bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6029: Multi-omic landscape of squamous cell lung cancer
Authors: Stewart Paul , Lui Ashley , Welsh Eric , Ercan Dalia , Rubio Vanessa , Ackerman Hayley , Li Guohui , Fang Bin , Eschrich Steven , Koomen John , Flores Elsa , Haura Eric , DeNicola Gina 
Published: April 2023

Abstract
Patients with squamous cell lung cancer (SCC) have high unmet medical need. Knowledge of these tumors is limited, and a lack of targetable genomic drivers means patients have few treatment options. To provide a detailed analysis on the influence of genomic alterations to proteome-level changes in SCC, we previously integrated DNA copy number, somatic mutations, RNA-sequencing, and expression proteomics in a cohort of 108 SCC patients. A major finding was identification of three proteomic subtypes, two of which made up the majority (87%) of tumors: the “Inflamed” subtype was enriched for B-cell rich tertiary lymphoid structures (TLS), and the “Redox” subtype was enriched for redox pathways and NFE2L2/KEAP1 alterations but had significantly less immune infiltration. We hypothesized these proteomic subtypes would give rise to distinct metabolic signatures. Therefore, we performed untargeted metabolomics on 87 tumors from the same cohort using chromatographic separation on a HILIC column, followed by analysis on a Q Exactive HF mass spectrometer. This analysis yielded 7,344 features corresponding to 7,072 unannotated metabolites and 272 identified metabolites. Glutathione, a key redox metabolite, was anticorrelated with immune score (R = -0.44, padj = 0.004) calculated from our transcriptomic data with the ESTIMATE algorithm, and glutathione was elevated in the Redox proteomic subtype (0.58 log2 ratio, padj = 9.87E-04). Consensus clustering was next used to identify novel metabolomic subtypes of SCC. Surprisingly, none of the five metabolomic subtypes we identified corresponded to proteomic subtype or NFE2L2/KEAP1 alteration (Fisher’s Exact test p-values &gt; 0.05). The fifth subtype had 332 metabolites (26 identified) differentially expressed (&gt; 1.5 fold-change, padj &lt; 0.05) with ascorbate and aldarate metabolism as the top enriched pathway (padj = 3.36E-04). Interestingly, this fifth metabolomic subtype had significantly higher DNp63-alpha (p = 2.40E-05), a primary transcript of delta-N p63 that is known to promote non-small cell lung cancer. Ongoing integrative analyses across omic types will determine how p53, p63, and p73 transcripts influence these metabolomic subtypes, how these transcripts relate to the poor immune infiltration in some SCC tumors, and if these transcripts relate to novel metabolic vulnerabilities in SCC.
Citation Format: Paul Stewart, Ashley Lui, Eric Welsh, Dalia Ercan, Vanessa Rubio, Hayley Ackerman, Guohui Li, Bin Fang, Steven Eschrich, John Koomen, Elsa Flores, Eric Haura, Gina DeNicola. Multi-omic landscape of squamous cell lung 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 6029.
Abstract 6043: Manipulation of mitochondrial metabolism, through SIRT3 agonists, in a novel immunoreactive melanoma organoids model
Authors: El-derby Azza M. , Wajih Nadeem , Arbiser Jack , Votanopoulos Konstantinous , Soker Shay 
Published: April 2023

Abstract
The interplay between tumor cell metabolism and immune cells in the tumor microenvironment has emerged as a determinant factor in cancer progression and treatment. Sirtuin 3 (SIRT3) is a mitochondrial deacetylase that modulates ROS levels and governs many enzymes that regulate mitochondrial metabolism and homeostasis. SIRT3 has a dual role in cancer; it is regarded as an oncogene and tumor suppressor gene simultaneously. It has tumor-promoting action via keeping ROS levels low and favoring cell proliferation; on the contrary, it can trigger cell death under stress conditions by modulating tumor cell glycolysis. Recent data suggest a role for SIRT3 in cancer immunology with PD-L1 levels are found to be inversely associated with SIRT3 level in cervical cancer, and CD8+ T cells from SIRT3 knockout donor mice exhibited low GVHD in recipients. In this study, we explored the potential role of SIRT3 agonists in sensitizing the immunoreactivity of melanoma cells in a novel immunoreactive melanoma organoids model. We used the B16-F10 melanoma cell line spheroids to determine the effects of SIRT3 agonists on cellular viability, using an ATP assay. Validation of SIRT3 expression was determined via Western blot. Non-toxic amounts of SIRT3 agonists were also applied to melanoma organoids prepared from patient-derived metastatic melanoma from a lymph node. Preliminary results revealed a significant decrease in the viability of the organoids treated with R-propranolol (20µM) and Imipramine blue (0.25µM) agonists. We further investigated the effect of SIRT3 agonists R-propranolol and Imipramine blue on immunotherapy targeting PD-1, Pembrolizumab (100 nM) and Nivolumab (100 nM), and CTLA-4 inhibitor Ipilimumab (100 nM). We found a limited effect of Pembrolizumab and Nivolumab. Anti-tumor cytotoxicity was markedly increased in combination of Imipramine blue with Pembrolizumab and R-propranolol with Nivolumab. We propose that these effects are mediated through the activation of the endogenous immune cells and/or via the regulation of the PD-L1 and NKD2 ligand expression levels in the melanoma cells to become more sensitized to immune cells. Further studies will aim to validate these results in immunoreactive organoids from both mice and human patients. Our studies will shed light on the immune and metabolic axes and the use of specific agonists to develop new immune therapy treatment strategies for melanoma.
Citation Format: Azza M. El-derby, Nadeem Wajih, Jack Arbiser, Konstantinous Votanopoulos, Shay Soker. Manipulation of mitochondrial metabolism, through SIRT3 agonists, in a novel immunoreactive melanoma organoids model. [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 6043.
Abstract 6051: Dissecting unique metabolic vulnerabilities in triple-negative breast cancer metastasis
Authors: Ramchandani Divya , Yoffe Liron , Singh Arshdeep , Vahdat Linda , Mittal Vivek 
Published: April 2023

Abstract
Introduction. Triple-negative breast cancer (TNBC) exhibits the worst outcome due to an aggressive clinical course, high rates of metastasis, and therapeutic resistance. Lack of effective FDA approved anti-metastatic targeted therapies has generated an unmet medical need for developing effective novel treatments. Targeting metastatic seeding and colonization remains a therapeutic challenge. Only recently, attention has been drawn to the idea that cancer cells selectively and dynamically adapt their metabolism along the changing microenvironments of the metastatic cascade. However, the precise nature of the metabolic reprograming in vivo is poorly understood and constitutes a major barrier in formulating a rationally designed therapeutic approach. Using a genetic lineage tracing approach, we identified a discrete subpopulation of highly metastatic SOX2/OCT4+ cells within primary tumors that exhibit enhanced invasion and metastasis, increased self-renewal, higher chromosomal instability, and marked resistance to chemotherapy. We posited that this lineage tracing system may allow assessment of precise metabolic alterations as a function of tumor progression directly in vivo.
Methods and data. Transcriptomic analysis of sorted cellular fractions from progressing primary TNBC tumor identified metabolic heterogeneities between metastatic SOX2/OCT4+ and the SOX2/OCT4- counterparts. SOX2/OCT4+ metastatic cells exhibited elevated levels of mitochondrial respiration (OXPHOS) and fatty acid (FA) metabolism; a finding supported by proteomic analysis. Using a combination of CRISPR knockout of key pathway genes, seahorse metabolic flux analysis, metabolomics, and stable isotope tracing, we provide evidence for increased dependence of the metastatic SOX2/OCT4+ population on these unique metabolic adaptions. Importantly, we have identified upstream regulators of these pathways and demonstrate impact of both genetic and pharmacological inhibition of the metabolic regulatory networks on metastasis in vivo.
Conclusion. By identifying metabolic adaptations unique to the metastatic compartment of the primary tumor, we provide evidence for using clinical grade pharmacological inhibitors including metformin, tetrathiomolybdate and FA pathway inhibitors like TVB-2640 and BMS-303141, as an anti-metastatic approach in TNBC. This knowledge of metabolic remodeling could therefore be employed as a next-generation therapeutic approach for high-risk TNBC patients.
Citation Format: Divya Ramchandani, Liron Yoffe, Arshdeep Singh, Linda Vahdat, Vivek Mittal. Dissecting unique metabolic vulnerabilities in triple-negative breast cancer 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 6051.
Abstract 6053: Sulfation is required for prostate cancer xenograft tumor formation but is dispensable for cell viabilityin vitro
Authors: Chen Ko-Chien , Liu Yonhong , Lin Chenchu , Yen Er-Yen (Nick) , Citron Francesca , Ma Xingdi , Lin Tan , Lorenzi Philip , Muller Florian , DePinho Ronald 
Published: April 2023

Abstract
Sulfation of proteins, carbohydrates, lipids, and xenobiotics is an essential post-translational modification (PTM) process thought to play critical roles in diverse biological processes ranging from detoxification, cell signaling, and extracellular matrix architecture, to immune modulation. Sulfation is accomplished by the universal sulfate donor, PAPS (3'-Phosphoadenosine-5'-phosphosulfate), which is synthesized by bifunctional enzymes PAPSS1 and PAPSS2 (PAPS synthases). The PAPSS2 gene situates near PTEN and is frequently deleted with PTEN across cancer types. Approximately 20% of prostate cancer patients exhibit loss of PTEN, and ~50% of these cases also sustain a loss of PAPSS2. However, the loss of PAPSS2 appears to be tolerated and possibly compensated by its functionally redundant paralogue, PAPSS1, located on chromosome 4q24. The functional redundancy between PAPSS1 and PAPSS2 suggests that these two genes may be collateral lethality pair provided that sulfation is essential for cancer cell viability. Thus, we hypothesize that targeting PAPSS1 in PTEN/PAPSS2-null prostate cancer can generate cancer-specific vulnerabilities while leaving normal cells undisturbed. To assess this possibility, knockdown and knockout of PAPSS1 in cell lines of PAPSS2-null and PAPSS2-wildtype background were generated to characterize cell viability in vitro and tumor formation in vivo. PAPS and APS, an intermediary product of the sulfation pathway, are measured to verify that no alternative pathways for sulfate donors exist and that the co-extinction of PAPSS1/2 eliminates all avenues of generating sulfate donors. Combined extinction of PAPSS1/2 across multiple cancer cell lines was shown to be tolerated in vitro, and recurrent changes in morphology were observed. Loss of sulfation verified by the disappearance of sulfotyrosine and mass spectrometry measurements of PAPS and APS are pending. Our In vitro results surprisingly indicate that a major PTM, like sulfation is entirely dispensable for cancer cell viability under normal culture conditions. However, PAPSS1/2-null cell lines demonstrated a profound delay in tumor formation and prolonged survival, suggesting that sulfation may be required for stromal and innate immune modulation.
Citation Format: Ko-Chien Chen, Yonhong Liu, Chenchu Lin, Er-Yen (Nick) Yen, Francesca Citron, Xingdi Ma, Tan Lin, Philip Lorenzi, Florian Muller, Ronald DePinho. Sulfation is required for prostate cancer xenograft tumor formation but is dispensable for cell viabilityin vitro [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 6053.
Abstract 606: Cis-B7:CD28 interactions at invaginated synaptic membranes activate CD28 and promote T cell function
Authors: Zhao Yunlong , Caron Christine , Chan Ya-Yuan , Lee Calvin K. , Xu Xiaozheng , Bui Jack D. , Hui Enfu 
Published: April 2023

Abstract
Absence of adequate CD28 costimulation is a common feature of dysfunctional T cells in cancer. However, although augmentation of CD28 signaling is well known to be essential for restoring dysfunctional T cell immune responses upon immune checkpoint blockade treatment, it is unclear how CD28 in tumor-infiltrated T cells is activated in the absence of corresponding ligands on cancer. In current dogma, the T cell CD28 can be activated in trans by CD80 (B7-1) or CD86 (B7-2) expressed on professional antigen presenting cells (APCs) enriched in secondary lymphoid organs. Notably, besides professional APCs, B7 ligands are also displayed by T cells, but their functions are unclear. Here we report that B7 ligands expressed on T cells interact with CD28 in cis at membrane invaginations of the immunological synapse, as a result of phosphoinositide-3-kinase (PI3K) mediated membrane remodeling. Cis-B7:CD28 interactions triggered CD28 signaling through protein-kinase-C-theta (PKCθ) and promoted T cell survival, migration and cytokine production. In a B7 deficient tumor model grafted with primed CD8+ T cells, blockade of T cell intrinsic B7:CD28 interactions accelerated tumor growth and decreased intratumoral T cells. Thus, B7 ligands on T cells can evoke cell autonomous CD28 costimulation in cis in peripheral tissues, suggesting cis-signaling as a general mechanism for boosting T cell functionality.
Citation Format: Yunlong Zhao, Christine Caron, Ya-Yuan Chan, Calvin K. Lee, Xiaozheng Xu, Jack D. Bui, Enfu Hui. Cis-B7:CD28 interactions at invaginated synaptic membranes activate CD28 and promote T cell function [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 606.
Abstract 61: PRDM16 is key for promoting bone metastatic prostate cancer cell survival during entry into dormancy
Authors: Nasr Mostafa , Li Tao , Bishop Ryan T. , Lynch Conor C. 
Published: April 2023

Abstract
Recurrent metastatic prostate cancer (PC) typically manifests in the skeleton. Despite our knowledge that DTCs give rise to incurable bone metastatic PC, the molecular mechanisms underpinning their entry into dormancy and exit, remain under-investigated. To address this, we developed a novel in vitro model of PC dormancy as determined by increased entry into G0/G1 state (flowcytometry) and increased p38/ERK activity ratio & p27 (immunoblotting). Interestingly, we also observed dormancy entry resulted in the formation of clusters that remained dormant for long periods (21 days) and could be reawakened via serum addition. RNASeq and bioinformatic analysis of control vs. dormant cells revealed PRDM16 to be significantly elevated during entry into dormancy across mouse (RM1) and human cell lines (LAPC4, 22RV1). In vitro, we observed that genetic silencing of PRDM16 leads to a significant reduction in the ability of PC cells to enter dormancy. Analyses show that PRDM16 increases the expression of anti-apoptotic proteins including BCL-2 while inhibiting pro-apoptotic proteins such as BIM and NOXA. Our preliminary data shows that PRDM16 expression in CRPC cells can be induced by BMP7 and conversely decreased by the BMP signaling antagonist, noggin, factors with known critical roles in regulating bone homeostasis. In vivo, we used intrailiac-artery technique to deliver actively growing RM1 cells or dormant RM1 clusters (D-RM1) to the hind limbs (n = 8) of syngeneic mice (C57BL/6). Bioluminescence shows that D-RM1 remains dormant for more than 30 days. Subsequent histological analyses show that D-RM1 home preferentially to the endosteal niche where, compared to RM1 controls, they remain largely negative for ki-67 and cleaved caspase 3 and exhibit high expression of PRDM16. In conclusion, our data points to PRDM16 as a key regulator of survival pathways during PC entry into dormancy.
Citation Format: Mostafa Nasr, Tao Li, Ryan T. Bishop, Conor C. Lynch. PRDM16 is key for promoting bone metastatic prostate cancer cell survival during entry into dormancy [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 61.
Abstract 6101: PUM3 is a novel R-loop regulator and is essential for efficient DNA damage repair
Authors: Lin Chenyu , Ouyang Jian , Wine Robert , Qiu Chen , Williams Jason , Hall Traci M. , Zou Lee , Miles Wayne 
Published: April 2023

Abstract
R-loops have important roles in regulating transcription and genome integrity. To identify novel proteins that function to modulate DNA damage repair, we screened a library of CRISPR-engineered RNA binding protein knock-out cells. From this analysis, we found that a poorly characterized protein, PUM3, is important DNA damage repair and that PUM3-deficient cells were very sensitive the chemotoxic agents. We show that under normal conditions, PUM3 is localized to the nucleolus and nucleus, where it binds to R-loops and modulates transcription. In this setting, PUM3 functions to suppress/resolve R-loops and that PUM3-/- cells have elevated R-loop levels. Following DNA damage, PUM3 is rapidly re-localized from the nucleolus to sites of DNA damage in the nucleus by members of the DDX/DHX family of RNA-helicases. Using small molecule inhibitors and quantitative assays, we find that PUM3 functions in homologous recombination (HR) mediated DNA repair and that PUM3-/- cells have significantly reduced HR-efficiency. PUM3 function at sites of DNA breaks are not affected by transcription or R-loops, implicating PUM3 as functioning after DNA resection during DNA repair. Analysis of TCGA patient data shows that PUM3 levels correlate with Cisplatin resistance and patient outcome. Collectively, our data shows that PUM3 is a previously unknown regulator of R-loops and DNA damage repair that has an important role in chemotherapy sensitivity in cancer patients.
Citation Format: Chenyu Lin, Jian Ouyang, Robert Wine, Chen Qiu, Jason Williams, Traci M. Hall, Lee Zou, Wayne Miles. PUM3 is a novel R-loop regulator and is essential for efficient DNA damage repair [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 6101.
Abstract 6105: Unravelling the mechanistic basis of chromoplexy, a mutational process driving early cancer genome evolution
Authors: Serbyn Nataliia , Smit Myrthe M. , Gummalla Vimathi S. , Brunette Gregory J. , Pellman David S. 
Published: April 2023

Abstract
Genome evolution can happen gradually or via bursts of rearrangements. Chromoplexy is an example of a process driving rapid genome evolution. This mutational signature is detected in ~18% of human cancers (PCAWG Consortium, 2020) and is frequently observed in prostate adenocarcinoma, lymphoid malignancies, and thyroid adenocarcinoma. Chromoplexy is inferred to happen as one catastrophic event that generates copy-neutral chains of translocations involving multiple chromosomes (Baca et al., 2013). Existing studies of chromoplexy monitor the outcome of massive cancer genome reorganization, thus early molecular events leading to catastrophic chromosome rearrangements remain elusive. In this work, we aimed to recapitulate molecular mechanisms underlying chromoplexy. For this, we set out to establish a cell line model and use fluorescence-based reporter systems to enrich for and allow isolation of cells containing signatures of chromoplexy. We additionally address whether colocalization of multiple double-strand breaks, for example in transcription hubs or abnormal nuclear structures, might stimulate chained inter- and intra- chromosomal translocations typical for chromoplexy. If successful, this work will provide a mechanistic understanding of an important mutational process driving rapid genome evolution in cancer, congenital disease, and potentially organismal evolution.
Citation Format: Nataliia Serbyn, Myrthe M. Smit, Vimathi S. Gummalla, Gregory J. Brunette, David S. Pellman. Unravelling the mechanistic basis of chromoplexy, a mutational process driving early cancer genome evolution. [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 6105.