analysis revealed that genetic deletion of GAL3 altered the phenotypes of immune cells, cancer cells, and other cell populations. GAL3 deletion significantly enriched the anti-tumor myeloid cell subpopulation with high major histocompatibility complex class II (MHCII) expression. We also identified that GAL3 depletion resulted in CXCL12 upregulation, which could act as a potential compensating mechanism upon GAL3 deficiency. Combined inhibition of CXCL12-CXCR4 axis and GAL3 enhanced the efficacy of anti-PD-1 immunotherapy, leading to significantly inhibited PDAC progression. In addition, deletion of GAL3 also inhibited the basal/mesenchymal-like phenotype of pancreatic cancer cells. CONCLUSIONSGAL3 promotes PDAC progression and immunosuppression via both cancer cell-intrinsic and immune-related mechanisms. Combined treatment targeting GAL3, CXCL12-CXCR4 axis, and PD-1 represents a novel therapeutic strategy for PDAC.

Temporal progression of pancreatic cancer computed tomography findings until diagnosis: A large-scale multicenter study.

Focal parenchymal atrophy and main pancreatic duct (MPD) dilatation have been identified as early signs of pancreatic ductal adenocarcinoma. However, limited evidence exists regarding their temporal progression due to previous study limitations with restricted case numbers. To ascertain a more precise frequency assessment of suspicious pancreatic ductal adenocarcinoma findings as well as delineate the temporal progression of them. A multicenter retrospective study was conducted on patients diagnosed with pancreatic ductal adenocarcinoma between 2015 and 2021. We included patients who had undergone at least one computed tomography (CT) scan ≥6months before diagnosing pancreatic ductal adenocarcinoma. The temporal progression of suspicious pancreatic ductal adenocarcinoma findings on CT was investigated. Out of 1832 patients diagnosed with pancreatic ductal adenocarcinoma, 320 had a previous CT before their diagnosis. Suspicious pancreatic ductal adenocarcinoma findings were detected in 153 cases (47.8%), with focal parenchymal atrophy (26.6%) being the most common followed by MPD dilatation (11.3%). Focal parenchymal atrophy was the earliest detectable sign among all suspicious findings and became visible on average 2.7years before diagnosis, and the next most common, MPD dilatation, 1.1years before diagnosis. Other findings, such as retention cysts, were less frequent and appeared around 1year before diagnosis. Focal parenchymal atrophy followed by MPD dilatation was observed in 10 patients but not in reverse order. Focal parenchymal atrophy was more frequently detected in the pancreatic body/tail. No significant relationship was found between the pathological pancreatic ductal adenocarcinoma differentiation or tumor stage and the time course of the CT findings. All cases of focal parenchymal atrophy progressed just prior to diagnosis, and the atrophic area was occupied by tumor at diagnosis. Main pancreatic duct dilatation continued to progress until diagnosis. This large-scale study revealed that the temporal progression of focal parenchymal atrophy is the earliest detectable sign indicating pancreatic ductal adenocarcinoma. These results provide crucial insights for early pancreatic ductal adenocarcinoma detection.

Tumor-associated macrophages drive glycolysis through the IL-8/STAT3/GLUT3 signaling pathway in pancreatic cancer progression

Glycolytic metabolism is a hallmark of pancreatic ductal adenocarcinoma (PDAC), and tumor-associated stromal cells play important roles in tumor metabolism. We previously reported that tumor-associated macrophages (TAMs) facilitate PDAC progression. However, little is known about whether TAMs are involved in regulating glycolysis in PDAC. Here, we found a positive correlation between CD68+ TAM infiltration and FDG maximal standardized uptake (FDG SUVmax) on PET-CT images of PDAC. We discovered that the glycolytic gene set was prominently enriched in the high TAM infiltration group through Gene Set Enrichment Analysis using The Cancer Genome Atlas database. Mechanistically, TAMs secreted IL-8 to promote GLUT3 expression in PDAC cells, enhancing tumor glycolysis both in vitro and in vivo, whereas this effect could be blocked by the IL-8 receptor inhibitor reparixin. Furthermore, IL-8 promoted the translocation of phosphorylated STAT3 into the nucleus to activate the GLUT3 promoter. Overall, we demonstrated that TAMs boosted PDAC cell glycolysis through the IL-8/STAT3/GLUT3 signaling pathway. Our cumulative findings suggest that the abrogation of TAM-induced tumor glycolysis by reparixin might exhibit an antitumor impact and offer a potential therapeutic target for PDAC.

LINC02086 inhibits ferroptosis and promotes malignant phenotypes of pancreatic cancer via miR-342-3p/CA9 axis.

Long noncoding RNAs (lncRNAs) play important roles in modulating the tumorigenesis and progression of malignant tumors. LINC02086 is a newly identified oncogene associated with tumorigenesis, but its role in pancreatic cancer (PC) has not been fully elucidated. In this study we examined the expression levels of LINC02086, miR-342-3p, and CA9 in PC. The relationship of ferroptosis with these factors was analyzed by detecting the expression levels of Fe2+, reactive oxygen species (ROS), and ferroptosis marker proteins. The expression of these genes was altered to observe their effects on cell proliferation, migration, and invasion ability. Bioinformatics was used to predict target genes, and the binding relationship was verified luciferase reporter assay. Finally, the function of LINC02086 was evaluated in vivo. The findings suggest that LINC02086 is highly expressed in PC tissues and cell lines and is correlated with a poor prognosis. In vitro experiments demonstrated that LINC02086 knockdown promoted ferroptosis in PC cells to suppress their malignant phenotype. LINC02086 acts as a competitive endogenous RNA that adsorbed miR-342-3p. miR-342-3p hinders the malignant progression of PC by promoting ferroptosis. In addition, miR-342-3p targets CA9 and affects its function. Further mechanistic studies revealed that LINC02086 inhibits ferroptosis and promotes PC progression by acting as a sponge for miR-342-3p to upregulate CA9 expression. In vivo experiments further confirmed this mechanism. Taken together, LINC02086 upregulates CA9 expression by competitively binding with miR-342-3p, thereby inhibiting ferroptosis in PC cells and promoting their malignant phenotype. The results of our study provide new insights into how LINC02086 contributes to the progression of PC.

Pancreatic Cancer Treatment Targeting the HGF/c-MET Pathway: The MEK Inhibitor Trametinib.

Pancreatic cancer is characterized by fibrosis/desmoplasia in the tumor microenvironment, which is primarily mediated by pancreatic stellate cells and cancer-associated fibroblasts. HGF/c-MET signaling, which is instrumental in embryonic development and wound healing, is also implicated for its mitogenic and motogenic properties. In pancreatic cancer, this pathway, along with its downstream signaling pathways, is associated with disease progression, prognosis, metastasis, chemoresistance, and other tumor-related factors. Other features of the microenvironment in pancreatic cancer with the HGF/c-MET pathway include hypoxia, angiogenesis, metastasis, and the urokinase plasminogen activator positive feed-forward loop. All these attributes critically influence the initiation, progression, and metastasis of pancreatic cancer. Therefore, targeting the HGF/c-MET signaling pathway appears promising for the development of innovative drugs for pancreatic cancer treatment. One of the primary downstream effects of c-MET activation is the MAPK/ERK (Ras, Ras/Raf/MEK/ERK) signaling cascade, and MEK (Mitogen-activated protein kinase kinase) inhibitors have demonstrated therapeutic value in RAS-mutant melanoma and lung cancer. Trametinib is a selective MEK1 and MEK2 inhibitor, and it has evolved as a pivotal therapeutic agent targeting the MAPK/ERK pathway in various malignancies, including BRAF-mutated melanoma, non-small cell lung cancer and thyroid cancer. The drug's effectiveness increases when combined with agents like BRAF inhibitors. However, resistance remains a challenge, necessitating ongoing research to counteract the resistance mechanisms. This review offers an in-depth exploration of the HGF/c-MET signaling pathway, trametinib's mechanism, clinical applications, combination strategies, and future directions in the context of pancreatic cancer.

The NF-κB/NUAK2 signaling axis regulates pancreatic cancer progression by targeting SMAD2/3

Nuclear factor kappa B (NF-κB) plays a pivotal role in the development of pancreatic cancer, and its phosphorylation has previously been linked to the regulation of NUAK2. However, the regulatory connection between NF-κB and NUAK2, as well as NUAK2's role in pancreatic cancer, remains unclear. In this study, we observed that inhibiting NUAK2 impeded the proliferation, migration, and invasion of pancreatic cancer cells while triggering apoptosis. NUAK2 overexpression partially resisted apoptosis and reversed the inhibitory effects of the NF-κB inhibitor. NF-κB transcriptionally regulated NUAK2 transcription by binding to the promoter region of NUAK2. Mechanistically, NUAK2 knockdown remarkably reduced the expression levels of p-SMAD2/3 and SMAD2/3, resulting in decreased nuclear translocation of SMAD4. In SMAD4-negative cells, NUAK2 knockdown impacted FAK signaling by downregulating SMAD2/3. Moreover, NUAK2 knockdown heightened the sensitivity of pancreatic cancer cells to gemcitabine, suggesting that NUAK2 inhibitors could be a promising strategy for pancreatic cancer treatment.

HMGA2 overexpression activates IGF2BP2 to stabilize APLP2 via m6A modification and promote pancreatic cancer progression

Pancreatic cancer is a highly aggressive malignancy of the digestive system, with occult onset, rapid progression, and poor prognosis. The genetic heterogeneity of pancreatic cancer contributes to its highly malignant biological behavior. HMGA2 is overexpressed in tumors and is known to regulate tumor progression in various cancers through the HMGA2-IGF2BP2 axis, but its role and mechanism in pancreatic cancer remain unclear. In this study, we demonstrated that HMGA2 promotes pancreatic cancer progression. We further revealed that HMGA2 upregulates IGF2BP2, which stabilizes APLP2 mRNA via m6A modification, thereby promoting pancreatic cancer progression. These results indicate that HMGA2/IGF2BP2/APLP2 signaling axis regulates the progression of pancreatic cancer.

Computational insights into KRAS G12C inhibition: exploring possible repurposing of Azacitidine and Ribavirin

Kirsten rat sarcoma (KRAS) stands out as the most prevalent mutated oncogene, playing a crucial role in the initiation and progression of various cancer types, including colorectal, lung and pancreatic cancer. The oncogenic modifications of KRAS are intricately linked to tumor development and are identified in 22% of cancer patients. This has spurred the necessity to explore inhibition mechanisms, with the aim of investigating and repurposing existing drugs for diagnosing cancers dependent on KRAS G12C In this investigation, 26 nucleoside-based drugs were collected from literature to assess their effectiveness against KRAS G12C. The study incorporates in-silico molecular simulations and molecular docking examinations of these nucleoside-derived drugs with the KRAS G12C protein using Protein Data Bank (PDB) ID: 5V71. The docking outcomes indicated that two drugs, Azacitidine and Ribavirin, exhibited substantial binding affinities of −8.7 and −8.3 kcal/mol, respectively. These drugs demonstrated stability in binding to the active site of the protein during simulation studies. Root mean square deviation (RMSD) analyses indicated that the complexes closely adhered to an equilibrium RMSD value ranging from 0.17 to 0.2 nm. Additionally, % occupancies, bond angles and the length of hydrogen bonds were calculated. These findings suggest that Azacitidine and Ribavirin may potentially serve as candidates for repurposing in individuals with KRAS-dependent cancers. Communicated by Ramaswamy H. Sarma

Global burden of pancreatic cancer attributable to metabolic risks from 1990 to 2019, with projections of mortality to 2030

ObjectiveMetabolic risks play a key role in the progression of pancreatic cancer. This study aimed to present global, regional and national data on mortality and disability-adjusted life-year (DALY) for pancreatic cancer attributable to metabolic risk and to forecast mortality to 2030 using data from the Global Burden of Disease (GBD).MethodsData on mortality and DALYs due to pancreatic cancer attributable to metabolic risks were obtained from GBD 2019. Metabolic risks include high fasting plasma glucose (FPG) and high body mass index (BMI). Total numbers and age-standardized rates per 100,000 people for mortality and DALYs were reported by age, sex, region and country/territory from 1990 to 2019. The “Bayes age-period-cohort” method was used for projections of mortality to 2030.ResultsGlobally, there was a 3.5-fold increase in the number of pancreatic cancer deaths attributable to metabolic risk, from 22,091 in 1990 to 77,215 in 2019. High-income North America and Central Europe had the highest age-standardized mortality rates (ASMRs) of pancreatic cancer attributable to high FPG and high BMI in 2019, respectively. From 1990 to 2019, the global ASMR of pancreatic cancer attributable to high FPG and high BMI increased. Countries with high healthcare access quality had much higher age-standardized DALY rates. In the next 10 years, the ASMR of pancreatic cancer attributable to high FPG and high BMI will continue to increase.ConclusionPancreatic cancer mortality and DALYs attributable to metabolic factors remain high, particularly in high-income regions or countries. Studies on the metabolic mechanism of pancreatic cancer and effective treatment strategies are needed.

The Role of Local Angiotensin II/Angiotensin Type 1-receptor Mechanisms in Adipose Tissue Dysfunction to Promote Pancreatic Cancer.

Obesity and adipose tissue dysfunction are important risk factors for pancreatic cancer. Pancreatic cancer is one of the most lethal cancers globally. The renin-angiotensin system (RAS) is expressed in many tissues, including adipose tissue. Dysregulation of angiotensin II and angiotensin II receptors in adipose tissue through the activation of different signaling pathways leads to adipose tissue dysfunction, including insulin resistance, adipose tissue inflammation, adipocytokines secretion, and metabolic alterations. The pathogenesis of pancreatic cancer remains uncertain. However, there is evidence that dysregulation of local angiotensin II in adipose tissue that occurs in association with obesity is, in part, responsible for the initiation and progression of pancreatic cancer. Due to the role of local angiotensin II in the dysfunction of adipose tissue, angiotensin receptor blockers may be considered a new therapeutic strategy in the amelioration of the complications related to adipose tissue dysfunction and prevention of pancreatic cancer. This review aims to consider the biological roles of local angiotensin II and angiotensin II receptors in adipose tissue dysfunction to promote pancreatic cancer progression with a focus on adipose tissue inflammation and metabolic reprogramming.