bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1586: CCL18 signaling from breast tumor-associated macrophages fosters the activation of fibroblasts into a chemoresistance-inducing phenotype
Authors: Zhang Xiaoqian , Chen Jianing , Su Shicheng , Song Erwei 
Published: September 2020

Abstract
Carcinoma-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in tumor microenvironment critically involved in cancer progression. Our recent study identified a specific CAFs subset by two cell-surface molecules, CD10 and GPR77. We proved that CD10+GPR77+ CAFs could promote tumor formation and chemoresistance by providing a survival niche for cancer stem cells (CSCs). However, their origin and underlying activating initiation mechanism are unclear. Tumor-associated macrophages (TAMs) are the most abundant immune-related stromal cells and the important source of inflammatory cytokine. Here, we demonstrated that CCL18 secreted by TAMs could induces the activation of normal breast fibroblasts into a CD10+GPR77+ CAFs phenotype, which are not only resistant to chemotherapy themselves, but also can induce chemoresistance in cancer cells by abundantly producing IL-8 and IL-6 and enriching the population of cancer stem cells. In conclusion, our studies have identified an inflammatory signaling network in the interaction of different kind of stroma cells in tumor microenvironment and highlighted its potential values as predictive markers and therapeutic targets to abrogate tumor formation and improve chemotherapeutic efficacy.
Citation Format: Xiaoqian Zhang, Jianing Chen, Shicheng Su, Erwei Song. CCL18 signaling from breast tumor-associated macrophages fosters the activation of fibroblasts into a chemoresistance-inducing phenotype [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1586.
Abstract 1597: The landscape of PD1-PD-L1 axis in the context of immune cells: Tumors versus stromal compartments
Authors: Lin Xiaoqian , Sulaiman Raed , Aske Jennifer C. , Meyer Paul , RojasEspaillat Luis , Starks David , De Pradip , Dey Nandini 
Published: September 2020

Abstract
Introduction: Immune response, tolerance, suppression, and resistance are the result of a complex dynamic interaction comprising PD1-PD-L1 axis in the context of immune cells (ICs) involving tumor cells, and anti/pro-tumor immune-cells of the stromal compartment.
Aim: Here we present the landscape of PD1-PD-L1 axis in the context of CD3, CD4, CD8, PD1, FOXP3, and IL12RB2 positive ICs in the tumor (T) and the tumor-adjacent normal (TAN) tissues from patients with ovarian cancers (OC), and lung cancers (LC).
Methods: The study was approved by Avera IRB. Surgically resected paired T and TAN tissue samples (from patients with OC and LC) were used to identify CD3 (ab16669), CD4 (ab133616), CD8 (ab85792), FOXP3 ([236A/E7], PD1 (ab137132), IL12RB2 (NBP1-85983), CD68 (Dako. #M0876), CD163 (Cell Signaling #93498) in ICs and PD-L1 (Clone 22C3; Dako) in T cells & tumor-associated macrophages (TAMs). Tonsil tissue was used for the IHC validation. Paired specimens were morphologically evaluated by H&E stain & Ki-67, cl-caspase 3. Anatomic pathological evaluation for the diagnosis of the disease was carried out by a Pathologist.
Results: Expression of CD3, CD4, CD8, PD1, and FOXP3 was heterogeneous, with each tumor presenting an individual pattern of distribution of ICs. However in most tumor samples, the distribution of ICs was of tumor-cooperating phenotypes. PD-L1 expression in tumors did not correlate with any other ICs of the tumor-microenvironment. In TAN tissues from OC, PD1-PD-L1 staining was absent. While macrophages in TAN tissue from LC were moderately positive for PD-L1. In T tissue from OC and LC, PD1-PD-L1 staining was only present in the stroma, lymphocytes, and absent in the tumor compartments while PD-L1 staining was identified only in the macrophages. Tumoricidal cells were rarely observed within the tumor compartment of T tissues from OC. The tumors cells from LC was only positive for PD-L1.
Conclusion: Using dual stain of PD1 and PD-L1, we present for the first time, the co-distribution pattern of PD1-PD-L1 axis in the context of the expression of CD3, CD4, CD8, FOXP3 T cells as well as CD68, and CD163 positive TAMs in the paired sample of a T tissue and its TAN tissue in LC and OC. The relationship between the PD1-PD-L1 axis and the expression of IL12 Receptor in the context of immune-landscape is being worked out and will be presented in the meeting.
Citation Format: Xiaoqian Lin, Raed Sulaiman, Jennifer C. Aske, Paul Meyer, Luis RojasEspaillat, David Starks, Pradip De, Nandini Dey. The landscape of PD1-PD-L1 axis in the context of immune cells: Tumors versus stromal compartments [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1597.
Abstract 162: DNA methylation activates TP73 expression in human breast cancer tumorigenesis
Authors: Yao Zhixing , Yao David R. , Yu William , Sherif Zaki A. 
Published: September 2020

Abstract
Epigenetic events that cause changes in gene expression are common in human cancers. However, the connection between TP73 expression and its epigenetic functionality in tumorigenesis has not been widely explored. As a transcription factor, p73 is activated in a similar manner to p53 in response to DNA damage and regulates the expression of downstream genes involved in cell cycle arrest and apoptosis. However, there are other compounding functions of this gene that reflect its non-tumor-related characters, thus making it very difficult to assess its specific role in tumorigenesis, which results from an accumulation of mutational and epigenetic changes that alter normal cell growth and survival pathways. TP73 is the homologue of the master tumor suppressor TP53 involved in cellular responses to stress and development. The TP73 gene encodes two different proteins TAp73 and ΔNp73 and maps to a region on chromosome 1p36 that is frequently deleted in neuroblastoma and other tumors and is thought to contain multiple tumor suppressor genes. However, the analysis of p73-knockout mice yielded conflicting results with respect to tumor suppression. World-wide efforts in sequencing the TP73 gene in patient tumor samples have not provided evidence for genetic alterations as a common cause of TP73 inactivation in human cancers. Therefore, the role of TP73 in tumorigenesis has remained elusive to date. In this study, we determined TP73 expression in normal human mammary epithelial cells (HMEC), non-cancerous Li-Fraumeni Syndrome (LFS) skin fibroblasts, human breast cancer cell lines (MCF7 & MDA321), neuroblastoma cell lines (IMR32 & SK-N-SH) and normal skin fibroblast cell line (HS27). We also conducted an immunohistochemistry analysis of TP73 expression in human normal breast tissues, cancerous breast tissues and non-cancerous (cancer-adjacent) breast tissues. The results show that TP73 expression is evident only in cancer cell lines and breast cancer tissues. Moreover, methylation-specific PCR and bisulfite sequencing studies revealed that TP73 promoter is activated only in cancer cell lines by DNA methylation. Furthermore, ChIP assay results demonstrated that CTCF (a chromosomal networking protein CCCTC binding factor) and tumor protein p53 (TP53) bind to TP73 promoter and regulate TP73 expression. These observations demonstrate the existence of a positive correlation at the promoter site of TP73 between its expression and DNA methylation. However, TP73 expression is not involved in cell proliferation, which may prove significant for the development of future diagnostic and therapeutic applications.
Citation Format: Zhixing Yao, David R. Yao, William Yu, Zaki A. Sherif. DNA methylation activates TP73 expression in human breast cancer tumorigenesis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 162.
Abstract 1654: Highly multiplexed analysis of FFPE breast tissues using the codex technology
Authors: Nikulina Nadezhda , Braubach Oliver , Basak Sayantani , Gallina Maria Elena , Lee Won-Mean , Kim Joseph , Hempel Cassandra , Williams Edek , Shang Olive , Cheung Ben , Kennedy-Darling Julia 
Published: September 2020

Abstract
Highly multiplexed imaging has emerged as a critical tool in understanding the complexities of the tumor microenvironment. This technology enables detection of tens of markers within the same tissue specimen, thereby allowing for key cell identification, quantification and spatial localization. These measurements can in turn provide insights into disease mechanisms and effective treatment modalities. In particular, with the high incidence of breast cancer and the need for early diagnosis and precise treatment regimens, highly multiplexed imaging could improve our understanding of this disease and provide the necessary data for improvements to patient health. Here, we demonstrate the development of a breast cancer specific CODEX panel for the measurement of more than 30 specific markers. The CODEX (Co-Detection by indEXing) platform enables detection of tens of markers within the same tissue specimen through a DNA-based tagging approach, whereby antibodies are labeled with specific oligonucleotide tags (barcodes) and dye-oligonucleotides (reporters) are iteratively hybridized and dehybridized across multiple cycles. This process is completely automated through the CODEX instrument in combination with existing fluorescent microscopes.
Using FFPE Human breast cancer tissues at different stages as well as normal FFPE Human breast tissue utilizing the CODEX platform, data was generated for 30+ different biomarkers. This antibody panel was designed to detect cancer cells as well as non-malignant cells as part of tumor microenvironment to enable a better understanding of communication between the cells. The CODEX generated data was analyzed using the CODEX software suite to identify key cell types and analyze the spatial association between them. Upon analysis of data obtained, it was found that the biomarkers expression between the three samples were distinctly different. Using the CODEX technology, we were able to identify and classify key cell types and map the spatial localization of more than 20 key cell types.
Citation Format: Nadezhda Nikulina, Oliver Braubach, Sayantani Basak, Maria Elena Gallina, Won-Mean Lee, Joseph Kim, Cassandra Hempel, Edek Williams, Olive Shang, Ben Cheung, Julia Kennedy-Darling. Highly multiplexed analysis of FFPE breast tissues using the codex technology [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1654.
Abstract 1657: Paired agent fluorescence imaging of cancer in a living mouse using targeted molecular probes with emission wavelengths of 690 and 830 nm
Authors: Spires (Schreiber) Cynthia L. , Zhai Canjia , Dempsey Janel , McGarraugh Hannah , Matthews Braden , Christmann Caroline , Smith Bradley 
Published: September 2020

Abstract
Targeted fluorescent probes were used for cancer imaging and assessing tumor targeting performance in a living mouse model. Untargeted probes and targeted probes (appended with cRGDfK peptide units for integrin targeting on cancer cells) were fabricated with emission wavelengths of 690 and 830 nm. Selective targeting of cancer cells was proved by series of cell microscopy experiments followed by in vivo imaging of subcutaneous tumors in living mice. The mouse imaging studies included a mock surgery that completely removed a fluorescently labeled tumor. Enhanced tumor accumulation due to probe targeting was first evaluated by conducting Single Agent Imaging (SAI) experiments that compared tumor imaging performance of a targeted probe and untargeted probe in separate mouse cohorts. Although there was imaging evidence for enhanced tumor accumulation of the targeted probe, there was moderate scatter in the data due to tumor-to-tumor variability of the vasculature structure and interstitial pressure. A subsequent Paired Agent Imaging (PAI) study co-injected a binary mixture of targeted probe (with emission at 690 nm) and untargeted probe (with emission at 830 nm) into the same tumor-burdened animal. The conclusion of the PAI experiment also indicated enhanced tumor accumulation of the targeted probe but the statistical significance was much higher, even though the experiment required a much smaller cohort of mice. The imaging data from the PAI experiment was analyzed to determine the targeted probe's Binding Potential (BP) for available integrin receptors within the tumor tissue. In addition, pixelated maps of BP within each tumor indicated a heterogenous spatial distribution of BP values. The results of this study show that PAI is a promising new way to analyze tumor heterogeneity and its eventual use in clinical applications such as targeted therapy, image guided surgery, and personalized medicine.
Citation Format: Cynthia L. Spires (Schreiber), Canjia Zhai, Janel Dempsey, Hannah McGarraugh, Braden Matthews, Caroline Christmann, Bradley Smith. Paired agent fluorescence imaging of cancer in a living mouse using targeted molecular probes with emission wavelengths of 690 and 830 nm [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1657.
Abstract 1660: Reflectance confocal microscopy modeling of lentigo maligna
Authors: Hanlon Katharine L. , Grichnik James M. 
Published: September 2020

Abstract
Early melanoma detection in sun-damaged skin can be a challenge. Clinically, some solar lentigines or flat seborrheic keratoses may be relatively indistinguishable from Lentigo Maligna. Reflectance Confocal Microscopy can now be used in the clinic to evaluate these lesions in vivo and increase biopsy accuracy. Spatial relationships of cells and architecture of associated skin structures play a critical role in appropriate diagnoses. As we move toward artificial intelligence using computer diagnostic platforms, it will be important to base algorithms on data with high diagnostic yield. We have undertaken efforts to create 3D reconstructions from sequential depths of confocal images of skin lesion in vivo in order to allow for more precise definition spatial relationships. These efforts have facilitated clearer evaluation of architectural changes at the dermal epidermal junction, location of cells around adnexal structures, and extent of melanocytic dendricity and diversity within the lesion. The use of color maps for efficient identification and accurate localization of cellular and architectural features of interest is another approach to advanced evaluation of confocal image data. We anticipate that these efforts will further improve accuracy for both human and computer diagnoses from reflectance confocal images.
We appreciate generous support of the Theodora B Betz Foundation.
Citation Format: Katharine L. Hanlon, James M. Grichnik. Reflectance confocal microscopy modeling of lentigo maligna [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1660.
Abstract 1671: Deregulation of mTOR signaling contributes to chemoradiation resistance in lung squamous cell carcinoma
Authors: Shen Changxian , Shyu Duan-Liang , Xu Min , Yang Linlin , Duan Wenrui , Williams Terence M. 
Published: September 2020

Abstract
Non-small cell lung carcinoma (NSCLC) represents ~ 85% of lung cancer, and ~1/3 of these patients present with locally-advanced, unresectable/medically-inoperable disease. Patients who present with locally-advanced NSCLC are commonly treated with definitive chemoradiation. Even though an initial response to concurrent chemoradiation is commonly observed, disease relapse in the radiation fields occurs in 1/3 of cases, likely driven by therapy-resistant tumor cells. However, the underlying molecular mechanisms of chemoradiation resistance of NSCLC remains largely unknown. We herein report that upregulation of mTOR signaling plays an important role in the chemoradiation resistance of NSCLC. Patient-derived xenograft (PDX) models of lung squamous cell carcinoma (LUSC) were established in the flanks of NOD-SCID gamma (NSG) mice. Chemoradiation resistant tumor models were developed by treating the tumors with a regimen of 2-4 weeks of chemoradiation (20, 30 or 40 Gy at 2 Gy per day, concurrent with cisplatin). Recurrent tumor models were collected and subjected to functional proteomics using reverse phase protein analysis (RPPA). Several LUSC tumors recurred in the 20 Gy+cisplatin, and 40 Gy+cisplatin groups. RPPA analysis of the recurrent and parental (untreated) PDX tumors showed that there were enhanced mTOR signaling in the chemoradiation resistant 20 Gy+cisplatin and 40 Gy+cisplatin tumors compared to that in the control tumors. Of note, phospho-AKT-S473, phospho-AKT-S308, phospho-S6-S235/6 and phospho-GSK3β-S9/21 were the highest upregulated signaling and were validated by immunoblotting. Consistently, pharmacological inhibition of mTOR kinase by Torin2 significantly sensitized LUSC cell lines to ionizing radiation. Our results demonstrate that utilization of PDX models is a useful method to elucidate the molecular mechanisms of chemoradiation resistance of NSCLC and deregulation of mTOR signaling contributes to the chemoradiation resistance of NSCLC. Our findings suggest that clonal selection of subpopulations with high mTOR signaling in heterogeneous NSCLC tumors might contribute to the relapse of NSCLC after chemoradiation and that mTOR kinase inhibitors are promising agents for the upfront treatment of NSCLC patients in combination with chemoradiation.
Citation Format: Changxian Shen, Duan-Liang Shyu, Min Xu, Linlin Yang, Wenrui Duan, Terence M. Williams. Deregulation of mTOR signaling contributes to chemoradiation resistance in lung squamous cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1671.
Abstract 1674: Correlation of the mutational pattern and gene expression data of patient-derived Non-Hodgkin lymphoma xenografts (PDX) with the response to targeted therapies
Authors: Brzezicha Bernadette , Conrad Theresia , Becker Michael , Bittner Aitomi , Janz Martin , Schmitt Clemens A. , Keilholz Ulrich , Hoffmann Jens 
Published: September 2020

Abstract
Non-Hodgkin lymphomas (NHL) are lymphoid malignant neoplasms that represent a very heterogeneous group and still pose an important clinical challenge. In particular, the frequent development of resistance to the treatment with standard-of-care (SoC) drugs is associated with a high incidence of disease recurrence. Recent progress in molecular high-throughput profiling has helped to identify genetic drivers for many subtypes of B-cell lymphomas as well as T-cell lymphomas. Target validation and drug development depend on corresponding preclinical models representing the different subtypes. Therefore, we established and characterized a panel of patient-derived NHL xenografts. All lymphoma PDX were derived from peripheral blood, lymph node extirpations or core needle biopsies, respectively, and were routinely implanted subcutaneously into immunodeficient mice. For further characterization, established lymphoma PDX models were treated with SoC (e.g., cyclophosphamide, doxorubicine, vincristine, etoposide) and investigational drugs. To gain a deeper insight into the molecular biology of the lymphoma models, RNA sequencing was performed. More than 20 PDX models from different NHL entities have been successfully established and characterized. We observed heterogeneous individual responses to the SoC treatments as well as to target treatments such as rituximab or ibrutinib. Explorative analysis of RNA sequencing data confirmed the representation of the clinical lymphoma subgroups (e.g. DLBCL, Burkitt, AITL) in our panel of lymphoma models. Based on the RNA sequencing data, the individual Human Leukocyte Antigen (HLA) type of each lymphoma PDX was determined with the aim to enable personalized, HLA type-specific studies. Our lymphoma PDX portfolio provides an exceptional platform for the identification and validation of new targets and allows the preclinical screening of new combinations in translational research projects.
Citation Format: Bernadette Brzezicha, Theresia Conrad, Michael Becker, Aitomi Bittner, Martin Janz, Clemens A. Schmitt, Ulrich Keilholz, Jens Hoffmann. Correlation of the mutational pattern and gene expression data of patient-derived Non-Hodgkin lymphoma xenografts (PDX) with the response to targeted therapies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1674.