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1. A Histone Methylation–MAPK Signaling Axis Drives Durable Epithelial–Mesenchymal Transition in Hypoxic Pancreatic Cancer

   https://doi.org/10.1158/0008-5472.CAN-22-2945  

   Brown, Brooke A; Myers, Paul J; Adair, Sara J; Pitarresi, Jason R; Sah-Teli, Shiv K; Campbell, Logan A; Hart, William S; Barbeau, Michelle C; Leong, Kelsey; Seyler, Nicholas; et al (March 2024, Cancer Research)

   Abstract The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) plays a key role in tumor progression and response to therapy. The dense PDAC stroma causes hypovascularity, which leads to hypoxia. Here, we showed that hypoxia drives long-lasting epithelial–mesenchymal transition (EMT) in PDAC primarily through a positive-feedback histone methylation–MAPK signaling axis. Transformed cells preferentially underwent EMT in hypoxic tumor regions in multiple model systems. Hypoxia drove a cell autonomous EMT in PDAC cells, which, unlike EMT in response to growth factors, could last for weeks. Furthermore, hypoxia reduced histone demethylase KDM2A activity, suppressed PP2 family phosphatase expression, and activated MAPKs to post-translationally stabilize histone methyltransferase NSD2, leading to an H3K36me2-dependent EMT in which hypoxia-inducible factors played only a supporting role. Hypoxia-driven EMT could be antagonized in vivo by combinations of MAPK inhibitors. Collectively, these results suggest that hypoxia promotes durable EMT in PDAC by inducing a histone methylation–MAPK axis that can be effectively targeted with multidrug therapies, providing a potential strategy for overcoming chemoresistance. Significance:Integrated regulation of histone methylation and MAPK signaling by the low-oxygen environment of pancreatic cancer drives long-lasting EMT that promotes chemoresistance and shortens patient survival and that can be pharmacologically inhibited.See related commentary by Wirth and Schneider, p. 1739 

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2. Intracellular Salmonella delivery of an exogenous immunization antigen refocuses CD8 T cells against cancer cells, eliminates pancreatic tumors and forms antitumor immunity

   https://doi.org/10.3389/fimmu.2023.1228532  

   Raman, Vishnu; Howell, Lars M.; Bloom, Shoshana M.; Hall, Christopher L.; Wetherby, Victoria E.; Minter, Lisa M.; Kulkarni, Ashish A.; Forbes, Neil S. (October 2023, Frontiers in Immunology)

   IntroductionImmunotherapies have shown great promise, but are not effective for all tumors types and are effective in less than 3% of patients with pancreatic ductal adenocarcinomas (PDAC). To make an immune treatment that is effective for more cancer patients and those with PDAC specifically, we genetically engineered Salmonella to deliver exogenous antigens directly into the cytoplasm of tumor cells. We hypothesized that intracellular delivery of an exogenous immunization antigen would activate antigen-specific CD8 T cells and reduce tumors in immunized mice. MethodsTo test this hypothesis, we administered intracellular delivering (ID) Salmonella that deliver ovalbumin as a model antigen into tumor-bearing, ovalbumin-vaccinated mice. ID Salmonella delivers antigens by autonomously lysing in cells after the induction of cell invasion. ResultsWe showed that the delivered ovalbumin disperses throughout the cytoplasm of cells in culture and in tumors. This delivery into the cytoplasm is essential for antigen cross-presentation. We showed that co-culture of ovalbumin-recipient cancer cells with ovalbumin-specific CD8 T cells triggered a cytotoxic T cell response. After the adoptive transfer of OT-I CD8 T cells, intracellular delivery of ovalbumin reduced tumor growth and eliminated tumors. This effect was dependent on the presence of the ovalbumin-specific T cells. Following vaccination with the exogenous antigen in mice, intracellular delivery of the antigen cleared 43% of established KPC pancreatic tumors, increased survival, and prevented tumor re-implantation. DiscussionThis response in the immunosuppressive KPC model demonstrates the potential to treat tumors that do not respond to checkpoint inhibitors, and the response to re-challenge indicates that new immunity was established against intrinsic tumor antigens. In the clinic, ID Salmonella could be used to deliver a protein antigen from a childhood immunization to refocus pre-existing T cell immunity against tumors. As an off-the-shelf immunotherapy, this bacterial system has the potential to be effective in a broad range of cancer patients. 

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3. 3DGAUnet: 3D Generative Adversarial Networks with a 3D U-Net Based Generator to Achieve the Accurate and Effective Synthesis of Clinical Tumor Image Data for Pancreatic Cancer

   https://doi.org/10.3390/cancers15235496  

   Shi, Yu; Tang, Hannah; Baine, Michael J.; Hollingsworth, Michael A.; Du, Huijing; Zheng, Dandan; Zhang, Chi; Yu, Hongfeng (December 2023, Cancers)

   Pancreatic ductal adenocarcinoma (PDAC) presents a critical global health challenge, and early detection is crucial for improving the 5-year survival rate. Recent medical imaging and computational algorithm advances offer potential solutions for early diagnosis. Deep learning, particularly in the form of convolutional neural networks (CNNs), has demonstrated success in medical image analysis tasks, including classification and segmentation. However, the limited availability of clinical data for training purposes continues to represent a significant obstacle. Data augmentation, generative adversarial networks (GANs), and cross-validation are potential techniques to address this limitation and improve model performance, but effective solutions are still rare for 3D PDAC, where the contrast is especially poor, owing to the high heterogeneity in both tumor and background tissues. In this study, we developed a new GAN-based model, named 3DGAUnet, for generating realistic 3D CT images of PDAC tumors and pancreatic tissue, which can generate the inter-slice connection data that the existing 2D CT image synthesis models lack. The transition to 3D models allowed the preservation of contextual information from adjacent slices, improving efficiency and accuracy, especially for the poor-contrast challenging case of PDAC. PDAC’s challenging characteristics, such as an iso-attenuating or hypodense appearance and lack of well-defined margins, make tumor shape and texture learning challenging. To overcome these challenges and improve the performance of 3D GAN models, our innovation was to develop a 3D U-Net architecture for the generator, to improve shape and texture learning for PDAC tumors and pancreatic tissue. Thorough examination and validation across many datasets were conducted on the developed 3D GAN model, to ascertain the efficacy and applicability of the model in clinical contexts. Our approach offers a promising path for tackling the urgent requirement for creative and synergistic methods to combat PDAC. The development of this GAN-based model has the potential to alleviate data scarcity issues, elevate the quality of synthesized data, and thereby facilitate the progression of deep learning models, to enhance the accuracy and early detection of PDAC tumors, which could profoundly impact patient outcomes. Furthermore, the model has the potential to be adapted to other types of solid tumors, hence making significant contributions to the field of medical imaging in terms of image processing models. 

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4. CD73-Dependent Adenosine Signaling through Adora2b Drives Immunosuppression in Ductal Pancreatic Cancer

   https://doi.org/10.1158/0008-5472.CAN-22-2553  

   Faraoni, Erika Y.; Singh, Kanchan; Chandra, Vidhi; Le Roux, Olivereen; Dai, Yulin; Sahin, Ismet; O'Brien, Baylee J.; Strickland, Lincoln N.; Li, Le; Vucic, Emily; et al (January 2023, Cancer Research)

   Abstract The microenvironment that surrounds pancreatic ductal adenocarcinoma (PDAC) is profoundly desmoplastic and immunosuppressive. Understanding triggers of immunosuppression during the process of pancreatic tumorigenesis would aid in establishing targets for effective prevention and therapy. Here, we interrogated differential molecular mechanisms dependent on cell of origin and subtype that promote immunosuppression during PDAC initiation and in established tumors. Transcriptomic analysis of cell-of-origin–dependent epithelial gene signatures revealed that Nt5e/CD73, a cell-surface enzyme required for extracellular adenosine generation, is one of the top 10% of genes overexpressed in murine tumors arising from the ductal pancreatic epithelium as opposed to those rising from acinar cells. These findings were confirmed by IHC and high-performance liquid chromatography. Analysis in human PDAC subtypes indicated that high Nt5e in murine ductal PDAC models overlaps with high NT5E in human PDAC squamous and basal subtypes, considered to have the highest immunosuppression and worst prognosis. Multiplex immunofluorescent analysis showed that activated CD8+ T cells in the PDAC tumor microenvironment express high levels of CD73, indicating an opportunity for immunotherapeutic targeting. Delivery of CD73 small-molecule inhibitors through various delivery routes reduced tumor development and growth in genetically engineered and syngeneic mouse models. In addition, the adenosine receptor Adora2b was a determinant of adenosine-mediated immunosuppression in PDAC. These findings highlight a molecular trigger of the immunosuppressive PDAC microenvironment elevated in the ductal cell of origin, linking biology with subtype classification, critical components for PDAC immunoprevention and personalized approaches for immunotherapeutic intervention. Significance: Ductal-derived pancreatic tumors have elevated epithelial and CD8+GZM+ T-cell CD73 expression that confers sensitivity to small-molecule inhibition of CD73 or Adora2b to promote CD8+ T-cell–mediated tumor regression. See related commentary by DelGiorno, p. 977 

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5. Integrated human organ-on-a-chip model for predictive studies of anti-tumor drug efficacy and cardiac safety

   https://doi.org/10.1039/d0lc00424c  

   Chramiec, Alan; Teles, Diogo; Yeager, Keith; Marturano-Kruik, Alessandro; Pak, Joseph; Chen, Timothy; Hao, Luke; Wang, Miranda; Lock, Roberta; Tavakol, Daniel Naveed; et al (November 2020, Lab on a Chip)

   Traditional drug screening models are often unable to faithfully recapitulate human physiology in health and disease, motivating the development of microfluidic organs-on-a-chip (OOC) platforms that can mimic many aspects of human physiology and in the process alleviate many of the discrepancies between preclinical studies and clinical trials outcomes. Linsitinib, a novel anti-cancer drug, showed promising results in pre-clinical models of Ewing Sarcoma (ES), where it suppressed tumor growth. However, a Phase II clinical trial in several European centers with patients showed relapsed and/or refractory ES. We report an integrated, open setting, imaging and sampling accessible, polysulfone-based platform, featuring minimal hydrophobic compound binding. Two bioengineered human tissues – bone ES tumor and heart muscle – were cultured either in isolation or in the integrated platform and subjected to a clinically used linsitinib dosage. The measured anti-tumor efficacy and cardiotoxicity were compared with the results observed in the clinical trial. Only the engineered tumor tissues, and not monolayers, recapitulated the bone microenvironment pathways targeted by linsitinib, and the clinically-relevant differences in drug responses between non-metastatic and metastatic ES tumors. The responses of non-metastatic ES tumor tissues and heart muscle to linsitinib were much closer to those observed in the clinical trial for tissues cultured in an integrated setting than for tissues cultured in isolation. Drug treatment of isolated tissues resulted in significant decreases in tumor viability and cardiac function. Meanwhile, drug treatment in an integrated setting showed poor tumor response and less cardiotoxicity, which matched the results of the clinical trial. Overall, the integration of engineered human tumor and cardiac tissues in the integrated platform improved the predictive accuracy for both the direct and off-target effects of linsitinib. The proposed approach could be readily extended to other drugs and tissue systems. 

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