bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2726: Characterization of immune microenvironment and heterogeneity in breast cancer subtypes
Authors: Jain Drashti , Liao Linda , Hopkins Megan , Quintayo Mary Anne , Talebian Vida , Bayani Jane , Cheung Alison , Yaffe Martin , Bartlett John , Spears Melanie 
Published: July 2021

Abstract
Despite ongoing advancements in the clinical management of breast cancer (BC), the variability in the response to treatment requires continued understanding of the molecular biology of this disease. Receptor status for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) along with pathological features dictate the course of therapy. Tumor cells in BC are phenotypically diverse between and within patients due to underlying differences in their cellular biology. This heterogeneity in the expression of key molecular targets renders some tumor cells resistant to therapy. While the etiology of intra-tumor heterogeneity is under investigation, it is equally important to characterize the heterogeneous nature of the tumor microenvironment as both of these compartments are engaged in the molecular crosstalk; with the latter known to contribute to tumor progression. Traditionally considered to be immunologically cold, recent advances have demonstrated that some BC subtypes elicit immunological response. However, further research is warranted to broadly illustrate the immune cell contexture in BC in a spatial context. In this study, the immune microenvironment was characterized through proteomic analysis using NanoString's GeoMX Digital Spatial Profiling (DSP) platform, in a cohort of early BC patients. This cohort consists of Luminal A, Luminal B, Basal, and HER2 BC subtypes. Correlation of proteomic and genomic data will reveal the role of genomic alterations in differential immune response. Protein markers were analyzed in both the tumor microenvironment (TME) and tumor compartments with beta-2-microglobulin, CD40, and CD11 significantly expressed in the TME compartment while PanCK, ERalpha, and HER2 were enriched in the tumor. Interestingly, CD127 was also expressed in the tumor compartment, indicating infiltration by memory T cells. Through this study we spatially characterize the immune microenvironment in BC subtypes, providing further evidence against the “immunologically cold” view of this disease. In addition, we demonstrate the potential clinical use of this novel platform in diagnosing and better stratifying BC patients based on spatial heterogeneity in tumor and TME.
Citation Format: Drashti Jain, Linda Liao, Megan Hopkins, Mary Anne Quintayo, Vida Talebian, Jane Bayani, Alison Cheung, Martin Yaffe, John Bartlett, Melanie Spears. Characterization of immune microenvironment and heterogeneity in breast cancer subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2726.
Abstract 275: Lack of electron acceptors contributes to redox stress and growth arrest in asparagine-starved sarcoma cells
Authors: Bauer Christoph , Quante Meret , Regina Carla , Schneider Michaela , Andrieux Geoffroy , Gorka Oliver , Groß Olaf , Boerries Melanie , Kammerer Bernd , Hettmer Simone 
Published: July 2021

Abstract
Background. Amino acids are integral components of cancer metabolism. Adequate availability of the non-essential amino acid asparagine is necessary to support growth and survival of various cancer cell types, including sarcoma cells.
Methods. Different mass spectrometry approaches were employed to determine changes in the metabolome of asparagine-deprived mouse and human sarcoma cells, which may be responsible for arrested growth and apoptosis due to asparagine depletion.
Results. Lower aspartate levels, higher aspartate/glutamine ratios and lower levels of tricarboxylic acid (TCA) cycle metabolites in asparagine-deprived sarcoma cells indicated a redirection of TCA cycle flux and were accompanied by reduced NAD+/NADH ratios, consistent with relative deficiency of electron acceptors in asparagine-starved cells. Elevated lactate/pyruvate ratios may be due to compensatory regeneration of NAD+ through increased pyruvate to lactate conversion by lactate dehydrogenase in asparagine-deprived cells. Supplementation with exogenous pyruvate, which was previously shown to serve as electron acceptor in cells challenged by reductive stress, restored aspartate levels, NAD+/NADH ratios, lactate/pyruvate ratios and cell growth in asparagine-deprived cells. Treatment with chemicals disrupting regeneration of NAD+ in the electron transport chain (e.g. metformin) further enhanced the anti-proliferative and pro-apoptotic effects of asparagine depletion.
Conclusions. We conclude that asparagine deprivation, through metabolic reprogramming, causes reductive stress, which, in turn, results in lower aspartate levels in asparagine-starved cells. These changes are major contributors to the growth arrest observed in asparagine-starved cells. Future studies are needed to further elucidate the cellular processes that contribute to lack of electron acceptors in asparagine-starved tumor cells.
Citation Format: Christoph Bauer, Meret Quante, Carla Regina, Michaela Schneider, Geoffroy Andrieux, Oliver Gorka, Olaf Groß, Melanie Boerries, Bernd Kammerer, Simone Hettmer. Lack of electron acceptors contributes to redox stress and growth arrest in asparagine-starved sarcoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 275.
Abstract 2790: Temporal immune changes of murine breast and melanoma tumor microenvironments following pulsed focused ultrasound
Authors: Cohen Gadi , Chandran Parwathy , Lorsung Rebecca M. , Tomlinson Lauren E. , Rosenblatt Robert B. , Burks Scott R. , Frank Joseph A. 
Published: July 2021

Abstract
Various cellular and biological immunotherapies have revolutionized the treatment of human malignancies by augmenting endogenous immune responses within the tumor microenvironment (TME). Although non-ablative pulsed-FUS (pFUS) has received less attention, it has been successfully used as a noninvasive treatment of solid malignancies by stimulating a pro-inflammatory immune response within the TME. Such an approach could be useful to treat peripheral micro-metastases in normal-appearing tissues. In the present study, we interrogated the immune-modulatory changes that occur within the TME following pFUS exposure. Murine B16 melanoma and 4T1 mammary carcinoma cells were subcutaneously implanted into both mice flanks (n=10 tumors/group/time point). The natural histories cytokine, chemokine, trophic factor (CCTF), and cell adhesion molecule (CAM) expression was evaluated within the TME of untreated flank tumors over 11 days. Ultrasound-guided pFUS at 1 MHz and peak negative pressures of 6 MPa was administered to tumors after reaching ~5 mm in diameter. Temporal immune-related changes in tumors were assessed following sonication using using proteomic, transcriptomic and histological analyses. Natural history growth characteristics showed a progressive increase in size for both tumors, and proteomic analysis revealed a shift toward an immunosuppressive TME. An anti-tumor TME was detected following pFUS treatment with increased expression of various pro-inflammatory CCTF and CAM as well as reduced tumor growth rates. Transcriptomic analyses following sonication identified inverted gene expression patterns in the two tumor types. Functional analysis of B16 tumors revealed increased intracellular signaling pathways associated with immune response regulations, while 4T1 tumors demonstrated reduced expression of proliferation genes. This study provides a macroscopic overview on the temporal dynamics of the TME and underline the profound magnitude of tumoral heterogeneity between tumor types as well as through progressive stages of similar primary tumors. Nevertheless, the induced immune-modulation changes suggest that pFUS may alter the expression of pro-inflammatory CCTF, CAM, towards an anti-tumoral TME, and supports the potential use of pFUS as a neoadjuvant treatment approach.
Citation Format: Gadi Cohen, Parwathy Chandran, Rebecca M. Lorsung, Lauren E. Tomlinson, Robert B. Rosenblatt, Scott R. Burks, Joseph A. Frank. Temporal immune changes of murine breast and melanoma tumor microenvironments following pulsed focused ultrasound [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2790.
Abstract 2826: BAG2 promotes tumorigenesis and metastasis by regulating the Cathepsin B cleavage in triple-negative breast cancer cells
Authors: Yang Kyung-Min , Pang Kyoungwha , Ooshima Akira , Lee Jihee , Kim Seong-jin 
Published: July 2021

Abstract
Breast cancer is classified into clinical subtypes based upon receptor expression (ER, PR, Her2). Among the breast cancer subtypes, triple-negative breast cancer (TNBC) refers to a form of breast cancer which lacks expression of ER, PR and HER2. Most of breast cancer treatments can be targeted for cancers that express hormonal receptors or HER2, whereas traditional chemotherapy does not work in TNBCs. Therefore, TNBC remains a clinical challenge for discovery novel specific target biomarker because of no targeted therapies for TNBC. In this study, we show that BAG2 promotes cancer progression by regulating the dual function of Cathepsin B in TNBC cells. We found that BAG2 is highly expressed in basal-like breast cancer cells, where it was associated with recurrence or distant metastasis-free survival in patients. In loss-of-function experiment, BAG2 knockdown strongly decreased the ability of tumor formation and lung metastasis in vivo in TNBC cells. Mechanistically, BAG2 induces metastasis through regulation of secretion of pro-form Cathepsin B and prevents lysosome-mediated cell death through decrease of intracellular single-chain form of Cathepsin B into cytoplasm. Thus, our results suggest that BAG2 promotes tumorigenesis and metastasis through regulation of Cathepsin B cleavage in TNBC cells and may be possible as a novel specific target for treatment of TNBC. [This work was supported by National R&D Program for Cancer Control, Ministry for Health and Welfare, Republic of Korea (HA17C0037).]
Citation Format: Kyung-Min Yang, Kyoungwha Pang, Akira Ooshima, Jihee Lee, Seong-jin Kim. BAG2 promotes tumorigenesis and metastasis by regulating the Cathepsin B cleavage in triple-negative breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2826.
Abstract 2829: Identifying germline variants for metastatic risk assessment in sporadic colorectal carcinomas
Authors: Cheah PehYean , Thean Lai Fun , Wong Michelle , Lo Michelle , Tan Emile , Tang Choong Leong 
Published: July 2021

Abstract
Colorectal carcinoma (CRC) is the third highest incidence cancer and leading cause of cancer mortality worldwide. Metastasis to distal organ is the major cause of cancer mortality. This trend is expected to be exacerbated by an aging population in the developed world. Genetic predisposition plays a greater role in disease progression than disease etiology in sporadic CRC. However, the underlying genetic factors for metastasis are currently unclear. We identified germline single nucleotide polymorphism (SNP) variants contributing to metastasis risk from a case-case (metastasis-positive vs metastasis-negative) genome-wide association study (GWAS) comprising 3,000 sporadic Chinese CRC cases with definitive metastasis status. Metastasis-positive case is defined as one with distal-organ involvement attributable to primary CRC; metastasis-negative case is defined as metastasis-free with 5 years or more follow-up. By interrogating summarized SNP statistics from the case-case GWAS using the Functional Mapping and Annotation (FUMA) software, we identified 5 genomic risk loci and 74 disease-relevant genes based on gene set enrichment analysis and the Molecular Signatures Database. These genes are in various pathways implicated in different metastasis steps, from epithelial-mesenchymal transition (EMT) to implantation at distal organs. They are different from the risk variants identified by case-control GWAS for disease occurrence. We will expression-profile 250 metastasis-positive vs metastasis negative cases from the GWAS panel to validate the bioinformatics analysis by quantitative real-time PCR. We will focus first on the five genes implicated in glycolysis as this is a biochemical fingerprint of malignant cells that represents one of the ‘hallmarks of cancer'. Expression profile of these genes will be validated in a second independent panel. Kaplan Meier survival analysis as function of the median expression value will be performed to assess prognostic value of these genes. The ultimate goal is to improve metastasis risk assessment for secondary prevention to reduce cancer mortality and morbidity for individual patient as well as reducing public health expenditure.
Citation Format: PehYean Cheah, Lai Fun Thean, Michelle Wong, Michelle Lo, Emile Tan, Choong Leong Tang. Identifying germline variants for metastatic risk assessment in sporadic colorectal carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2829.
Abstract 2838: Epigenetic regulator MLL3 mutations promote tumor metastasis by enhancing the epithelial-mesenchymal transition state
Authors: Cui Jihong , Ge Kai , Guo Wenjun 
Published: July 2021

Abstract
Epigenetic dysregulations have a recognized role in cancer pathogenesis. Histone methyltransferase MLL3 (mixed-lineage leukemia protein 3) (gene symbol - KMT2C) is one of the most frequently altered genes in human breast cancer. In addition to the loss-of-function mutations, the expression levels of MLL3 are downregulated significantly in the tumor, compared to normal breast samples. Consistent with these cancer genome findings, functional studies in mouse models and human cancer cells showed loss of MLL3 promotes tumor initiation and growth. However, the role of MLL3 mutation in metastasis has not been determined.
Here we showed that the MLL3 levels were further reduced in distant metastases compared to primary tumors, suggesting a potential role of MLL3 loss in metastasis. We demonstrate that MLL3 loss markedly promoted distant metastasis through specifically enhancing the step of colonization during the metastatic cascade. MLL3 loss facilitated the acquisition of an epithelial/mesenchymal (E/M) transition state by cancer cells disseminated to the lung. These cells have a hybrid phenotype of epithelial and mesenchymal features. We further showed that the E/M transitional cells induced by MLL3 loss have greatly increased tumor-initiating ability and multi-organ metastatic ability. We further demonstrated that MLL3 lose facilitated luminal breast tumor cells to acquire the E/M hybrid features and promoted endocrine therapy resistance, suggesting that loss of MLL3 also promotes the epithelial-mesenchymal plasticity and therapeutic resistance.
To identify vulnerability of MLL3-mutant cancer cells, we performed small molecule screening and discovered that MLL3-mutant cancer cells are markedly more sensitive to BET inhibitors than MLL3-WT cells. The in vivo study confirmed that the BET inhibitor repressed the MLL3-mutant tumor growth much more efficiently than MLL3-WT tumors. Furthermore, the BET inhibitor is effective in suppressing the growth of established MLL3-mutant lung metastasis. Taken together, our findings indicate that MLL3 mutations promotes metastasis and therapeutic resistance by enhancing epithelial-mesenchymal plasticity. However, these aggressive cancer cells are uniquely vulnerable to BET inhibition, suggesting a potential therapeutic strategy for MLL3-mutant cancers.
Citation Format: Jihong Cui, Kai Ge, Wenjun Guo. Epigenetic regulator MLL3 mutations promote tumor metastasis by enhancing the epithelial-mesenchymal transition state [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2838.
Abstract 2851: Trop-2 inactivates E-cadherin for metastatic diffusion in the absence of EMT
Authors: Alberti Saverio , Guerra Emanuela , Relli Valeria , Lattanzio Rossano , Ceci Martina , Boujnah Khouloud , Garbo Valeria , Moschella Antonino , Altomare donato F. , Depalo Raffaella , Trerotola Marco 
Published: July 2021

Abstract
Trop-2 is a type I transmembrane glycoprotein, which is overexpressed in the majority of carcinomas, where it drives tumor cell proliferation. In its mature, glycosylated/functionally-competent form, Trop-2 associates with worse prognosis. A global quest was conducted for identifying decisive drivers of cancer metastasis. Cancer cell spheroids, wound healing and cell aggregation assays were utilized to assess cell-cell adhesion capacity. Immunofluorescence confocal microscopy and flow cytometry analysis were utilized to quantify expression of target signaling proteins, IHC analysis quantified the expression of target molecules in primary tumors and metastases. Pre-clinical models of orthotopic growth of colon cancer and metastatic diffusion to the liver were utilized. Xenotransplant transcriptome profiling analyzed transcription of EMT-related determinants. This led us to identify Trop-2 as a unique upregulated gene in colon cancer metastasis. Trop-2 was here shown to bind highly-expressed E-cadherin at the cell membrane. Trop-2 binding released E-cadherin from the cytoskeleton, inhibited cell-cell adhesion functions and activated signaling through β-catenin. This occurred in the absence of transcriptional downregulation of the CDH1 gene by EMT-associated transcription factors. The Trop-2/E-cadherin/β-catenin program was shown to lead to anti-apoptotic signaling, increased cell migration and enhanced cancer cell survival. In an orthotopic model of colon cancer, Trop-2 caused metastatic diffusion to the liver. The Trop-2-led E-cadherin-inactivation metastasis program was then found to induce metastatic relapse and shorter overall survival of colon cancer patients. Corresponding impact was indicated on breast, colon, ovary, uterus, stomach cancer metastatic diffusion, for broad impact on metastatic diffusion in human cancer.
Acknowledgments:Support was provided by grants of Italian Ministry of Development (MI01_00424) and of University and Research (SCN_00558). M.T. was supported by the Programma Per Giovani Ricercatori “Rita Levi Montalcini” (Grant PGR12I7N1Z).
Citation Format: Saverio Alberti, Emanuela Guerra, Valeria Relli, Rossano Lattanzio, Martina Ceci, Khouloud Boujnah, Valeria Garbo, Antonino Moschella, donato F. Altomare, Raffaella Depalo, Marco Trerotola. Trop-2 inactivates E-cadherin for metastatic diffusion in the absence of EMT [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2851.
Abstract 286: Conception and preparation of new potent antimicrotubule agents
Authors: Gagné-Boulet Mathieu , Bouzriba Chahrazed , Alvarez Atziri Corin Chavez , Fortin Sébastien 
Published: July 2021

Abstract
Cancer is still to this day one of the first causes of death in industrialized countries. Despite great progress made so far, there is still no treatment completely efficient and without toxicity. Therefore, the development of new anticancer drugs is sought. To this end, we developed a novel family of potent antimicrotubule agents designated as N-phenyl 4-(2-oxoimidazolidin-1-yl)benzenesulfonates (PIB-SOs). Our previous structure-activity relationship studies were focused on the aromatic rings A and B of PIB-SOs leaving the sulfonate bridge poorly studied. In the present study, we have designed, prepared and evaluated in vitro new PIB-SO analogs by replacing the sulfonate moiety with a sulfur atom. The new PIB-SO analogs were prepared using classical organic chemistry tools. The antiproliferative activity of PIB-SO analogs was assessed on HT-1080 fibrosarcoma, HT-29 colon adenocarcinoma, M21 skin melanoma and MCF7 estrogen-dependent breast adenocarcinoma. Then, the most potent analogs were assessed for their effect on the cell cycle progression, their capacity to disrupt the microtubules and their ability to bind to the colchicine-binding site (C-BS). Lastly, their theoretical properties were calculated with SwissADME tool. The new PIB-SO analogs bearing the sulfur bridge exhibit antiproliferative activities in the low nanomolar to mid micromolar ranges. The most potent compounds block the cell cycle progression in G2/M phase, disrupt microtubules and bind to the C-BS. Finally, their theoretical pharmacokinetic profiles show that they are potentially suitable for animal experiments. In addition to show that the sulfonate moiety of PIB-SOs can be modulated with a sulfur atom, our study led to the discovery of a new family of potent antimicrotubule agents targeting the C-BS. This study will contribute in the long term to the development of new treatments for cancer patients.
Citation Format: Mathieu Gagné-Boulet, Chahrazed Bouzriba, Atziri Corin Chavez Alvarez, Sébastien Fortin. Conception and preparation of new potent antimicrotubule agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 286.