bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5547: Non-invasive monitoring of tumor biomechanics and implications for immunotherapy in HCC
Authors: Cortes Andrea C. , Minamiguchi Kiyoyuki , Kostan Hannah , Stenkamp Maria S. , Anfossi Simone , Fowlkes Natalie Wall , Avritcsher Rony 
Published: March 2024

Abstract
Shear-wave elastography (SWE) is a novel non-invasive technique used to quantify tissue stiffness. This approach can be used to longitudinally monitor tumor biomechanics and holds promise for guiding informed clinical decision-making. This study aims to explore the impact of tumor stiffness, as evaluated by SWE, on the proliferative potential of endothelial, tumor, and immune cells in a preclinical model of hepatocellular carcinoma. Tumor tissue sections from a Buffalo-McA-RH7777 rat HCC tumor model, utilizing a rat hepatoma cell line stably expressing green fluorescent protein genes (fluc/GFP) were selected based on the degree of tumor stiffness assessed by SWE. Nodules were separated based on mean shear wave values (3.05 versus 2.26 m/s) and categorized as stiff or soft, respectively. A 6-color panel was used to assess the percentages of different tumor, immune, and endothelial phenotypes in different areas of the tumor including immune cells (CD45+), endothelial cells (CD34+), green fluorescent protein (GFP), Ki67 (cell proliferation), and class-III intermediate filaments - vimentin. Our findings demonstrated increased expression of vimentin on immune cells (CD45+) within the tumor margin interphase. Stiffer tumors exhibited a higher percentage of CD45 cells co-expressing vimentin compared to softer tumors (P=0.01), whereas softer tumors showed an increased prevalence of CD34+ cells concurrently expressing Ki67 (P=0.01). Same pattern persisted in the tumor margin interphase regarding the proliferation of tumor cells identified by the expression of GFP co-expressing Ki67 (P&lt;0.01). These findings highlight a significant association between tumor mechanical properties and the proliferative activity of endothelial and tumor cells, suggesting a link between tissue stiffness and the regulatory mechanisms associated with cellular proliferation and aggressiveness in HCC. Additionally, the presence of vimentin in immune cells may suggest that stiffer tumors may require enhanced migratory and invasive properties to compensate for changes in tumor mechanics thus potentially influencing immune function.
Citation Format: Andrea C. Cortes, Kiyoyuki Minamiguchi, Hannah Kostan, Maria S. Stenkamp, Simone Anfossi, Natalie Wall Fowlkes, Rony Avritcsher. Non-invasive monitoring of tumor biomechanics and implications for immunotherapy in HCC [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 5547.
Abstract 5550: Crosstalk of estrogen receptor Β with tumor microenvironment signaling explains tumor suppressor actions in TNBC
Authors: Zambo Kristina Diana A. , Nagandla Harika , Cap Kim Cuong , Phillips Aireana , Nikolos Fotis , Qian Wei , Zhou Jianying , Chang Jenny , Thomas Christoforos 
Published: March 2024

Abstract
Triple Negative Breast Cancer (TNBC) is a subtype of breast cancer lacking molecular targets, possessing one of the poorest prognoses of all breast cancers. Recent studies using breast tumor samples show an association between the expression of estrogen receptor β (ERβ) and improved survival of patients with TNBC. ERβ - whose function largely opposes that of oncogenic ERα - is involved in the regulation of many tumor repressive pathways and has lately been observed to partake in immune modulation, thus presenting a promising target for TNBC. Discovering selective ERβ agonists is critical to understanding the potential of activating the receptor as a therapy approach for TNBC. It enables us to elicit estrogen signaling response specific to the tumor suppressive function of the β receptor subtype. We have set out a screening process to test and identify ligands that display the greatest activation and specificity for ERβ as determined by reporter assays and changes in downstream target gene expression. We selected to study in vitro and in vivo the compounds with optimal biological activity to delineate tumor-intrinsic and -extrinsic effects and validate the mechanism of action employing human and mouse cell models that reflect the heterogeneity of the disease. We propose that activation of ERβ decreases the proliferative and metastatic ability of breast cancer cells by altering cellular pathways and crosstalk with immune cells. The results of these studies help lay the groundwork for further research on the clinical potential of ERβ especially in the realm of immunotherapy and treatment of TNBC.
Citation Format: Kristina Diana A. Zambo, Harika Nagandla, Kim Cuong Cap, Aireana Phillips, Fotis Nikolos, Wei Qian, Jianying Zhou, Jenny Chang, Christoforos Thomas. Crosstalk of estrogen receptor Β with tumor microenvironment signaling explains tumor suppressor actions in TNBC [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 5550.
Abstract 5555: Lung squamous cancer cell mTORC2 signaling suppresses antitumor immunity by up-regulation of PSGL-1, a ligand of VISTA/PD-1H checkpoint receptor
Authors: Ngwa Verra M. , Hwang Yoonha , Edwards Deanna N. , Song Wenqiang , Chen Jin 
Published: March 2024

Abstract
Lung squamous cell carcinoma (LUSC) represents 30% of non-small cell lung cancer (NSCLC) cases and has a high mortality rate with limited targeted therapies. Unlike lung adenocarcinoma (LUAD), which has seen advancements in targeted therapies, LUSC has not benefited from similar breakthroughs despite having similar genetic abnormalities. While immune checkpoint inhibitor therapies have shown promise in some LUSC patients, a significant portion does not respond effectively, leaving limited treatment options. In this study, we investigated vulnerabilities in NSCLC and found that a substantial number of LUSC patients have genetic alterations in the PI3K-mTORC2-AKT signaling pathway. By using CRISPR/CAS-9, we showed that disrupting mTORC2 function in LUSC cells reduced glycolysis and lactate secretion, which in turn reduced tumor growth in vivo. Remarkably, the loss of mTORC2 also enhanced the activity of CD4+ and CD8+ T cells within the tumors. To further understand the metabolic and immune changes associated with mTORC2 loss of function, we performed RNA sequencing comparing wild-type (WT) and mTORC2-deficient cells. Our results confirmed a link between mTORC2 and HIF-2α, while regulating PSGL-1, a ligand of the VISTA/PD-1H checkpoint receptor. Furthermore, introducing a stable, non-degradable form of HIF-2α in mTORC2-deficient tumor cells restored PSGL-1 expression in vitro and in vivo. These results suggest that the interaction between PSGL-1 and VISTA plays a role in suppressing the anti-tumor immune response in LUSC tumors. Indeed, anti-VISTA treatment inhibited the growth of LUSC WT tumors in vivo, suggesting that mTORC2 plays a role in regulating PSGL-1 expression in the tumor microenvironment. Together, these data demonstrate that targeting mTORC2 or inhibiting VISTA checkpoint receptor may serve as a potential therapeutic strategy for improving immunotherapy in LUSC.
Citation Format: Verra M. Ngwa, Yoonha Hwang, Deanna N. Edwards, Wenqiang Song, Jin Chen. Lung squamous cancer cell mTORC2 signaling suppresses antitumor immunity by up-regulation of PSGL-1, a ligand of VISTA/PD-1H checkpoint receptor [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 5555.
Abstract 5562: Altered tumor microenvironment in animal model of concomitant GBM and Alzheimer's pathology
Authors: Nascari David , Eghlimi Ryan , Beniwal Angad , Alton Drake , Fryer John , Tran Nhan L. 
Published: March 2024

Abstract
Glioblastoma (GBM) and Alzheimer’s disease (AD) are two devastating central nervous system diagnoses with no known cure. Both diseases are associated with advanced age. The majority of GBM tumors form in the frontal and temporal lobes, two of the brain regions most impacted by amyloid and tau pathology in AD. Females have a higher risk of AD, while males have a higher risk of GBM. Several large case series have established epidemiological evidence that the two diseases are inversely correlated. Nevertheless, it remains unknown whether presence of subclinical amyloid or tau pathology antagonizes the establishment or progression of GBM. The present study sought to characterize GBM growth, progression, and immune response in the setting of concomitant AD pathology using the syngeneic murine GL261 tumor model. To further understand the tumor cell changes that occur in the presence or absence of AD pathology, we engineered GL261 with a dual-tagged vector consisting of RiboTag (to allow for full-length mRNA profiling) and TurboID (to allow for proteomic profiling). GL261 cells were injected intracranially into APPNL-G-F/NL-G-F - MAPThuman/human, APPNL-G-F/+ - MAPThuman/+, and wildtype C57BL/6J mice. Tumors in both wildtype and AD conditions contained ~50% intratumoral myeloid cells (Iba+, P2RY12-). Differential activation of intratumoral myeloid cells will be assessed with immunohistochemistry. Microgliosis (IBA1, P2RY12) and astrogliosis (GFAP) around the tumor in the setting of Alzheimer’s pathology versus normal conditions will be compared. Invasiveness, proliferation, DNA damage (pH2AX), and apoptosis (cleaved PARP, cleaved Caspase 3) will be compared. Tumor cell-specific changes unique to tumors in the AD microenvironment will be assessed transcriptionally with RiboTag profiling as well as proteomically with TurboID purifications. Our preliminary data suggests that the presence of concomitant AD pathology affects GBM growth and progression as well as the immune response to the tumor, and warrants further investigation.
Citation Format: David Nascari, Ryan Eghlimi, Angad Beniwal, Drake Alton, John Fryer, Nhan L. Tran. Altered tumor microenvironment in animal model of concomitant GBM and Alzheimer's pathology [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 5562.
Abstract 5605: Cutibacterium acnes invades prostate epithelial cells to induce BRCAness as a possible pathogen of prostate cancer
Authors: Ashida Shingo , Kawada Chiaki , Tanaka Hiroko , Kurabayashi Atsushi , Yagyu Ken-ichi , Sakamoto Shuji , Maejima Kazuhiro , Miyano Satoru , Daibata Masanori , Nakagawa Hidewaki , Inoue Keiji 
Published: March 2024

Abstract
Abundant evidence suggests that chronic inflammation is linked to prostate cancer and that infection is a possible cause of prostate cancer. However, pathogen of prostate cancer remains to be found. To identify microbiota or pathogens associated with prostate cancer, we investigated the transcriptomes of 20 human prostate cancer tissues. We performed de novo assembly of non-human sequences from RNA-seq data and identified four bacteria as candidate microbiota in the prostate, including Moraxella osloensis, Uncultured chroococcidiopsis, Cutibacterium acnes, and Micrococcus luteus. Among these, C. acnes was detected in 19 of 20 prostate cancer tissue samples by immunohistochemistry. We then analyzed the gene expression profiles of prostate epithelial cells infected in vitro with C. acnes and found significant alterations in homologous recombination (HR) and Fanconi anemia pathway. Notably, electron microscopy showed that C. acnes invaded prostate epithelial cells and localized in perinuclear vesicles, whereas analysis of γH2AX foci and HR assay demonstrated impaired HR repair. In particular, BRCA2 was significantly down-regulated in C. acnes-infected cells. These findings suggest that C. acnes infection in the prostate could lead to HR deficiency and BRCAness which promotes DNA double-strand breaks, thereby increasing the risk of cancer development.
Citation Format: Shingo Ashida, Chiaki Kawada, Hiroko Tanaka, Atsushi Kurabayashi, Ken-ichi Yagyu, Shuji Sakamoto, Kazuhiro Maejima, Satoru Miyano, Masanori Daibata, Hidewaki Nakagawa, Keiji Inoue. Cutibacterium acnes invades prostate epithelial cells to induce BRCAness as a possible pathogen of prostate cancer [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 5605.
Abstract 5614: Mechanical regulation of cisplatin-DNA adduct repair in mesenchymal stem cells
Authors: Zavala Anamaria Gabriella , Nikitina Nina , Cantu Crystal , DeLaCruz Dalia , Uzer Gunes 
Published: March 2024

Abstract
This study examined whether loss of mechanotransduction in pluripotent mesenchymal stem cells (MSCs) disrupted repair of bulky DNA adducts, such as those induced by ultraviolet light or cisplatin. MSCs are important for the maintenance and responsiveness of skeletal tissues to environmental mechanical challenges. Beyond regulating proliferative and differentiative capacity of MSCs, emerging evidence suggests that physical activity is associated with improved recovery from DNA damage caused by environmental genotoxic stressors associated with stress and aging. Highlighting the possible crosstalk between DNA repair and bone health, defects in nucleotide excision repair (NER), which removes bulky DNA adducts, are associated with myelosuppression and progeroid aging phenotypes that result in bone defects and lipidodystrophies in mice. Cancer, early aging syndromes, and certain musculoskeletal diseases are associated with disruption of the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex that transduces environmental mechanical signals from the extracellular matrix into the nucleus of a cell. Loss of LINC complex elements is associated with breast cancer progression and poorer prognosis. We hypothesize that LINC-mediated mechanical stimulation into the nucleus is critical for repair of bulky DNA adducts. Our pilot project showed that mechanical stimulation applied in the form of low intensity vibration (LIV) improved NER of cisplatin-induced DNA adducts in cultured MSCs. Our findings show a 20% increase in repair of cisplatin-induced DNA adducts in LIV treated samples compared to non-vibrated samples at 24 hours (P&lt;0.005). We also quantified the effect of LINC complex disruption on cisplatin-induced DNA damage removal. Intact MSCs showed significant adduct removal after 24 hours, while LINC disruption significantly reduced DNA repair (P&lt;0.001). Furthermore, initial experiments suggest that LINC disrupted cells do not arrest at DNA repair checkpoints, therefore, loss of LINC complex may reduce entry into senescence increasing DNA mutagenesis. In conclusion, these findings suggest a novel interaction between mechanical stimulation, the DNA damage response, and LINC complex in DNA repair in multipotent mesenchymal stem cells. Furthermore, we suggest that LINC-mediated mechanical changes associated with LIV treatment may lead to novel therapeutic approaches to combat deleterious musculoskeletal conditions associated with anti-cancer treatments.
Citation Format: Anamaria Gabriella Zavala, Nina Nikitina, Crystal Cantu, Dalia DeLaCruz, Gunes Uzer. Mechanical regulation of cisplatin-DNA adduct repair in mesenchymal stem cells [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 5614.
Abstract 5624: Dec2, a circadian rhythm gene facilitates pancreatic cancer dormancy through evasion of antitumor immunity
Authors: Wang Lan , Harris Chris , Prela Orjola , Narrow Wade C. , Carpizo Darren R. 
Published: March 2024

Abstract
Metastatic recurrence following curative intent oncologic surgery is a major clinical problem in patients with pancreatic ductal adenocarcinoma (PDAC). These recurrences are from disseminated tumor cells (DTCs) and can sometimes occur years after surgery indicating that DTCs undergo a period of dormancy. The mechanisms that drive cancer dormancy and its awakening are poorly understood in part due to a lack of animal models that recapitulate dormant tumor cell biology. We created a novel model of PDAC dormancy where mice undergo surgery to remove the primary tumor and are followed for evidence of metastatic recurrence. Dormant DTCs can be isolated from mice without clinical evidence of recurrence for molecular studies. Single cell RNAseq of dormant DTCs detected that the circadian rhythm gene, Dec2 is upregulated. We knocked out (KO) Dec2 from murine pancreatic cancer cells and when implanted into the model we found almost no mice developed metastatic recurrence. When immunodeficient or immunocompetent mice depleted of CD4 and CD8 T cells were used as hosts, we observed no difference in survival in mice engrafted with Dec WT vs. KO cells indicating the survival benefit in the Dec KO group was due to an immune mediated mechanism. We performed a differential expression analysis on bulk RNAseq data comparing the Dec2 WT vs. KO cells and found antigen presentation a top upregulated pathway. We then observed that surface MHC-I was significantly upregulated in Dec2 KO cells as compared to wild type cells. Further mechanistic studies revealed that proteosome activity was significantly higher in Dec2 KO cells and treatment with proteosome inhibitors decreased surface MHCI levels in Dec2 KO cells. Cut and tag experiments revealed that Dec2 binds the promoter of a number of genes that regulate the proteosome. In conclusion, Dec2 promotes cancer dormancy by down regulating cell surface MHCI which facilitates immune evasion.
Citation Format: Lan Wang, Chris Harris, Orjola Prela, Wade C. Narrow, Darren R. Carpizo. Dec2, a circadian rhythm gene facilitates pancreatic cancer dormancy through evasion of antitumor immunity [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 5624.
Abstract 5644: The impact of ATF3, JDP2, FOXR2, NAA10, FOXL2, DDX20, and p14ARF on the transactivation of p53
Authors: Yang William H. , Yang Wei-Hsiung 
Published: March 2024

Abstract
Cancer stands as a formidable health challenge in the 21st century, evoking widespread fear. Presently, the mortality rate associated with cancer in humans ranges from approximately 11% to 25%. Numerous nuclear and cytoplasmic proteins have demonstrated interactions with p53, influencing both its activity and abundance. In our prior, unpublished findings, we established that JDP2 interacts with p53, modulating its activity. Consequently, in the present investigation, we broaden our exploration to identify novel proteins capable of regulating p53 transactivation. First, we found a synergistic effect of ATF3 and JDP2 on p53 transactivation. Moreover, deSUMOylation of ATF3 and dephosphorylation of JDP2 further enhance p53 transactivation. Secondly, FOXR2 (an epigenetically regulated pan-cancer oncogene) and NAA10 (an acetyltransferase) also remarkably increase p53 transactivation in H1299 (p53 null) cells. Thirdly, in addition to MDM2 and MDM4 (MDMX) as p53 negative regulators, we further found that FOXL2 (a transcription factor in steroidogenesis regulation), DDX20 (a transcription factor for embryonic development and ovarian function), and p14ARF (for cell cycle regulation) significantly down-regulate p53 transactivation. Taken together, our preliminary results demonstrate that several transcription factors regulate p53 transactivation and possible p53 stability and/or degradation. This data is presented to substantiate the idea that numerous newly discovered proteins may engage with p53 and control its transactivation.
Citation Format: William H. Yang, Wei-Hsiung Yang. The impact of ATF3, JDP2, FOXR2, NAA10, FOXL2, DDX20, and p14ARF on the transactivation of p53 [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 5644.
Abstract 5649: PRRX1-TOP2A interaction is a malignancy-promoting factor in human malignant peripheral nerve sheath tumors
Authors: Takihira Shota , Nakata Eiji , Yamada Daisuke , Osone Tatsunori , Takao Tomoka , Takarada Takeshi , Hirasawa Akira , Itano Takuto , Fujiwara Tomohiro , Kunisada Toshiyuki , Ozaki Toshifumi 
Published: March 2024

Abstract
Background: Paired related-homeobox 1 (PRRX1) is a transcription factor in the regulation of developmental morphogenetic processes. There is growing evidence that PRRX1 is highly expressed in certain cancers and is critically involved in human survival prognosis. However, the molecular mechanism of PRRX1 in cancer malignancy remains to be elucidated.
Methods: PRRX1 expression in human Malignant peripheral nerve sheath tumors (MPNSTs) samples was detected immunohistochemically to evaluate survival prognosis. MPNST models with PRRX1 gene knockdown or overexpression were constructed in vitro, and the phenotype of MPNST cells was evaluated. Bioinformatics analysis combined with co-immunoprecipitation, mass spectrometry, RNA seq, and structural prediction were used to identify proteins interacting with PRRX1.
Results: High expression of PRRX1 was associated with a poor prognosis for MPNST. PRRX1 knockdown suppressed the tumorigenic potential. PRRX1 overexpressed in MPNSTs directly interacts with topoisomerase 2A (TOP2A) to cooperatively promote epithelial-mesenchymal transition and increase expression of tumor malignancy-related gene sets including mTORC1, KRAS, and SRC signaling pathways. Etoposide, a TOP2A inhibitor used in the treatment of MPNST, may exhibit one of its anticancer effects by inhibiting the PRRX1-TOP2A interaction.
Conclusion: Targeting the PRRX1-TOP2A interaction in malignant tumors with high PRRX1 expression might provide a novel tumor-selective therapeutic strategy.
Significance: MPNST is a malignant tumor with a poor prognosis and still lacks definitive treatment. Our results could hold promise as an alternative therapeutic strategy to inhibit the interaction between PRRX1 and TOP2A, and may improve the prognosis for malignant tumor patients with high expression of PRRX1 and TOP2A such as MPNSTs.
Citation Format: Shota Takihira, Eiji Nakata, Daisuke Yamada, Tatsunori Osone, Tomoka Takao, Takeshi Takarada, Akira Hirasawa, Takuto Itano, Tomohiro Fujiwara, Toshiyuki Kunisada, Toshifumi Ozaki. PRRX1-TOP2A interaction is a malignancy-promoting factor in human malignant peripheral nerve sheath tumors [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 5649.