bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2414: Retinoic acid induced 14 drives pancreatic cancer progression and metastasis
Authors: Runa Farhana , Tomaneng Luke , Adamian Yvess , Cox Nathan , Aquino Albert-Fred , Wallace Matthew , Gonzalez Carolina , Bhakta Kishan , Hoover Malachia , Wolfenden Laurelin , Humphries Jonathan D. , Humphries Martin J. , Boyce Michael , Kelber Jonathan A. 
Published: June 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is associated with very poor outcomes - fewer than 10 percent of patients survive beyond five years after diagnosis. The primary hurdles facing PDAC patients and clinicians are early dissemination, a lack of therapeutic targets and desmoplasia that renders the primary tumor refractory to chemotherapy. In this regard, we have previously reported that pseudopodium-enriched atypical kinase 1 (PEAK1) and integrin α1 (ITGA1) mediate gemcitabine resistance and metastasis in PDAC. To identify new mechanisms of PDAC progression, we mined the Cancer BioPortal and Human Cell Map BioID databases for additional pseudopodium-enriched (PDE) proteins that predict poor patient outcomes, correlate with PEAK1 and ITGA1 expression in PDAC, and interact with PEAK1 and ITGA1. Here, we identify Retinoic Acid Induced 14 (RAI14, Ankycorbin or NORPEG) as a new candidate driver of PDAC that is a constituent of the KRasG12D PDAC cell autonomous phosphoproteome, localizes to cytoskeleton/adhesion domains in PDAC cells and correlates in expression with ITGA1-binding collagens in PDAC. Knockdown or knockout of RAI14 in KRas mutant PDAC cells impaired adhesion-dependent proliferation/survival in vitro and tumor growth and metastasis in vivo. Single cell cyclic immunofluorescence (CycIF) further revealed that RAI14 supports a subpopulation of PDAC cells positive for proliferation, epithelial to mesenchymal transition (EMT) and antiapoptotic programs. By using a RAI14-focused bioinformatics pipeline in combination with proteomic and immunofluorescence data on the composition of ITGA1-dependent adhesion complexes in PDAC cells, we identified Polo-Like Kinase 1 (PLK1) as a candidate that may control RAI14 function and adhesion-regulated mitosis during PDAC progression. Notably, the potency of volasertib, a PLK1-specific inhibitor, was reduced in RAI14 knockout cells, supporting a model in which RAI14 mediates adhesion-dependent PLK1 functions in PDAC. Taken together, these studies uncover a mechanism for RAI14-driven PDAC progression and the development of strategies to increase chemotherapy sensitivity, reduce primary/metastatic tumor burden and improve patient outcomes.
Citation Format: Farhana Runa, Luke Tomaneng, Yvess Adamian, Nathan Cox, Albert-Fred Aquino, Matthew Wallace, Carolina Gonzalez, Kishan Bhakta, Malachia Hoover, Laurelin Wolfenden, Jonathan D. Humphries, Martin J. Humphries, Michael Boyce, Jonathan A. Kelber. Retinoic acid induced 14 drives pancreatic cancer progression and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2414.
Abstract 244: Limiting metastatic breast cancer progression by targeting MK2 stromal signaling
Authors: Oliveira Renata Ramalho , Faget Douglas V. , Luo Xianmin , Ye Jiayu , Monahan Joseph B. , Stewart Sheila A. 
Published: June 2022

Abstract
Breast cancer is now the most common cancer among women in the US and metastasis to distant organs is the major cause of death in these patients. Among metastatic sites, bone is the most frequent destination of breast cancer metastasis and once the disease is found in the bone, it is often refractory to standard therapy. In addition, bone metastasis is associated with significant skeletal related events that greatly impact quality of life. Thus, there is a significant need to develop novel therapies that extend survival and improve quality of life. Previously we found that MK2 inhibition (MK2i) limits metastatic growth by targeting the tumor stromal compartment. To determine which stromal cells are targeted by MK2i we isolated stromal cells from within a metastatic bone lesion and carried out single cell RNA sequencing (scRNA-Seq). Using this approach, we found numerous gene expression changes in both the immune (CD45+) and non-immune (CD45-) populations upon MK2i. Indeed, we found significant numbers of p16+ senescent fibroblasts were present inside the metastatic lesion. We also found vascular cancer-associated fibroblasts (vCAF) and matrix CAFs (mCAF) inside the metastatic lesion suggesting that CAFs are not limited to primary disease. Numerous changes in gene expression in CD45+ cells were also observed, and these changes are being used to identify viable immunotherapies to deploy in our model. Finally, we are using conditional MK2 mice to establish the cell type targeted by MK2i. Our data demonstrate that MK2i is as effective as chemotherapy at limiting metastatic progression and our approach to leverage the scRNA-Seq data may allow us to optimize MK2i therapy to improve patient outcomes and quality of life.
Citation Format: Renata Ramalho Oliveira, Douglas V. Faget, Xianmin Luo, Jiayu Ye, Joseph B. Monahan, Sheila A. Stewart. Limiting metastatic breast cancer progression by targeting MK2 stromal signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 244.
Abstract 2442: Seminal fluid enhances cervical squamous carcinoma cell proliferation, epithelial mesenchymal transition (EMT), migration & invasion
Authors: Mkwanazi Nonkululeko , Leaner Virna D. , Katz Arieh A. 
Published: June 2022

Abstract
Cervical cancer is the leading cause of cancer related deaths & the second most common cancer amongst South African women. Though there are various risk factors, the most common risk factor for cervical cancer development is sexual transmission & persistent infection with high-risk Human Papillomavirus (HPV). Although most HPV infections are cleared naturally in women, persistent infection with high-risk HPV types promotes neoplastic transformation & tumorigenesis. Furthermore, exposure of neoplastic cervical epithelial cells to inflammatory mediators may drive the progression of cervical cancer. Seminal fluid (SF), a biological fluid rich in inflammatory mediators & growth factors, has been implicated in cervical cancer progression. SF has been shown to induce the expression of proinflammatory mediators which promotes cell proliferation in culture & growth of explants in mice injected with HeLa cervical adenocarcinoma cells. Since majority of cervical cancer cases are squamous cell carcinoma, in this study, we examined the effect of SF on cell proliferation, EMT, cell migration & invasion employing SiHa and Me180 squamous cell carcinoma cell lines. Our results showed that SF significantly enhanced cell proliferation in both cell lines. Using Confocal microscopy and phalloidin staining we further showed that SF caused morphological changes and stress fibre formation. RT-qPCR showed that SF up regulated EMT transcription factors Snail, ZEB1 & TWIST mRNA expression. EMT induction was further confirmed by the increase of N-cadherin & a subsequent decrease in E-cadherin protein expression. Additionally, we showed that the induction of EMT transcription factors by SF occurs via the EGF/ERK/COX pathway. To investigate the effect of SF on migration and invasion, transwell migration assays were used. Results showed that SF significantly enhanced cell migration & invasion of the SiHa and Me180 cells. Our results show that SF plays a role in enhancing the migratory & invasive potential of squamous cell carcinoma cells & that this associates with increased expression of EMT transcription factors. These findings together implicate SF as a possible factor that may promote cervical cancer progression.
Citation Format: Nonkululeko Mkwanazi, Virna D. Leaner, Arieh A. Katz. Seminal fluid enhances cervical squamous carcinoma cell proliferation, epithelial mesenchymal transition (EMT), migration & invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2442.
Abstract 2444: The integrin alpha10beta1 antibody TARG10 reduces tumor growth and metastasis of triple negative breast cancer
Authors: Masoumi Katarzyna , Huang Xiaoli , Mirkov Anna , Smedenfors Kristine , Norlén Per , Lundgren-Åkerlund Evy 
Published: June 2022

Abstract
Triple negative breast cancer (TNBC) is an aggressive form of breast cancer that accounts for 10-15% of all breast cancer diagnoses. It is far more aggressive than other breast cancer types due to a higher degree of metastases and frequent relapses following current treatment options. Integrin alpha10beta1 is a collagen binding receptor that has emerged as a promising new cancer target due to its role in tumor cell proliferation and migration. The aim of the present study was to investigate the function blocking activity of the human integrin alpha10beta1 antibody TARG10 on growth and metastasis of TNBC.We have found that integrin alpha10beta1 is highly expressed in TNBC, with minimal expression in healthy tissue, and that high expression is correlated with poor prognosis in TNBC patients. In vitro studies showed significant inhibiting effects of TARG10 on the adhesion, migration, proliferation, and viability of TNBC cells. In an orthotopic xenograft TNBC model, TARG10 confirmed inhibitory effects on both tumor growth and metastasis as demonstrated by In Vivo Imaging System (IVIS-CT). The effect on metastasis was further demonstrated in a tail vein xenograft TNBC model of experimental metastasis. Pharmaceutical evaluation demonstrated excellent developability properties, including low post translational liabilities, high melting point, low aggregation and high yield.In summary, integrin alpha10beta1 represents a promising target for directed antibody-based therapy of TNBC. Our in vitro and in vivo data supports pre-clinical and clinical development of TARG10 as a candidate drug for treatment of patients with triple negative breast cancer.
Citation Format: Katarzyna Masoumi, Xiaoli Huang, Anna Mirkov, Kristine Smedenfors, Per Norlén, Evy Lundgren-Åkerlund. The integrin alpha10beta1 antibody TARG10 reduces tumor growth and metastasis of triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2444.
Abstract 246: Application of the 3d fresh patient tumoroid platform 3d-explore to assess the immunomodulatory and phagocytic activity of the receptor tyrosine kinase inhibitor, Sunitinib
Authors: Bunch Brittany , Kodumudi Krithika N. , Ehrhart Jared , Weitzman Matt , MacIntosh Olivia , Sussman Kelly , Altiok Soner 
Published: June 2022

Abstract
Background: The receptor tyrosine kinase inhibitor (TKI) Sunitinib has proven useful in the treatment of a variety of tumors. Sunitinib has shown therapeutic activity in patients with metastatic renal cell carcinoma and currently represents a frontline therapy for this disease. The immune modulatory effect of Sunitinib on immune cells within the tumor microenvironment has been well documented. Here, we developed a novel 3D ex-vivo platform (3D-EXplore) using fresh patient tumor samples with intact stromal components and tumor immune microenvironment to assess the therapeutic efficacy of Sunitinib.
Methods: All tumor samples were obtained with patient consent and relevant IRB approval. Unpropagated 3D tumoroids with intact TME measuring 150 µm in size were prepared from fresh tumor samples of renal cell carcinoma using a proprietary technology developed at Nilogen Oncosystems. Tumoroids prepared from each patient’s tumor sample were pooled to represent the tumor heterogeneity and treated ex vivo with Sunitinib for 48h to detect treatment-mediated changes in tumor immune cell composition including CD4 and CD8 T-cells, NK cells, and macrophages. Additionally, we analyzed treatment-mediated changes in T-cell activation and phagocytic activity of myeloid cells.
Results: Multiparameter flow analysis revealed that Sunitinib treatment led to an increase in CD8+CD25+ central memory-like phenotype and increased granzyme B expression in CD4 and CD8+ T cells indicating T cell activation. Furthermore, multiparameter flow cytometry analysis showed increased EdU uptake by CD8 and NK cells with sunitinib treatment, while cytokine release assays demonstrated increased IFN-γ and IL-2 production accompanied by downregulation of IL-10 and IL-6 cytokines. We observed Sunitinib mediated phagocytotic activity by tumor resident myeloid macrophages, monocytes, and dendritic cells using a quantitative phagocytosis assay.
Conclusions: These results demonstrate that 3D-EXplore using fresh tumor samples provides a clinically relevant platform to assess drug response and serves as a critical tool for reflecting the true intact tumor microenvironment for novel immune-oncology drug development.
Citation Format: Brittany Bunch, Krithika N. Kodumudi, Jared Ehrhart, Matt Weitzman, Olivia MacIntosh, Kelly Sussman, Soner Altiok. Application of the 3d fresh patient tumoroid platform 3d-explore to assess the immunomodulatory and phagocytic activity of the receptor tyrosine kinase inhibitor, Sunitinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 246.
Abstract 2485: Applications of multimodality ex-vivo tissue imaging to improve breast cancer diagnosis and treatment
Authors: Avila Corazon , Karczmar Gregory , Mustafi Devkumar 
Published: June 2022

Abstract
Breast cancer is the most common malignancy affecting women worldwide. Existing models being used to study breast cancer include the Patient-Derived Tumor Organoid (PDTO) Model and the Patient-Derived Tumor Xenograft (PDTX) Model. Both models involve the surgical removal of a tumor from a patient which then undergoes processing to grow an organoid or injected into mice to test different therapies outside the body. However, these models not only take a considerable amount of time to develop properly, but in many cases aren’t representative of the most aggressive tumor cells present within a heterogeneous tissue sample in order to draw the most clinically accurate conclusions of a tumor's response to therapy. In order to advance clinical research, more efficient culture systems that are faster growing and more representative of biological characteristics in-vivo are needed. Previous work from the Karczmar Lab discovered that high-resolution magnetic resonance imaging (MRI) can detect regions of aggressive cancer in biopsy specimens from mouse models, and give additional information on characteristics including cell density, tissue composition, and cancer stage. With this recent discovery, it is hypothesized that ex-vivo imaging could be used to identify aggressive tumor cells in human heterogeneous breast cancer tissue samples to produce higher quality and faster-growing models for testing new therapies and guiding individual patient therapy for breast cancer. The primary aim for this study was to specifically identify image-based markers for regions of aggressive cancer by comparing ex-vivo high-resolution MRI with histology and immunohistochemistry in 3D. Distant normal (DN) and tumor (Tu) tissue samples from breast cancer patients were obtained and imaged using T2-weighted 3D Rapid Imaging with Refocused Echoes (RARE) and stained using hematoxylin and eosin (H&E), commonly used by pathologists to diagnose cancers. Then, the ex-vivo T2-weighted 3D RARE images were correlated to the histopathological H&E staining and confirmed by breast radiologists and pathologists. Preliminary results revealed that high-resolution MR imaging detects mammary glands, ducts, and white adipose tissue in DN tissue samples and regions of invasive cancer, including ductal carcinoma in-situ (DCIS) and necrosis, in Tu tissue. Based on these results, aggressive cancer regions were proven to be identified using image-based guidance and potentially be extracted using core-needle biopsy to improve PDTO and PDTX models for studying breast cancer and advancing individual patient therapy.
Citation Format: Corazon Avila, Gregory Karczmar, Devkumar Mustafi. Applications of multimodality ex-vivo tissue imaging to improve breast cancer diagnosis and treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2485.
Abstract 2521: Impact of peritoneal lavage on omentum immune cell dynamics and metastasis
Authors: Akasaka Hironari , Naora Honami 
Published: June 2022

Abstract
Peritoneal lavage is a routine procedure in which normal saline solution is administered into the abdominal cavity and the washings are cytologically examined for cancer cells. Peritoneal lavage often strips protective mesothelial linings and can promote formation of peritoneal adhesions. However, the impact of peritoneal lavage on the omentum, which is also exposed to this procedure, is unclear. The omentum is a fatty tissue that suspends from the stomach and contains highly vascularized immune cell structures called milky spots. Because circulating ovarian and gastric cancer cells have strong predilection for implanting in milky spots, it is important to understand the impact of peritoneal lavage on the omentum, as not all patients with these cancers undergo omentectomy. In this study, we administered clinically relevant amounts of normal saline solution to immunecompetent mice to mimic peritoneal lavage, and evaluated the absorption of saline solution and the gross architecture and immune cell composition of the omentum and other peritoneal fat tissues. As compared to other peritoneal fat tissues, the omentum showed the highest capability to absorb saline solution. Following administration of saline, a dramatic expansion in milky spots and increased vessel density were observed in the omentum. Immunophenotyping and functional studies revealed that these cellular changes were due in part to the expansion of a sub-population of peritoneal macrophages. Furthermore, studies using mouse allograft models of ovarian cancer revealed that saline administration stimulated the implantation of circulating cancer cells on to the omentum. Collectively, these findings raise the possibility that peritoneal lavage ‘primes’ the omentum to be conducive for colonization by occult cancer cells that circulate in the peritoneal fluid.
Citation Format: Hironari Akasaka, Honami Naora. Impact of peritoneal lavage on omentum immune cell dynamics and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2521.
Abstract 2538: Role of Argonaute 2 in regulation of immune microenvironment in pancreatic cancer
Authors: Hon Jennifer , Kenum Carson , Bawa Pushpinder S. , Dommeti Vijaya L. , Sahu Anastasia A. , Gandham Miriam , Li Chi-Chiang , Taher Zainab I. , Zelenka-Wang Sylvia , Tien Jean C. , Shankar Sunita , Chugh Seema , Chinnaiyan Arul M. 
Published: June 2022

Abstract
KRAS mutations have been observed in nearly 95% of pancreatic ductal adenocarcinoma (PDAC), however targeting KRAS remains a major therapeutic challenge. Previous studies from our group have discovered a novel interaction between KRAS and Argonaute 2 (AGO2) and have uncovered a significant role of this interaction in regulating KRAS signaling. Knockout of AGO2 in genetically engineered mouse models of KRAS driven pancreatic and lung cancer dramatically impacted tumor progression. Intriguingly, in pancreatic cancer loss of AGO2 expression resulted in early pancreatic intraepithelial lesions (PanINs) that failed to progress to PDAC. We observed increased senescence in these AGO2 knockout lesions that abrogated PDAC progression. Further, there was pronounced infiltration of immune cells in pancreata lacking AGO2 in comparison to wild type. We particularly observed a 20-fold increase in natural killer (NK) cells population in pancreata lacking AGO2. This instigated us to evaluate potential role of AGO2 in regulating immune microenvironment in pancreatic cancer. Gene set enrichment analysis of AGO2 knockout SW1990 PDAC cells revealed significant upregulation of inflammatory and interferon response pathways. We observed increased expression of several signaling proteins implicated in immune activation pathways. Further characterization of these knockout cells indicated upregulation of MHC proteins that consequently added to mechanistic insights. Additionally, we are also exploring syngeneic models of pancreatic cancer and we will present findings from our ongoing studies to evaluate the impact of AGO2 knockout on immune axis. Overall, our findings suggest potential involvement of AGO2 in regulating immune microenvironment in pancreatic cancer.
Citation Format: Jennifer Hon, Carson Kenum, Pushpinder S. Bawa, Vijaya L. Dommeti, Anastasia A. Sahu, Miriam Gandham, Chi-Chiang Li, Zainab I. Taher, Sylvia Zelenka-Wang, Jean C. Tien, Sunita Shankar, Seema Chugh, Arul M. Chinnaiyan. Role of Argonaute 2 in regulation of immune microenvironment in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2538.