bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB183: Network biology approach reveals multiple non-essential helper genes to target cancer cell lethality
Authors: Li Yongsheng , Sahni Nidhi , Yi S. Stephen 
Published: April 2023

Abstract
Understanding the determinants of human gene essentiality is critical for developing anticancer therapeutics. Here, we systematically analyzed the human essentialome from a network perspective. We found that essential genes are mostly context-specific and predicted synthetic lethal interactions based on analysis of context-specific essentiality in distinct genetic backgrounds. The predicted gene pairs are significantly overlapped with known synthetic lethality and further validated across more than 300 cancer cell lines. Moreover, analysis of synthetic lethal interactions among actionable genes helps prioritizing rational drug combinations. Surprisingly, genes in human essentialome (especially spliceosome, RNA transport and cell cycle genes) are enriched for cancer mutations with high functional impact and disease risks. Our network analyses suggest that protein interactome topology and neighborhood community integrated with gene expression, are highly predictive of gene essentiality. Thus, we devised network-based method (SYE-NET) to systematically prioritize the essentialome, which is further validated by functional screens in independent cell lines. Taken together, our study provides a holistic insight into molecular determinants for cell fate and implicates potential biomarkers for synthetic lethality and drug combinations in cancer, a critical step towards precision medicine.
Citation Format: Yongsheng Li, Nidhi Sahni, S. Stephen Yi. Network biology approach reveals multiple non-essential helper genes to target cancer cell lethality [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB183.
Abstract LB195: Immunotherapies that repolarize macrophages and CD4 T cells enhance the effect of chemotherapy in high-grade serous ovarian cancer
Authors: Elorbany Samar , Berlato Chiara , Carnevalli Larissa , Maniati Eleni , Wang Jun , Barry Simon , Manchanda Ranjit , Kzhyshkowska Julia , Balkwill Frances 
Published: April 2023

Abstract
We asked if single-cell RNA sequencing (scRNA-seq) analysis of tumor immune cells in high-grade serous ovarian cancer (HGSOC) would reveal ways to enhance effects of neo-adjuvant chemotherapy (NACT). Analysis of 64,097 immune cells from seven HGSOC omental metastases showed that positive effects of NACT on immune responses were counterbalanced by induction of immunosuppressive mechanisms, especially related to antigen presentation and Treg activity. We identified stabilin-1 (Clever-1) on macrophages and FOXP3 in Tregs as targets and validated actions of their inhibitors in vitro. ScRNA-seq analysis of 69,781 cells from chemotherapy-treated syngeneic mouse HGSOC tumors showed significant agreement with the patient results. Combinations of chemotherapy with anti-stabilin1 antibody and/or FOXP3 inhibitor (AZD8701), FOXP3i, significantly increased median survival of mice with established peritoneal disease. Long-term survivors (300 days+) were resistant to tumor rechallenge. Analysis of bulk RNA sequencing data from treated murine tumors confirmed our hypothesis and suggested potential mechanisms to explain the anti-tumor response seen in the murine models. Tumors treated with chemotherapy plus anti-stabilin1 antibody showed significant enrichment of anti-tumor macrophage signature and antigen presentation pathway compared to chemotherapy alone. Tumors treated with chemotherapy plus FOXP3i in combination with anti-stabilin1 antibody showed significant upregulation of antigen presentation, T cell activation and cytotoxicity and T helper 1 differentiation pathways. There was significant reduction in FOXP3 positive cells and significant increase of Tbet positive cells in FOXP3i treated murine tumors suggesting repolarization of naive T cells in the tumor microenvironment towards a more anti-tumor T helper phenotype. As there are early phase clinical trials of FOXP3 inhibitor and anti-stabilin1 (Clever-1) antibody in patients with advanced cancer, these results suggest ways of improving response to chemotherapy not only in HGSOC but in other cancers that are treated by NACT.
Citation Format: Samar Elorbany, Chiara Berlato, Larissa Carnevalli, Eleni Maniati, Jun Wang, Simon Barry, Ranjit Manchanda, Julia Kzhyshkowska, Frances Balkwill. Immunotherapies that repolarize macrophages and CD4 T cells enhance the effect of chemotherapy in high-grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB195.
Abstract LB224: STC-1010 a new therapeutic vaccine promotes tumor cell death
Authors: Bessede Alban , Alzeeb George , Tortorelli Corinne , Guegan Jean-Philippe , Rey Christophe , Chalus Lionel , Pinteur Benoit , Bravetti Paul , Italiano Antoine 
Published: April 2023

Abstract
BACKGROUND Colorectal cancer (CRC) is the third most commonly diagnosed cancer (10% of new cases in 2020) and the second leading cause of cancer-related death (9.4%) worldwide. CRC is often detected at late stages, with 38% of metastasis cases at diagnosis. This makes the development of efficient treatments crucial. Recent tremendous progress sets immunotherapy as a treatment option and opens multiple ways to address therapeutic challenges in CRC. Accordingly, we have previously developed therapeutic cancer vaccine based on stimulated tumor cells (STC) technology, that have already shown efficacy in immunocompetent mouse models. Same strategy was used in this study to generate the STC-1010 therapeutic vaccine, a novel human therapeutic CRC vaccine derivate from 3 human CRC cell lines, HCT116, HT29 and LOVO exposed to irradiation, heat shock, chemotherapy agents and haptenized.
METHODS We evaluate STC-1010 for its potential to favor an immune stimulatory response on human monocytes-derived dendritic cells (moDCs) from 2 different donors through i) a derived Mixed Lymphocyte Reaction (dMLR) assay, ii) the assessment of their cytokine profile, iii) the evaluation of their capacity to activate autologous CD8+ T cells and finally iv) to promote apoptosis of three CRC cell lines (HCT116, HT29 and LS-174T).
RESULTS We showed that STC-1010 induced IL-8 and IL-12 production, and reduced IL-10 during moDCs maturation. In addition, dendritic cells (DCs) exposed to STC-1010 during the maturation enhanced Interferon gamma (IFNg) production by CD8+ T cells (p=0,06 for donor 1 and p=0,0004 for donor 2) and amplified their anti-tumor activity, in combination with LPS/IFNg and CD40L. CD8+ T cells primed with STC-1010-treated DCs promote massive apoptosis of HCT116 and HT29 cells compared to the condition without STC-1010 (p&lt;0,001 for all donors). The benefit of STC-1010 was not detectable with LS174T cells characterized by a low expression of HLA-ABC and used as negative control in this study.
CONCLUSION Taken together, our results showed that Brenus STC-1010 human vaccine is an efficient strategy to educate immune system and promote the CRC cells death in vitro lending further support in favor of STC technology based on physical or chemical stimulation and haptenization to generate human cancer therapeutic vaccine.
Citation Format: Alban Bessede, George Alzeeb, Corinne Tortorelli, Jean-Philippe Guegan, Christophe Rey, Lionel Chalus, Benoit Pinteur, Paul Bravetti, Antoine Italiano. STC-1010 a new therapeutic vaccine promotes tumor cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB224.
Abstract LB228: Replication stress activates the DNA damage response and contributes to lapatinib resistance in HER2-positive SK-BR-3 cells
Authors: Kim So Hyeon , Min Ahrum , Kim Seongyeong , Kim Yu Jin , Ham Sujin , Hwang Hae Min , Lee Minyoung , Lee Changyun , Kim Jinyong , Lee Dae-Won , Lee Kyung-Hun , Im Seock-Ah 
Published: April 2023

Abstract
Background: Lapatinib is a small molecular inhibitor of HER2 and EGFR tyrosine kinases, which is approved for HER2-positive metastatic breast cancer as second line treatment. Significant proportion of patients experience disease progression due to acquired resistance. Activation of DNA damage repair (DDR) is one of the drug-resistance mechanism, however, the impact of DDR on sensitivity to lapatinib is unclear. Thus, lapatinib resistance mechanism was explored from the standpoint of DDR activation.
Methods: Acquired lapatinib-resistant (LR) SK-BR-3 cell lines were generated by continuously exposing to lapatinib, starting with 30 nmol/L and incrementally increasing to 10 μmol/L over 7 months. MTT assay was used to confirm lapatinib sensitivity. Cell cycle progression was analyzed using BrdU assay. Replication fork speed and stalled fork were analyzed by DNA fiber assay. Expression of the molecules was examined using Western blotting, immunofluorescence assay and transcriptome data analysis. DNA strand breaks and repair efficacy were evaluated through alkaline comet assay.
Results: G1/S phase transition was increased and early/late S phase population was increased in SK-BR-3 LR cells. Replication fork speed was accelerated and replication stress are elevated in SK-BR-3 LR cells. p-Chk1, Rad51, Rad51B, Rad51C and XRCC3 were upregulated in SK-BR-3 LR cells. After irradiation or treatment with ATR inhibitor, γ-H2AX was continuously increased in parental cells. In contrast, γ-H2AX did not change significantly in SK-BR-3 LR cells, and Chk1 was activated after irradiation or treatment with ATR inhibitor. Tail of comet disappeared at early time point in in SK-BR-3 LR cells after induction of DNA damage compared with parental cells. These results demonstrated that DDR was activated and DNA damage repair capacity was enhanced in LR cells.
Conclusion: Replication stress is elevated in SK-BR-3 LR cells. Up-regulation of molecules involved in the homologous recombination repair pathway was observed in SK-BR-3 LR cells. Moreover, DNA repair capacity was increased in SK-BR-3 LR cells. These data suggested that activation of DNA damage repair pathway caused by replication stress contributes to lapatinib resistance.
Citation Format: So Hyeon Kim, Ahrum Min, Seongyeong Kim, Yu Jin Kim, Sujin Ham, Hae Min Hwang, Minyoung Lee, Changyun Lee, Jinyong Kim, Dae-Won Lee, Kyung-Hun Lee, Seock-Ah Im. Replication stress activates the DNA damage response and contributes to lapatinib resistance in HER2-positive SK-BR-3 cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB228.
Abstract LB232: Targeting MEK activity in pancreatic tumors resistant to the combination of 5FU, irinotecan, and oxaliplatin promotes response to immunotherapy
Authors: Pham Thao D. , Metropulos Anastasia E. , Mubin Nida , Shah Dhavan N. , Spaulding Christina , Shields Mario , Bentrem David J. , Munshi Hidayatullah G. 
Published: April 2023

Abstract
FOLFIRINOX, a chemotherapy regimen consisting of 5FU, Leucovorin, Irinotecan, and Oxaliplatin, has been a first-line standard of care for patients with pancreatic adenocarcinoma (PDAC) for the last decade. However, low patient survival rates following treatment highlight frequent occurrence of resistance. Hence there is increasing interest in developing appropriate models of FOLFIRINOX resistance to identify subsequent line therapies. We have generated PDAC cell lines that exhibit acquired resistance to a combination of 5FU (F), Irinotecan (I), and Oxaliplatin (O) (FIO) in vitro. In mice, they form tumors that resemble FOLFIRINOX neoadjuvant-treated PDAC patients in regard to immune cell infiltration and a lack of response to single-agent anti-PD-1 therapy. We also show that similar to human PDAC tumors treated with neoadjuvant FOLFIRINOX, FIO-resistant tumors exhibit increased ERK1/2 phosphorylation. We demonstrate that the MEK inhibitor Trametinib reprograms the FIO-resistant tumors, but not the parental tumors, towards a less immunosuppressive tumor immune microenvironment. Importantly, Trametinib sensitizes FIO-resistant tumors to anti-PD-1 therapy, with the combination treatment significantly enhancing the cytolytic activity of the infiltrating CD8 + T cells and increasing tumor cell death. Taken together, our findings identify enhanced MEK/ERK signaling as a therapeutic target in FOLFIRINOX-resistant PDAC tumors, and suggest evaluating the combination of Trametinib and anti-PD-1 therapy in patients who progress on FOLFIRINOX.
Citation Format: Thao D. Pham, Anastasia E. Metropulos, Nida Mubin, Dhavan N. Shah, Christina Spaulding, Mario Shields, David J. Bentrem, Hidayatullah G. Munshi. Targeting MEK activity in pancreatic tumors resistant to the combination of 5FU, irinotecan, and oxaliplatin promotes response to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB232.
Abstract LB250: Multiplex screening of PBMCs with DNA barcoded peptide exchanged MHC trimers to identify peptide-specific paired VDJ TCRs at single cell level
Authors: Delcommenne Marc , Hou Xiaohong , Poluektov Yuri , Pan Wenjing , Sims Emily , Byrne-Steele Miranda 
Published: April 2023

Abstract
Elucidation of the paired TCR receptor-antigen synapse is important both for vaccine development and for targeted therapy. Linkage of T cell responses with specific antigenic peptides will not only guide the development of immunotherapies but also enable treatment response monitoring. Currently, single cell sequencing technology is well established, but the identification of specific pathogenic peptides and associated TCR in single cell level is still challenging. In most cases, ascertaining T cell responses to pathogenic peptides is based on the screening of pooled peptides that do not give the knowledge of corresponding responsive TCR to a particular peptide. We therefore developed a technique that uses DNA barcoded peptide exchanged MHC trimers to stain PBMCs. With this technique, multiple peptide-loaded trimers can be used to stain a PBMC sample in one test tube. Single cells positive for trimers are sorted, amplified, and sequenced together with the DNA barcode. Specific peptides can be identified with the DNA barcodes which are co-amplified with TCRs. Applying this technique, we screened one PBMC sample with several peptide-loaded trimers in one reaction. Utilizing the CDR3 identity of known clones against each of these peptides, we were able to demonstrate and validate that a multi-peptide screen using DNA barcodes is feasible. Further optimization is in progress to reduce background and to increase the multiplexing of barcoded peptide-trimers.
Citation Format: Marc Delcommenne, Xiaohong Hou, Yuri Poluektov, Wenjing Pan, Emily Sims, Miranda Byrne-Steele. Multiplex screening of PBMCs with DNA barcoded peptide exchanged MHC trimers to identify peptide-specific paired VDJ TCRs at single cell level [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB250.
Abstract LB253: Long-read single-cell sequencing of liver cancer
Authors: Luo Jian-Hua , Liu Silvia , Ren Bao-Guo , Yu Yan-Ping 
Published: April 2023

Abstract
The protein diversity of mammalian cells is determined by arrays of isoforms from genes. Protein mutation is essential in species evolution and cancer development. Accurate Long-read transcriptome sequencing at single-cell level is required to decipher the spectrum of protein expressions in mammalian organisms. In this report, we developed a synthetic long-read single-cell sequencing technology based on LOOPseq technique. We applied this technology to analyze 447 transcriptomes of hepatocellular carcinoma (HCC) and benign liver from an individual. Through Uniform Manifold Approximation and Projection (UMAP) analysis, we identified a panel of mutation mRNA isoforms highly specific to HCC cells. The evolution pathways that led to the hyper-mutation clusters in single human leukocyte antigen (HLA) molecules were identified. Novel fusion transcripts were detected. The combination of gene expressions, fusion gene transcripts, and mutation gene expressions significantly improved the classification of liver cancer cells versus benign hepatocytes. In conclusion, LOOPseq single-cell technology may hold promise to provide a new level of precision analysis on the mammalian transcriptome.
Citation Format: Jian-Hua Luo, Silvia Liu, Bao-Guo Ren, Yan-Ping Yu. Long-read single-cell sequencing of liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB253.
Abstract LB269: Inhibition Of C-C chemokine receptor 7 extends survival rate in murine model of T-cell acute lymphoblastic leukemia
Authors: Sanchez Anahi , Vazquez Aaron E. , Valenzuela Janet M. , Stanley Savannah , Bill Colin A. , Vines Charlotte M. 
Published: April 2023

Abstract
C-C Chemokine Receptor 7 (CCR7) expression in pediatric T-cell acute lymphoblastic leukemia (T-ALL) promotes entry of leukemic cells into the central nervous system (CNS), where the disease finds sanctuary from systemic chemotherapies. To confirm that Notch1 drives expression of CCR7, we modified the ROSA26-PRDM14 ([PRDI-BF1 (positive regulatory domain I-binding factor 1) and RIZ (retinoblastoma interacting zinc finger) homology domain containing 14]) MX-1 Cre inducible CD8+ T-ALL mouse model. This model, upon induction with polyI:C, expresses NOTCH1 downstream of PRDM14, and the T-ALL cells enter the CNS during leukemogenesis. We crossed these mice with ROSA26-Luc2 mice, which allows for tracking of T-ALL cells during disease progression. We questioned if these T-ALL cells expressed CCR7. We found that not only do the T-ALL cells express CCR7 and enter the CNS, but that a CCR7 antagonist, CCL198-83 administered during leukemogenesis doubles the mean survival of the CCL198-83 treated mice from 45 to 90 days. These studies provide a novel platform for a potential therapeutic that can be used to limit CNS entry and potentially recycling through the CNS.
Citation Format: Anahi Sanchez, Aaron E. Vazquez, Janet M. Valenzuela, Savannah Stanley, Colin A. Bill, Charlotte M. Vines. Inhibition Of C-C chemokine receptor 7 extends survival rate in murine model of T-cell acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB269.
Abstract LB270: LINGO2-microRNA cluster controls oral cancer stemness ability and cancer progression
Authors: Chang Wei-Min , Li Li-Jie , Lin Che-Hsuan , Hsiao Michael , Chang Peter Mu-Hsin 
Published: April 2023

Abstract
Cancer recurrence and metastasis are the primary reasons for treatment failure in late-stage oral cancer. Cancer stem cells are the root of cancer recurrence and metastasis. By using the microRNAome analysis of Taiwan OSCC cohort, we found miR-876-3p was highly correlated to OSCC recurrence. The precursor miR-876 promoted in vitro OSCC cell proliferation, migration, and cancer stemness and regulated several cancer stemness-relative genes such as NANOG, OCT4, and LIN28A expression. miR-876 and miR-873 are located in the second intron of the 5’-untransalation region (5’-UTR) at the alternative variant leucine-rich repeat and Ig domain containing 2 (LINGO2). Interestingly, only OSCC cells presented LINGO2 protein expression but did not show in primary oral keratinocytes (HOK). The unique CpG islands at the alternative transcription start site of LINGO2 hinted at crucial epigenetic regulation that controls LINGO2 activation. Silencing of LINGO2 expression reduced OSCC cell growth and cancer stemness abilities. LINGO2 expression was higher in OSCC tumor tissue than in adjacent normal tissue in both Taiwan and The Cancer Genome Atlas (TCGA) head and neck cancer cohorts. Moreover, LINGO2 also served as a poor prognostic marker in cancer patients' overall and recurrent free survival time. In summary, we found a novel LINGO2-microRNA cluster that regulates OSCC stemness and metastasis abilities. Those cancer specific expressions may provide a new therapy niche in OSCC cancer therapy.
Citation Format: Wei-Min Chang, Li-Jie Li, Che-Hsuan Lin, Michael Hsiao, Peter Mu-Hsin Chang. LINGO2-microRNA cluster controls oral cancer stemness ability and cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB270.