bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3604: Epithelial Caveolin-1 regulates lung metastasis in advanced stages of breast cancer
Authors: Singh Dhirendra Pratap , Pathak Rashmi , Pandit Abhishek , Ebenezer Philip J. , Jambunathan Nithya , Kumar Sanjay , Plooy Alexander Du , Francis Joseph , White Mary E. 
Published: April 2023

Abstract
Organotypic metastasis is a well-orchestrated sequence of events that takes place in tumors. The interplay between secretory factors from the primary tumor and the microenvironment of a distant organ determines the fate of metastasis. A significant concern in effective triple-negative breast cancer (TNBC) treatment is lung metastasis. Caveolin-1 (Cav-1), a lipid raft protein, is an important component of the metastatic interplay and is reported to be upregulated in the advanced metastatic stage of breast cancer. Although Cav-1 has been shown to have oncogenic potential, its role in TNBC lung metastasis is not fully understood. Our data illustrates, knocking out Cav-1 in the 4T1 cells (a mouse breast cancer cell line) affects cell morphology, extracellular vesicle formation, and MMP release in vitro. Furthermore, a wound healing/cell migration assay showed reduced migration in Cav-1 KO 4T1 cells when compared to control 4T1 cells, and these findings were validated using Cav-1 siRNA. For investigating the metastatic role, we injected Cav-1 KO 4T1 and control 4T1 cells into the mammary fat pad of female BALB/c mice, a syngeneic mouse model of triple-negative breast cancer. We found no evidence of lung metastasis in Cav-1 KO 4T1 injected mice when compared to control 4T1 injected mice. This was further supported by mRNA profiling of the tumor. We observed 21 epithelial cell migration genes that are differentially expressed in Cav-1 KO tumors when compared to WT tumors. Correlation analysis from Breast Cancer Gene-Expression Miner v4.8 (bc-GenExMiner), a human database, showed a significant correlation between Cav-1 expression and several of the 21 epithelial cell migration genes, along with integrin 3 alpha (ITGα3). Interestingly, in silico protein docking predicted an interaction between Cav-1 and ITGα3, which was later confirmed by co-immunoprecipitation. The role of ITGα3 in metastasis was further corroborated by cell migration assay, which was affected when siRNA was used to silence ITGα3 gene expression. Collectively, these findings provide evidence that Cav-1 KO, along with ITGa3, plays an important role in distant lung metastasis in the 4T1 tumor-induced mice model.
Citation Format: Dhirendra Pratap Singh, Rashmi Pathak, Abhishek Pandit, Philip J. Ebenezer, Nithya Jambunathan, Sanjay Kumar, Alexander Du Plooy, Joseph Francis, Mary E. White. Epithelial Caveolin-1 regulates lung metastasis in advanced stages of breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3604.
Abstract 3606: HDAC8-mediated inhibition of EP300 drives a neural crest-like transcriptional state that increases melanoma brain metastasis
Authors: Emmons Michael , Bennett Richard , Riva Alberto , Zhang Chao , Macaulay Robert , Dupéré-Richér Daphne , Fang Bin , Koomen John , Li Jiannong , Chen Ann , Seto Edward , Licht Jonathan , Smalley Keiran 
Published: April 2023

Abstract
Melanomas are heterogeneous and adopt multiple transcriptional states that can confer an invasive phenotype and resistance to therapy. Little is known about the epigenetic drivers of these cell states, limiting our ability to regulate melanoma heterogeneity and tumor progression. Here we identify stress-induced HDAC8 activity as the driver of a neural crest stem cell (NCSC)-like transcriptional state that increased the formation of melanoma brain metastases (MBM). Exposure of melanocytes and melanoma cells to multiple different stresses led to HDAC8 activation, a switch to a NCSC gene expression signature and the adoption of an amoeboid, invasive phenotype. This cell state enhanced the survival of melanoma cells under shear stress conditions and increased the formation of metastases in the brain. Single cell RNA-seq analyses showed that HDAC8 expression was correlated with the NCSC cell state in clinical MBM specimens. ATAC-Seq and ChIP-Seq analysis showed HDAC8 to alter chromatin structure by increasing H3K27ac and accessibility at c-Jun binding sites without changing global histone acetylation. The increased accessibility of Jun binding sites was paralleled by decreased H3K27ac and accessibility at MITF binding sites and loss of melanoma-lineage gene expression. Mass spectrometry-based acetylomics demonstrated that HDAC8 deacetylated the histone acetyltransferase (HAT) EP300 leading to its enzymatic inactivation. This, in turn, led to an increased binding of EP300 to Jun-transcriptional sites and decreased binding to MITF-transcriptional sites. Increased expression of EP300 decreased invasion and increased the sensitivity of melanoma cells to multiple stresses while inhibition of EP300 function increased invasion and resistance to stress. We identified HDAC8 as a novel mediator of transcriptional co-factor inactivation and chromatin accessibility that increases MBM development.
Citation Format: Michael Emmons, Richard Bennett, Alberto Riva, Chao Zhang, Robert Macaulay, Daphne Dupéré-Richér, Bin Fang, John Koomen, Jiannong Li, Ann Chen, Edward Seto, Jonathan Licht, Keiran Smalley. HDAC8-mediated inhibition of EP300 drives a neural crest-like transcriptional state that increases melanoma brain metastasis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3606.
Abstract 3647: Anti-tumor actions of neutrophils are mediated via STAT5 inhibition
Authors: Rajgopal Sanjana , Alsamraae Massar , Costanzo-Garvey Diane , Cook Leah 
Published: April 2023

Abstract
The overall patient survival rate drops dramatically when localized prostate cancer (PCa) progresses to bone metastatic prostate cancer (BM-PCa). The treatment for BM-PCa is limited to palliative therapy, and it is currently incurable. Neutrophils are the most prevalent immune cell in the bone, and we have found that PCa enhances their recruitment and infiltration into the prostate tumor-bone microenvironment of patients with BM-PCa. Additionally, we observed that bone marrow neutrophils directly induce apoptosis of PCa cells both in vitro and in vivo and that this is mediated by the inhibition of STAT5, a transcription factor that promotes PCa progression. Moreover, STAT5 has also been found to contribute to the development of resistance to standard care androgen deprivation therapy. Neutrophils specifically target and kill only cells that express STAT5, as stable knockdown of STAT5 in BM-PCa cells makes them resistant to neutrophil-mediated cytotoxicity, while the overexpression of STAT5 in STAT5-negative PCa cells, which are generally resistant to killing by neutrophils, sensitizes them to neutrophil-mediated killing. Furthermore, transcriptomic analyses derived from the STAT5 knockdown and STAT5 overexpressing cells suggest that STAT5 expression in PCa induces pro-inflammatory signaling and that neutrophil-mediated cytotoxicity may be exerted via STAT5-induced IL-1 and/or IL-6. Preliminary data in our laboratory show that STAT5-induced production of IL-1 by PCa cells leads to their death by neutrophils, as knocking out the IL-1 receptor on neutrophils reduces their cytotoxic potential against STAT5-positive PCa cells. Interestingly, in addition to killing BM-PCa cells, we have demonstrated that bone marrow-derived neutrophils are also capable of killing pancreatic cancer cells. Further delineation of the role of neutrophils in STAT5 signaling in BM-PCa growth holds promise for enhancing neutrophil cytotoxicity in the bone which could lead to novel therapeutic options for bone metastatic prostate cancer.
Citation Format: Sanjana Rajgopal, Massar Alsamraae, Diane Costanzo-Garvey, Leah Cook. Anti-tumor actions of neutrophils are mediated via STAT5 inhibition. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3647.
Abstract 3648: MSU-42011, alone and in combination with selumetinib, reduces pERK levels in NF1 cancer cells and decreases CCL2 expression in THP-1 macrophages
Authors: Hung Pei-Yu , Lockwood Lizbeth , Liby Karen T. 
Published: April 2023

Abstract
Neurofibromatosis type 1 (NF1) is a common genetic disease that predisposes approximately 50% of affected individuals to develop plexiform neurofibromas (PNFs), which can progress to highly aggressive malignant peripheral nerve sheath tumors (MPNSTs) in approximately 10% of patients. NF1 is caused by mutations in the tumor suppressor gene NF1, which encodes for neurofibromin, a negative regulator of RAS activity. Selumetinib, a specific inhibitor of MEK1/2, is the only FDA-approved drug for NF1-associated PNFs. However, the anti-tumor effects of selumetinib are limited in MPNSTs and have dose-limiting side effects. Deficiency of the NF1 gene not only promotes tumorigenesis but also has broad effects on the immune cells and cytokine signaling driven by hyperactive RAS signaling. Because macrophages account for almost half of cells in NF1 lesions and their infiltration highly correlates with disease progression, we hypothesized that targeting tumor-promoting immune cells could be an alternative approach for NF1 treatment. The novel retinoid X receptor (RXR) agonist MSU-42011 reduces tumor growth in experimental Kras-driven cancers by decreasing pERK expression, reducing tumor-promoting immune cells like CD206+ macrophages and regulatory T cells, and increasing activated cytotoxic T cells. Here, we tested MSU-42011 and selumetinib, either alone or in combination, to evaluate their efficacy against NF1 cancer cells and macrophages using monoculture and conditioned media (CM) treatments. Treatment with 200 nM MSU-40211, 50 nM selumetinib, and the combination for 3 hours reduced pERK protein levels by approximately 40%, 70% and 90%, respectively vs. untreated controls. Treatment for 72 hours with selumetinib and the combination reduced the viability of PNF cells in a dose-dependent manner. Moreover, CM from human PNF cells increased monocyte chemoattractant CCL2 (C-C motif chemokine ligand 2) mRNA expression in human THP1 monocytes and THP1 macrophages differentiated by PMA. Notably, MSU-42011 and selumetinib alone similarly inhibited CCL2 mRNA expression by 25% in THP1 macrophages stimulated with CM from PNF cells, and the inhibition of CCL2 mRNA expression was enhanced to 50% with combination treatment. Taken together, our data suggest that MSU-42011 should be tested in relevant preclinical models of NF1.
Citation Format: Pei-Yu Hung, Lizbeth Lockwood, Karen T. Liby. MSU-42011, alone and in combination with selumetinib, reduces pERK levels in NF1 cancer cells and decreases CCL2 expression in THP-1 macrophages. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3648.
Abstract 3652: Circular RNAs repress interferon responses in the sarcoma cells and promote sarcoma growth by forging a pro-tumorigenic immune microenvironment
Authors: Guarnerio Jlenia 
Published: April 2023

Abstract
Circular RNAs (CircRNA) arise from events of non-conventional splicing in which the 3'-tail of an exon back-splices and joins the 5'-head of the upstream exon. Because of their structural conformation, these RNAs are incredibly stable in the cellular space, where they can regulate tumor-associated and anti-immunogenic pathways. Although circRNAs have been profiled in many tumors, their functional contribution to cancer progression is still poorly understood. In the current study, we profiled the most abundant circRNAs expressed in Soft-tissue sarcomas (STS) and characterized them functionally and mechanistically. Surgery and chemotherapy are the standard treatments for STS, but the 5-year survival rate is still below 20% for the advanced cases. Response to immunotherapies, such as immune checkpoint inhibitors, is also marginal for STS, likely because sarcoma cells are not sufficiently immunogenic to recruit a high volume of cytotoxic T cells. To implement discoveries on STS, we recently generated novel immunocompetent STS mouse models and characterized the sarcoma-elicited mechanisms to block immune-recruitment. Interestingly, we observed that two circRNAs, circCsnk1g3, and circAnkib1, promote sarcoma growth by shaping a pro-tumorigenic microenvironment, possibly due to their capabilities to regulate tumor-promoting elements extrinsic to the sarcoma cells. More specifically, we observed that circCsnk1g3 and circAnkib1 control the expression of interferon-related genes and pro-inflammatory factors in the sarcoma cells, thus directing immune cell recruitment into the tumor mass and hence their activation. Mechanistically, we observed that circRNAs might repress pro-inflammatory elements by buffering activation of the pathways mediated by RIG-I, the cytosolic viral RNA sensor. The current findings suggest that targeting specific circRNAs could augment the efficacy of sarcoma immune response to mainstay therapies.
Citation Format: Jlenia Guarnerio. Circular RNAs repress interferon responses in the sarcoma cells and promote sarcoma growth by forging a pro-tumorigenic immune microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3652.
Abstract 3671: Targeting SLC2A1 and SLC38A2-mediated metabolic shift in SMARCA4/A2-dual deficient cancer
Authors: Zhu Xianbing , Fu Zheng , Chen Shary , Ong Dionzie , Aceto Giulio , Ho Rebecca , Steinberger Jutta , Li Eunice , Huntsman David , Foulkes William , Huang Sidong , Wang Yemin 
Published: April 2023

Abstract
SMARCA4 (BRG1) and SMARCA2 (BRM) are the two paralogous ATPases of the SWI/SNF chromatin remodelling complexes. These two ATPases are frequently inactivated in cancers and cancer cells deficient in either of them have been shown to depend on the remaining counterpart for survival. Contrary to this paralog synthetic lethality, concomitant loss of SMARCA4 and SMARCA2 occurs in a subset of cancers that are often associated with very poor patient outcomes. Here, we uncover that dual loss of SMARCA4/A2 represses the expression of SLC2A1, encoding the glucose transporter GLUT1, which results in reduced glucose uptake and glycolysis accompanied with increased dependency on oxidative phosphorylation (OXPHOS); adapting to this, these SMARCA4/A2-dual deficient cells rely on elevated SLC38A2, an amino acid transporter, to increase glutamine import for fueling OXPHOS. Consequently, SMARCA4/A2-dual deficient cells and tumours are highly sensitive to inhibitors targeting OXPHOS or glutamine metabolism. Furthermore, supplementation of alanine, also imported by SLC38A2, restricts glutamine uptake through competition and selectively induces death in SMARCA4/2-dual deficient cancer cells. At a clinically relevant dose, alanine supplementation synergizes with OXPHOS inhibition or conventional chemotherapy eliciting marked antitumor activities in SMARCA4/A2-dual deficient cancer cell lines and patient-derived xenografts. Our findings reveal multiple druggable vulnerabilities of SMARCA4/A2-dual loss exploiting a GLUT1/SLC38A2-mediated metabolic shift. Particularly, unlike dietary deprivation approaches, alanine supplementation can be readily applied to current regimens for better treatment of these aggressive cancers. * Authors contributed equally# Co-corresponding
Citation Format: Xianbing Zhu, Zheng Fu, Shary Chen, Dionzie Ong, Giulio Aceto, Rebecca Ho, Jutta Steinberger, Eunice Li, David Huntsman, William Foulkes, Sidong Huang, Yemin Wang. Targeting SLC2A1 and SLC38A2-mediated metabolic shift in SMARCA4/A2-dual deficient cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3671.
Abstract 3675: Targeting the mevalonate pathway, a novel anti-ferroptosis pathway, in hepatocellular carcinoma (HCC) treatment
Authors: Chen Yiling , Lee Derek , Shuo Zhang Misty , Wing-Sum Cheu Jacinth , Chak-Lui Wong Carmen 
Published: April 2023

Abstract
Ferroptosis is a novel immunogenic and regulated cell death caused by iron-dependent lipid peroxidation. Glutathione peroxidase 4(GPX4)/glutathione and ferroptosis suppressor protein 1(FSP1)/Coenzyme Q10(CoQ10) are two major anti-ferroptosis systems that prevent lipid ROS-induced cell death. Our current study unprecedentedly uncovered that the Mevalonate pathway (MVA) protects HCC from ferroptosis by two parallel mechanisms: 1) by providing the lipophilic antioxidant CoQ10 for FSP1; 2) by generating isopentenyl pyrophosphate (IPP), a substrate for Selenocysteine (Sec)-tRNA modification for selenoprotein GPX4 translation. Selenoproteins are a class of proteins composed of selenocysteine, the 21st amino acid not found in the codon table. Selenocysteine is recoded by the stop codon UGA and synthesized on its tRNA. The Sec-tRNA incorporates Sec into selenoproteins such as GPX4. We showed that perturbation of the MVA pathway by genetic knockdown or pharmacologic inhibition repressed CoQ10 synthesis and the translation of selenoproteins, thereby leading to lipid-derived ROS and ferroptotic cell death. Furthermore, we showed that Mevalonate diphosphate decarboxylase (MVD), a MVA enzyme, was a transcriptional target of Nuclear Factor Erythroid 2- related factor 2 (NRF2), a master regulator of oxidative stress response. High expression of MVD was associated with poor prognosis in HCC. Strikingly, MVD inhibitor treatment profoundly suppressed HCC. Reduced tumor size and increased tumor-infiltrated effector T cells and macrophages were found in vivo. To conclude, our study has provided novel mechanistic insight about how NRF2/MVA pathway promotes HCC and suggested that MVD might be a good prognostic indicator and therapeutic target in human HCC.
Funding Support: RGC Postdoctoral Fellowship Scheme 2021/22 (Project #102010048)
Citation Format: Yiling Chen, Derek Lee, Misty Shuo Zhang, Jacinth Wing-Sum Cheu, Carmen Chak-Lui Wong. Targeting the mevalonate pathway, a novel anti-ferroptosis pathway, in hepatocellular carcinoma (HCC) treatment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3675.
Abstract 3685: Targeting a novel cell surface serine protease TMPRSS11B for lung cancer therapy
Authors: Sunil Hari Shankar , Updegraff Barrett , Zhu Jingfei , Evers Bret M. , Minna John D. , Deberardinis Ralph J. , Oliver Trudy G. , O'Donnell Kathryn A. 
Published: April 2023

Abstract
Lung cancer is the leading cause of cancer-related deaths worldwide. Patients have few therapeutic options, and disease progression is inevitable. Anti-PD-1/PD-L1 antibodies can induce potent anti-tumor immunity and have been approved as a first-line therapy for non-small cell lung cancer (NSCLC). However, only ~20% of all NSCLCs benefit from checkpoint blockade, underscoring the critical need for the development of new and innovative approaches to identify actionable therapeutic targets to treat NSCLC. We identified the Transmembrane Serine Protease TMPRSS11B as a novel gene that promotes the transformation of human bronchial epithelial cells in vitro and induces tumorigenesis in vivo (Updegraff et al., Cell Reports, 2018). Our data show that TMPRSS11B promotes solubilization of Basigin, an obligate chaperone of the lactate monocarboxylate transporters MCT1 and MCT4, and that TMPRSS11B interacts and co-localizes with Basigin and MCT4. Moreover, Basigin release mediated by TMPRSS11B enhances lactate export and glycolytic metabolism, thereby promoting tumorigenesis. This is of significant interest because TMPRSS11B is frequently overexpressed in human lung squamous cell cancers (LSCC) and high expression is associated with poor survival of NSCLC patients. Moreover, as a cell surface protein and enzyme, TMPRSS11B represents an exciting putative target for therapeutic intervention. Our new studies demonstrate that the catalytic activity of TMPRSS11B may be important for the interaction with Basigin and enhanced lactate export. We also evaluated the effect of Tmprss11b depletion in the KLN205 syngeneic LSCC mouse model. CRISPR/Cas9 knockout of Tmprss11b in KLN205 LSCC cells significantly reduced tumor burden in immunocompetent DBA/2 WT mice. Moreover, mass spectrometry analysis revealed TMPRSS11B-interacting proteins that may represent novel substrates of this enzyme. Current studies are focused on elucidating the molecular mechanisms through which TMPRSS11B promotes tumorigenesis and investigating the efficacy of TMPRSS11B inhibition in syngeneic and autochthonous mouse models of LSCC, where the effects on immune cell function will be assessed.
Citation Format: Hari Shankar Sunil, Barrett Updegraff, Jingfei Zhu, Bret M. Evers, John D. Minna, Ralph J. Deberardinis, Trudy G. Oliver, Kathryn A. O'Donnell. Targeting a novel cell surface serine protease TMPRSS11B for lung cancer therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3685.