bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6087: Evaluation of intra-tumor heterogeneity by single-cell copy number profiling of circulating multiple myeloma cells using Shannon index
Authors: Ferrarini Alberto , Forcato Claudio , Monaco Valentina del , Terracciano Mario , Garonzi Marianna , Pellicano Massimiliano , Buson Genny , Fontana Francesca , Tononi Paola , Manaresi Nicolo 
Published: June 2022

Abstract
Tumors develop through an evolutionary process in which genomic lesions accumulate in different coexisting subclones leading to intra-tumor heterogeneity (ITH). ITH allows the tumor to adapt to microenvironments and to resist therapies and has been shown to be a prognostic marker. In this work we show the characterization of ITH in Multiple Myeloma (MM) at single cell resolution from a pool of Circulating Multiple Myeloma Cells (CMMCs) and we study the relationship between number of sampled cells and diversity detected.
Peripheral blood was collected from 3 patients affected by MM. Using CellSearch® system, blood was enriched for target CMMCs, with immuno-magnetic selection of CD138+, and immunofluorescently stained cells, positive for CD38-PE, DAPI and negative for CD45/CD19-APC, were enumerated. The samples were then analyzed and CMMCs were isolated with DEPArray platform. The DNA of each single cell (n=261) was amplified with Ampli1™ WGA kit and the WGA output was used for genome-wide single cell copy number alteration analysis with Ampli1 LowPass kit.
Copy number profiling revealed from 2 to 3 coexisting subclones per patient, with minor clones size going from 6.5% to 33%. ITH was assessed by determining the Shannon index, which showed a range of values from 0.44 (low diversity) to 1.01 (high diversity) depending on source sample. We evaluated the effect of number of cells/profiles on Shannon index by bootstrapping (200 times) a number of copy number profiles ranging from 2 to the total number of profiles available per patient. Results showed that the mean Shannon index almost reaches a plateau at 15-20 cells/profiles in the case of lower diversity samples and at about 30 cells/profiles for the highest diversity sample. Moreover, as few as 10 cells allowed to differentiate low vs. high diversity samples.
Cell enrichment and sorting by CellSearch and DEPArray platforms allow to quantify ITH at diversity level with high precision even from a limited number of initial single-cells and provide a promising method to objectively measure heterogeneity, as required in order to study its clinical implications.
Citation Format: Alberto Ferrarini, Claudio Forcato, Valentina del Monaco, Mario Terracciano, Marianna Garonzi, Massimiliano Pellicano, Genny Buson, Francesca Fontana, Paola Tononi, Nicolo Manaresi. Evaluation of intra-tumor heterogeneity by single-cell copy number profiling of circulating multiple myeloma cells using Shannon index [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 6087.
Abstract 6097: Ferroptosis resistance in epithelial populations of triple negative breast cancer is mediated by laminin 332 and integrin beta4
Authors: Karner Emmet R. , Goel Hira Lal , Mercurio Arthur M. 
Published: June 2022

Abstract
Ferroptosis is an iron dependent form of regulatory cell death caused by the accumulation of lipid peroxides that can be exploited as a therapeutic for carcinomas and possibly other cancers. However, some populations of carcinoma cells resist ferroptosis, especially those with an epithelial phenotype but the mechanisms that promote resistance are poorly understood. We discovered that ferroptosis resistance in triple-negative breast cancer cells (TNBC) with an epithelial phenotype is dependent on expression of the integrin β4 and its ligand laminin 332 (LM332). LM332 and the integrin β4 maintain an epithelial cell state by downregulation of the EMT factor ZEB1. We further demonstrate that repression of ZEB1 by integrin β4 and LM332 promotes YAP/TAZ-mediated transcription of the C2 subunit of LM332, activating a positive feedback loop. Lastly, we observed that disrupting the β4/LM332 signaling axis sensitizes epithelial TNBC cells to ferroptosis by inducing ZEB1 expression. Our findings reveal a novel role for the extracellular matrix in promoting ferroptosis resistance by sustaining an epithelial phenotype and they suggest potential therapeutic strategies for overcoming this resistance.
Citation Format: Emmet R. Karner, Hira Lal Goel, Arthur M. Mercurio. Ferroptosis resistance in epithelial populations of triple negative breast cancer is mediated by laminin 332 and integrin beta4 [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 6097.
Abstract 6137: Tumor-derived endothelin-1 recruits and activates fibroblasts to support tumor aggressiveness
Authors: Rio Danila Del , Caprara Valentina , Masi Ilenia , Spadaro Francesca , Giannitelli Sara , Rainer Alberto , Bagnato Anna , Rosanò Laura 
Published: June 2022

Abstract
The recruitment of fibroblasts to tumor and their activation to cancer-associated fibroblast (CAF) is an exploited strategy used by tumor to guide matrix remodeling, supporting cancer invasion and metastatic disease. CAFs are the major effectors of extracellular matrix (ECM) remodelling through secretion of collagens, cross-linking enzymes and proteases, and in turn engagement of integrins. Although several tumor cell-secreted factors have been identified in generating tumor-promoting stroma, there has been a great interest to define factors and associated molecular mechanisms involved in promoting CAF premetastatic function. Tumor-related endothelin-1 (ET-1) has an important role in the crosstalk between cancer and stromal cells supporting serous ovarian cancer (SOC) progression. By binding its receptors (ETAR and ETBR), ET-1 favours the recruitment of the protein β-arrestin-1 and the generation of signaling complexes regulating also cytoskeleton reorganization, thereby fine-tuning SOC cell invasion and metastasis. However, how the integration of ET-1 receptors might “educate” stroma to become permissive for invasion, supplying an altered ECM governing metastasis needs to be investigated. In this study, we identified endothelin-1 as a key factor in priming CAF conversion in SOC. We demonstrate that primary ovarian fibroblasts express ETA and ETB, along with β-arrestin1, and secrete ET-1; b) the autocrine and cancer-secreted ET-1 promotes fibroblast proliferation, and an increase in the expression of CAF markers (αSMA, vimentin and FAP), secretion of proinflammatory cytokines, collagen contraction ability and cell motility. Moreover, ET-1 induces activation of b1 integrin and downstream signaling. Mechanistically, ET1R/intb1 signaling allows ECM remodeling, either by promoting and invasive protrusion formation, invadosome, and collagen secretion. Importantly, therapeutical inhibition of ET-1 receptors with Ambrisentan and intβ1 with ATN-116 markedly reduced the ability of SOC cells to adhere in the intraperitoneal organs and to metastasize. Our findings support a model in which ET-1 educates the stromal fibroblasts to become permissive for tumor invasion and demonstrate for the time the significance of an ET-1-dependent integrin signaling in this process.
Citation Format: Danila Del Rio, Valentina Caprara, Ilenia Masi, Francesca Spadaro, Sara Giannitelli, Alberto Rainer, Anna Bagnato, Laura Rosanò. Tumor-derived endothelin-1 recruits and activates fibroblasts to support tumor aggressiveness [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 6137.
Abstract 6306: Genomic analysis markers of stemness in oral cancer progression
Authors: Unger Gretchen , Wuertz Beverly G. , Gaffney Patrick , Ondrey Frank G. 
Published: June 2022

Abstract
Introduction: In clinical cancer treatment there is an continuing effort to identify limited gene sets from high dimensional data to predict risk, treatment response, etc. Oral carcinogenesis is a multistep process of mutations, disordered growth, and the development of invasion. In the oral cancer milieu, inflammation and stemness has been demonstrated to be cooperative during carcinogenesis. We hypothesized that differences in inflammation, stemness, and EMT might distinguish lesion and adjacent normal mucosa in our RNA Seq data on preneoplastic lesions. Once candidate genes are identified they might be applied to other oral mucosal specimens to identify risk for malignancy development.
Materials and Methods: We collected lesion and adjacent normal mucosal tissues from 16 subjects with high risk leukoplakia and early oral cancer (T1N0 and T2N0). Sequencing libraries were generated using the Illumina Truseq Stranded mRNA library prep kit. Sequencing was performed on an Illumina Hiseq 3000 instrument with paired-end 75bp read and sequenced to an overall depth of 30 million reads per sample.
Results: After developing a biospecimen collection procedure that functions in the senior author’s clinic flow, we were able to isolate sequenceable total RNA from 100% of the specimens we collected. We identified several hundred differentially expressed genes between lesion and adjacent normal. With regard to stemness, inflammation, and EMT we multiple candidate genes that could be incorporated into a limited gene set for further studies. Aldehyde dehydrogenase family members were of particular interest in the stemness candidate genes, for example. ALD 1A1 and ALD 3B1, were significantly upregulated in lesion versus normal (P&lt; 0.02).
Conclusions: We conclude there are differentially expressed inflammatory, EMT, and stemness in oral preneoplastic specimens. We have identified multiple candidate genes that could be assembled into a limited gene panel (12-24 genes) for further studies of oral cancer risk in mucosal lesions
Citation Format: Gretchen Unger, Beverly G. Wuertz, Patrick Gaffney, Frank G. Ondrey. Genomic analysis markers of stemness in oral cancer progression [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 6306.
Abstract 6316: Minimizing ineffective treatment using an in vitro patient derived cancer cell screening platform for local oral squamous cell carcinoma patients in Pakistan
Authors: Zeb Sabaoon , Salim Khudeja , Zamir Hina , Shirdel Madina , Agha Momal , Qudrat Asma , Ahmad Sajjad , Faisal Muhammad , Munawar Muhammad Atif , Khattak Muhammad Mushtaq , Ahmad Mushtaq , Durrani Zubbair , Khan Faisal F. 
Published: June 2022

Abstract
According to GLOBOCAN’s 2020 report, in Pakistan, lip and oral cavity is the second most prevalent cancer with a low survival rate due to late detection and ineffective treatment regimens. To reduce ineffective treatment, this study aims to develop a cost-efficient in vitro drug screening platform using patient-derived primary cell lines to identify effective drugs against Oral Squamous Cell Carcinoma (OSCC) patients. Chemotherapeutic drugs to be screened were identified from NCCN guidelines as well as the local standard of care after oncologists from three tertiary care hospitals. These included 15 chemotherapeutic drugs along with 14 combinations. For this pilot study, tumor biopsies were collected, after relevant IRB approvals from consenting patients as part of the Oral Cancer Genomics Study project. Patient-derived primary cell lines were generated from tumor biopsies of 20 local OSCC patients recruited at Rehman Medical Institute and Hayatabad Medical Complex, Peshawar, Pakistan. Primary cell lines were derived from tumor biopsies within 30 minutes of resection and propagated till confluency using an optimized DMEM protocol. The readouts of our screen include cell viability, cell proliferation and cytotoxicity. This pilot screen presents a first of its kind dataset of the performance of drugs and drug combinations in primary cell lines derived from the tumors of local patients in Pakistan. This is not just an ideal platform to test novel and re-purposed drugs but also to develop into a service for personalized treatments, minimizing ineffective treatment and improving patient outcomes.
Citation Format: Sabaoon Zeb, Khudeja Salim, Hina Zamir, Madina Shirdel, Momal Agha, Asma Qudrat, Sajjad Ahmad, Muhammad Faisal, Muhammad Atif Munawar, Muhammad Mushtaq Khattak, Mushtaq Ahmad, Zubbair Durrani, Faisal F. Khan. Minimizing ineffective treatment using an in vitro patient derived cancer cell screening platform for local oral squamous cell carcinoma patients in Pakistan [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 6316.
Abstract 6317: Molecular subtyping in prostate cancer associate with outcomes to abiraterone and ipatasertib treatment from the phase III IPATential150 trial
Authors: Shi Zhen , Nowicka Malgorzata , de Bono Johann , Chi Kim N. , Sweeney Christopher , Sternberg Cora N. , Olmos David , Bracarda Sergio , Massard Christophe , Matsubara Nobuaki , Garcia Josep , Chen Geng , Wongchenko Matthew , Sandhu Shahneen K. 
Published: June 2022

Abstract
Prostate cancer is a heterogeneous disease and genomic subtyping offers an opportunity to better understand underlying disease biology. Here, we performed transcriptional profiling by RNA-Seq (n=582) and targeted genomic sequencing by FoundationONE CDx (n=743) from prostate cancer tumor specimens in the phase III IPATential150 trial of first-line ipatasertib (Ipat) plus abiraterone (Abi) in metastatic castration-resistant prostate cancer (N=1101). Unsupervised transcriptomic analysis of the 582 samples with RNA-Seq with Nonnegative Matrix Factorization (NMF) reveals four consensus subtypes. This includes an immune/cell cycle-high, an AR signature/cell cycle-high, a stroma program-enriched, and an ERG fusion-enriched subtype. Subgroups of patients with immune/cell cycle-high and AR signature/cell cycle-high tumors had the shortest radiographic progression-free survival (rPFS) and were characterized by high MYC and cell cycle-related gene signatures. Patients with AR signature/cell cycle-high tumors showed the greatest increase in rPFS with Ipat + Abi vs. Placebo (Pbo) + Abi (HR = 0.58).
Cluster n Enriched processes Median rPFS (Pbo + Abi) (months, 95% CI) Median rPFS (Ipat + Abi) (months, 95% CI) HR (95% CI) NMF1 84 Immune processes, metabolism, cell cycle 10.3 (8.3 - 12.7) 13.9 (10.9 - 16.4) 0.77 (0.47 - 1.28) NMF2 165 Androgen response signature, cell cycle, MYC signature 11.9 (8.8 - 16.5) 20.9 (16.4 - NA) 0.58 (0.38 - 0.90) NMF3 156 Fibroblast, Wnt, Notch, Hedgehog, TGFb 20.0 (16.4 - NA) 22.3 (15.6 - 24.9) 0.96 (0.59 - 1.56) NMF4 177 ERG fusion 18.4 (13.8 - 23.8) 24.7 (16.2 - NA) 0.78 (0.50 - 1.20)
Citation Format: Zhen Shi, Malgorzata Nowicka, Johann de Bono, Kim N. Chi, Christopher Sweeney, Cora N. Sternberg, David Olmos, Sergio Bracarda, Christophe Massard, Nobuaki Matsubara, Josep Garcia, Geng Chen, Matthew Wongchenko, Shahneen K. Sandhu. Molecular subtyping in prostate cancer associate with outcomes to abiraterone and ipatasertib treatment from the phase III IPATential150 trial [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 6317.
Abstract 6326: Reshaping immune lung populations to inhibit pulmonary fibrosis and cancer by activation of purinergic receptor P2RX7
Authors: Janho dit Hreich Serena , Ghinet Alina , Vouret-Craviari Valérie 
Published: June 2022

Abstract
Lung cancer is the most prevalent cancer worldwide with high mortality rate despite recent advances in therapies. Not only is fibrosis a major hallmark of lung cancer, it is also a risk factor for lung cancer development (mainly non-small cell lung cancer). In fact, patients diagnosed with idiopathic pulmonary fibrosis (IPF) are very likely to develop lung cancer. However, treatment and outcome of lung cancer patients with IPF is different than those without IPF despite their common genetic, molecular, cellular and immune properties. New therapeutic strategies are needed for improving outcome of patients bearing both diseases. To address this, we proposed that boosting the activation of P2RX7 with a positive modulator (HEI3090) would be a novel strategy to fight lung cancer. P2RX7 is a purinergic receptor activated by high extracellular ATP levels found in inflamed and tumor sites. It has anti-tumor and immunomodulatory properties by its ability to induce cell death and the release of IL-1b and IL-18. We showed previously that HEI3090 inhibits lung tumor growth by triggering an anti-tumor immune response that relies on IL-18. Indeed, HEI3090-release of IL-18 enhanced the cytotoxicity of NK cells and favored a Th1-biased immune response. Given that lung fibrosis is partly driven by inflammation with a dysregulated Th1/Th2/Th17 ratios and given the ability of HEI3090 to favor a Th1-biased immune response, we wondered if HEI3090 was able to inhibit fibrosis. To do so, we used the bleomycin mouse model where we show that activation of P2RX7 with HEI3090 inhibits lung fibrosis. HEI3090 targets P2RX7-expressing immune cells, decreases lung inflammation and favors an anti-fibrotic immune signature. Indeed, HEI3090 promotes the production of IFN-g by T cells and decreases pro-fibrotic IL-17A release by Th17 cells. Moreover, production of TGF-b, the key cytokine driving fibrosis, was greatly reduced in immune cells in HEI3090-treated mice. The antifibrotic effect of HEI3090 seems to rely on an increase of IL-18, known to induce the production of IFN-g by T cells. Overall, we show that reshaping lung immune phenotype by activation of P2RX7 is a promising strategy in lung fibrosis. HEI3090’s effect on cancer-related fibrosis is ongoing on a Kras mouse model. We highlight a new therapeutic strategy for patients with IPF that would ameliorate treatment and outcome of patients with both lung cancer and fibrosis
Citation Format: Serena Janho dit Hreich, Alina Ghinet, Valérie Vouret-Craviari. Reshaping immune lung populations to inhibit pulmonary fibrosis and cancer by activation of purinergic receptor P2RX7 [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 6326.
Abstract 6341: ImaGene: A robust AI-based software platform for tumor radiogenomic evaluation and reporting
Authors: Sukhadia Shrey S. , Tyagi Aayush , Venkatraman Vivek , Mukherjee Pritam , A.P. Prathosh , Divate Mayur , Gevaert Olivier , Nagaraj Shivashankar H. 
Published: June 2022

Abstract
The field of radiomics has undergone several advancements in approaches to uncovering hidden quantitative features from tumor imaging data for use in guiding clinical decision-making for cancer patients. Radiographic imaging techniques provide insight into the imaging features of tumor regions of interest (ROIs), while immunohistochemistry and sequencing techniques performed on biopsy samples yield omics data. These imaging and omics feature data can then be correlated and modeled using artificial intelligence (AI) techniques to highlight notable associations between tumor genotype and phenotype. Currently, however, the radiogenomics field lacks a unified and robust software platform capable of algorithmically analyzing imaging and omics features using modifiable parameters, detecting significant relationships among these features, and subjecting them to AI-based analysis. To address this gap, we developed ImaGene, a robust AI-based platform that uses omics and imaging features as inputs for different tumor types, performs statistical analyses of the correlations between these data types, and constructs AI models based upon significantly correlated features. It has several modifiable configuration parameters that provide users with complete control over their experiments. For each run, ImaGene produces comprehensive reports that can contribute to the construction of a novel radiogenomic knowledge base, in addition to enabling the deployment and sharing of AI models. To demonstrate the utility of ImaGene, we acquired imaging and omics datasets pertaining to Invasive Breast Cancer (IBC) and Head and Neck Squamous Cell Carcinoma (HNSCC) from public databases and analyzed them with this platform using specific parameters. In both cases, we uncovered significant associations between several imaging features and 11 genes: CRABP1, VRTN, SMTNL2, FABP1, HAND2, HAS1, C4BPA, FAM163A, DSG1, SMTNL2 and KCNJ16 for IBC, and 10 genes: CEACAM6, IGLL1, SERPINA1, NANOG, OCA2, PRLR, ACSM2B, CYP11B1, and VPREB1 for HNSCC. Overall, our software platform is capable of identifying, analyzing, and correlating important features from tumor scans, thereby providing researchers with a reliable and accurate tool for their radiogenomics experiments. We anticipate that ImaGene will become the gold standard for tumor analyses in the field of radiogenomics owing to its ease of use, flexibility, and reproducibility.
Citation Format: Shrey S. Sukhadia, Aayush Tyagi, Vivek Venkatraman, Pritam Mukherjee, Prathosh A.P., Mayur Divate, Olivier Gevaert, Shivashankar H. Nagaraj. ImaGene: A robust AI-based software platform for tumor radiogenomic evaluation and reporting [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 6341.