bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3085: Steroid receptor co-activators regulate metabolic kinases to drive therapy resistant ER+ breast cancer
Authors: Truong Thu Ha , Benner Elizabeth , Hagen Kyla M. , Temiz Nuri A. , Kerkvliet Carlos Perez , Wang Ying , Cortes-Sanchez Emilio , Yang Chieh-Hsiang , Pengo Thomas , Guillen Katrin P. , Welm Bryan E. , Telang Sucheta , Lange Carol A. , Ostrander Julie H. 
Published: July 2021

Abstract
Recurrence of metastatic breast cancer stemming from acquired endocrine and chemotherapy resistance remains a health burden for women with luminal (ER+) breast cancer. Disseminated ER+ tumor cells can remain viable but quiescent for years to decades. Contributing factors to metastatic spread include the maintenance and expansion of breast cancer stem cells (CSCs). Breast CSCs are poorly proliferative and frequently exist as a minority population in therapy resistant tumors. Our objective is to define novel signaling pathways that govern therapy resistance in ER+ breast cancer. In this study, we show that cytoplasmic complexes composed of steroid receptor (SR) co-activators, PELP1 and SRC-3, modulate breast CSC expansion through upregulation of the HIF-activated metabolic target genes PFKFB3 and PFKFB4. Seahorse metabolic assays demonstrated that cytoplasmic PELP1 influences cellular metabolism by increasing both glycolysis and mitochondrial respiration. PELP1 interacts with PFKFB3 and PFKFB4 proteins, and inhibition of PFKFB3 and PFKFB4 kinase activity blocks PELP1-induced tumorspheres and protein-protein interactions with SRC-3. PFKFB4 knockdown inhibited in vivo emergence of circulating tumor cell (CTC) populations in ER+ mammary intraductal (MIND) xenografts. Application of PFKFB inhibitors in combination with ER targeted therapies blocked tumorsphere formation in multiple models of advanced breast cancer, including tamoxifen (TamR) and paclitaxel (TaxR) resistant models and ER+ patient-derived organoids (PDxO). Together, our data suggest that PELP1, SRC-3, and PFKFBs cooperate to drive ER+ tumor cells that include CSCs and CTCs. Identifying non-ER pharmacological targets offers a useful approach to blocking metastatic escape from standard of care ER/estrogen (E2)-targeted strategies to overcome endocrine and chemotherapy resistance in ER+ breast cancer.
Citation Format: Thu Ha Truong, Elizabeth Benner, Kyla M. Hagen, Nuri A. Temiz, Carlos Perez Kerkvliet, Ying Wang, Emilio Cortes-Sanchez, Chieh-Hsiang Yang, Thomas Pengo, Katrin P. Guillen, Bryan E. Welm, Sucheta Telang, Carol A. Lange, Julie H. Ostrander. Steroid receptor co-activators regulate metabolic kinases to drive therapy resistant ER+ breast cancer [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 3085.
Abstract 3107: HSB-1216, A Novel Agent for the Treatment of Chemotherapy-Resistant ES-SCLC
Authors: Mohammad Anees , Tiwari Sachchidanand , Mehrotra Neha , Korczak Bozena , Laumas Steve , Appajosyula Sireesh , Singh Harpal , Kharbanda Surender M. 
Published: July 2021

Abstract
Small cell lung cancer (SCLC) is a highly malignant form of lung cancer that accounts for 15% of lung cancer cases. The tumor has a tendency to disseminate early resulting in ~ 85% patients being diagnosed with extensive stage disease (ES-SCLC). Chemotherapy has been the mainstay of treatment for many decades, until recently when immunotherapeutic agents have been approved as first-line agents. However, resistance to anti-cancer drugs represents the main cause of cancer-related deaths. Thus, new therapeutic approach to suppress chemotherapy-resistant ES-SCLC constitutes a significant unmet medical need. We have generated novel biodegradable QUATRAMERTM polymeric nanoparticles comprised of a polyethylene glycol (PEG)-polypropylene glycol (PPG)-PEG- polylactic acid (PLA)-tetra-block copolymer for the intracellular delivery of salinomycin (HSB-1216). Here we studied the HSB-1216 activity in a resistant SCLC cell line (NCI-H69AR). Compared to cisplatin and irinotecan, a second-line agent often used in ES-SCLC, HSB-1216 exhibited a ~7-fold and ~2-fold decrease in IC50in the aggressive and resistant variant of NCI-H69AR cell line and ~30-fold and ~18-fold decrease in a non-resistant NCI-H69 SCLC line. The tumorsphere formation assay has become an essential tool for quantifying cancer stem cells (CSC) and testing of anti-cancer agents. We used this assay to estimate an effect of HSB-1216 on NCI-H69AR tumorspheres .Our results demonstrated significant dose-dependent inhibition of tumorosphere formation in response to HSB-1216. In addition, exposure to HSB-1216 resulted in substantial decrease in number of CD44+/CD24- cells in comparison to untreated control. Furthermore, significant reduction in the expression of CSC markers such as ALDH1 and Oct3/Oct4 was seen when chemotherapy-resistant NCI-H69AR cells were treated with HSB-1216.Taken together, based on these findings, HSB-1216 is being developed as a novel agent in the treatment of second-line ES-SCLC in chemo-resistant tumors, where a gap exists in current standards of care. Further work of this novel agent is planned to outline its effect when combined with targeted and non-targeted therapies in both first- and third-line SCLC.
Citation Format: Anees Mohammad, Sachchidanand Tiwari, Neha Mehrotra, Bozena Korczak, Steve Laumas, Sireesh Appajosyula, Harpal Singh, Surender M. Kharbanda. HSB-1216, A Novel Agent for the Treatment of Chemotherapy-Resistant ES-SCLC [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 3107.
Abstract 3112: Human melanocyte development and melanoma dedifferentiation at single cell resolution
Authors: Belote Rachel L. , Le Daniel , Maynard Ashley , Lang Ursula E. , Sinclair Adriane , Planells-Palop Vincente , Baskin Laurence S. , Tward Aaron D. , Darmanis Spyros , Judson-Torres Robert L. 
Published: July 2021

Abstract
In humans, epidermal melanocytes are responsible for skin pigmentation, defense against ultraviolet radiation, and the deadliest common skin cancer, melanoma. While there is substantial overlap in melanocyte development pathways between different model organisms, species dependent differences are frequent and the conservation of these processes in human skin remains unresolved. Thus, the biology of developing and adult human melanocytes remains largely uncharacterized. Here, we used a single-cell enrichment and RNA-sequencing pipeline to study human epidermal melanocytes derived directly from skin, capturing transcriptomes across different anatomic sites, developmental age, sexes, and multiple skin tones. Using donor-matched skin from distinct volar and non-volar anatomic locations, we uncovered subpopulations of melanocytes exhibiting site-specific enrichment that occurs during gestation and persists through adulthood. In addition, we identified human melanocyte differentiation transcriptional programs that are distinct from gene signatures generated from model systems. Finally, we use these programs to define patterns of dedifferentiation that are predictive of melanoma prognosis. Overall, the characterization of human melanocytes fresh from skin revealed new subpopulations, human-specific transcriptional programs, and valuable insights into melanoma dedifferentiation.
Citation Format: Rachel L. Belote, Daniel Le, Ashley Maynard, Ursula E. Lang, Adriane Sinclair, Vincente Planells-Palop, Laurence S. Baskin, Aaron D. Tward, Spyros Darmanis, Robert L. Judson-Torres. Human melanocyte development and melanoma dedifferentiation at single cell resolution [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 3112.
Abstract 3116: Designing a model system for the study of CD44-Ezrin interactions in breast cancer progression and drug resistance
Authors: Birtch Rayanna Jane , Greer Peter , Gao Yan , Hoskin Victoria 
Published: July 2021

Abstract
Triple-negative breast cancer (TNBC) has the highest risk of relapse and is thought to be the most aggressive subtype of BC. This subtype is known to express high levels of the cancer stem cell (CSC) marker CD44. The tumor-initiating properties of CSC's, as well as their resistance to chemotherapy, contribute to the difficulty in successfully treating TNBCs.CD44 is a transmembrane glycoprotein that mediates communication between cells and the extracellular matrix. In doing so, it acts as a central node in several cancer-related signaling pathways through interactions with binding partners such as Ezrin to promote tumor growth, invasion and survival. Furthermore, expression of CD44 is associated clinically with positive lymph node status, recurrence and poor overall survival in BC. We aimed to validate CD44's role in these cancer promoting properties and develop a genetically tractable and engraftable TNBC cell model to study CD44 in the context of interactions with the Ezrin adaptor protein. We first hypothesize that disrupting CD44 expression will attenuate the metastatic and drug resistant potential of TNBC cells. To address this, we utilized CRISPR-Cas9 gene editing to knockout (KO) CD44 expression in the MDA-MB-231 human TNBC cell line and then subjected CD44 KO cells, KO cells rescued with wild type CD44, or the parental MDA-MB-231 cells to a variety of in vitro assays to assess proliferative, migratory and drug resistant potential, as well as mouse lung metastatic seeding in vivo. We show that the transmembrane glycoprotein CD44 plays an important role in cancer cell proliferation, migration, and chemotherapeutic resistance in vitro as well as having an essential role in metastatic seeding in vivo in the MDA-MB-231 cell model of TNBC. Our results validate the utility of this CRISPR-Cas9 KO and rescue TNBC cell model for the study of CD44 involvement in drug resistance and metastasis. More importantly we have set the stage for further investigating CD44's role in the context of interactions with the Ezrin adaptor protein.
Citation Format: Rayanna Jane Birtch, Peter Greer, Yan Gao, Victoria Hoskin. Designing a model system for the study of CD44-Ezrin interactions in breast cancer progression and drug resistance [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 3116.
Abstract 3121: Characterization of nab-paclitaxel resistant and gemcitabine resistant BxPC3 and MIA PaCa-2 pancreatic cancer cells
Authors: Arias Danielle M. , Collins John , Noel Pawan , Von Hoff Daniel D. , Han Haiyong 
Published: July 2021

Abstract
The gemcitabine (Gem) and nab-paclitaxel (Nab-p) combination is currently the FDA approved standard of care for patients with Stage IV metastatic pancreatic cancer. The response rate of the Gem and Nab-p regimen ranges from 23% to 46%, with many patients eventually becoming refractory. The specific aim of this research project is to determine which genes and pathways differ in Gem resistant (GemR) or Nab-p resistant (Nab-pR) MIA PaCa2 (MP2) and BxPC3 cells when compared with their parental cell lines. Cell proliferation assays were carried out to confirm resistance of the cell lines. The IC50 values of gemcitabine in the Gem resistant BxPC3 (BxPC3-GemR) and MP2 (MP2-GemR) are 26 and 64 fold higher than those in the corresponding parental cell lines, respectively. The IC50 values of nab-paclitaxel in the Nab-p resistant BxPC3 (BxPC3-Nab-pR) and MP2 (MP2-Nab-pR) are 13 and 140 fold higher than those in the corresponding parental cell lines, respectively. RNA sequencing (RNA-seq) was then performed to compare the gene expression profiles of the parental and resistant cell lines. Gene set enrichment analysis (GSEA) revealed that differentially expressed genes between Gem resistant and parental BxPC3 cell lines are often enriched in pathways associated with endoplasmic reticulum (ER) stress response (e.g. ATF-6 and XBP1) whereas in MP2 cells, The AMPK signaling pathway (e.g. PRKAB1, and PRKAG1) seemed to be activated in Gem resistant cells. NFkB signaling pathway (e.g. RIPK2 and NFKB2) was elevated in both Nab-p resistant BxPC3 and MP2 cell lines compared to their corresponding parental cell lines. Genes from these pathways were selected for further validation of their differential expression using RT-PCR. ATF6 which is a stress sensor and transducer in the ER is upregulated in BxPC3-GemR. PRKAB1 and PRKAG1 which regulate AMPK activity are upregulated in MP2-GemR. RIPK2 and NFKB1 are both up in the Nab-p resistant cell lines. Results from this study could provide insights on how to devise new therapeutic regimens to overcome resistance to gemcitabine and nab-paclitaxel.
Citation Format: Danielle M. Arias, John Collins, Pawan Noel, Daniel D. Von Hoff, Haiyong Han. Characterization of nab-paclitaxel resistant and gemcitabine resistant BxPC3 and MIA PaCa-2 pancreatic 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 3121.
Abstract 3159: Targeting the TGFΒ/TIMP-1/2 axes to re-educate pro-inflammatory/pro angiogenic NK cells in cancer patients
Authors: Gallazzi Matteo , Bruno Antonino , Noonan Douglas M. , Stetler-Stevenson William G. , Albini Adriana 
Published: July 2021

Abstract
Tissue inhibitors of metalloproteases (TIMPs) have been reported to exert dual roles in cancer, based on the different cancer type and interactions with the tumor microenvironments. As inhibitors of Matrix metalloproteases (MMP) they downregulate invasion, metastasis and angiogenesis. However, TIMP1 levels have been found increased in patients with different types of cancer. Natural Killer cells have been found to be phenotypically and functionally compromised in several solid and hematological cancers. We were the first in characterizing NK pro-angiogenic phenotype in the peripheral blood and tumor tissues of patients with Non-small Cell Lung cancer (NSCLC), colorectal cancers (CRC) and in pleural effusion (PE) of patients with metastatic cancers. Also, we found that pro-angiogenic NK cells in the peripheral blood of colorectal cancer patients release of TIMP-1 and TIMP-2, in a STAT3/STAT5-independent manner. Here, we investigated the effects of TIMP-1 and TIMP-2 recombinant proteins, using a TGFβ-mediated NK cell polarization model, in vitro. The effects of TGFβ, alone or in combination with TIMP-1 or TIMP-2 peptides, was determined by multicolor flow cytometry for surface antigens and cytokine productions, on cytolytic NK cells isolated from healthy subjects. Commercially available antibody membrane arrays was used to determine the modulation of the secretome, on FACS-sorted NK cells, from healthy subjects, following 72 hours of exposure to TGFβ, alone or in combination with TIMP-1 or TIMP-2 peptide. We found that NK cell from healthy donors, exposed to TGFβ, acquire the CD56brightCD9+CD49a+ decidual-like phenotype, together with decreased levels of the activation marker NKG2D. Administration of TIMP1 or TIMP2 peptides was effective in interfering with TGFβ-induced NK cell polarization towards the CD56brightCD9+CD49a+ decidual-like phenotype and in restoration of the levels of the NKG2D activation marker. We also observed that TGFβ-polarized NK cell, when co-treated with TIMP1 or TIMP2, exhibit a trend toward decreased production of VEGF and increased production of the anti-tumor cytokines IFNγ and TNFα Our results suggest a potential role of TIMPs in contrasting the angiogenic switch in NK cells and suggest a possible use of TIMPs peptides in the re-education of anergic/pro-angiogenic NK cells in cancer patients.
Citation Format: Matteo Gallazzi, Antonino Bruno, Douglas M. Noonan, William G. Stetler-Stevenson, Adriana Albini. Targeting the TGFΒ/TIMP-1/2 axes to re-educate pro-inflammatory/pro angiogenic NK cells in cancer patients [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 3159.
Abstract 3164: Modeling the metastatic niche interactions between patient tumor and mesenchymal cells to identify drivers of chemotherapy drug resistance
Authors: Deems Liam , Shahar Amit , Pepicelli Amy , Murphy Cheryl , Solomon Daniel , Deems David , Shvartsman Dmitry 
Published: July 2021

Abstract
Cancer research relies on a plethora of disease-relevant tumor models, but patient specific models are still being developed. In this study, we show the utility of patient-specific pancreatic, ovarian and breast cancer models in the context of the metastatic niche, composed of co-cultured mesenchymal stem cells (MSC) in three-dimensional tumor spheroids. Additionally, different ratios of MSC's were seeded with the cancer spheroids to interrogate the effect of MSC's on chemotherapeutic drug response in defined media conditions. The patient-specific and treatment-naive cancer models represent a diverse range of disease type, progression grade, and genetic profiles. These models were co-cultured with MSC's sourced from both bone marrow and adipose tissue. These co-culture models were tested with a panel of common, broad-range chemotherapeutic agents as well as several disease-specific drugs. The resulting drug responses show that the presence of MSC's within the context of the metastatic niche causes attenuation towards a higher chemotherapeutic drug resistance. The tumor models exhibit a varied chemotherapeutic response when MSC's are seeded in 50:1, 5:1, or 1:1 ratio with cancer cells, suggesting that even a small presence of MSC's may have a significant effect on the drug resistance of metastatic tumor spheroids. While this MSC-induced drug response attenuation is observed across the broad spectrum of patient profiles and disease types, the strength of the effect is not homogenous. The observed variability in the strength of the effect was impacted by the disease type of the cancer cells, the source of the MSC's, and the specific drug used in the metastatic tumor model. We propose that using these reproducible and easily scaled models of metastatic tumors to find effective chemotherapeutic drugs could increase our understanding of the tumor microenvironment, the onset of metastasis, and the process of cancer grafting into other tissues. Discovering effective and targeted therapies utilizing a more advanced model of the metastatic tumor niche could increase the success rate of an eventual clinical trial.
Citation Format: Liam Deems, Amit Shahar, Amy Pepicelli, Cheryl Murphy, Daniel Solomon, David Deems, Dmitry Shvartsman. Modeling the metastatic niche interactions between patient tumor and mesenchymal cells to identify drivers of chemotherapy drug resistance [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 3164.
Abstract 3169: The therapeutically inflamed tumor microenvironment drives melanoma progression
Authors: Bradshaw Andrew M. , Kuo Erica , Grahovac Jelena , Sylakowski Kyle , Sander Cindy , Edington Howard , Kirkwood John M. , Wells Alan 
Published: July 2021

Abstract
Even the most therapy responsive melanomas eventually evade immune checkpoint inhibition. Interestingly, initial responses seem to benefit from localized inflammation, but this can become prohibitive when treating advanced disease. Subsequently, there is an urgent need to elucidate how inflammation impacts the tumor microenvironment (TME). Here, inhibition of EGFR and Ras/Raf/MEK is shown to drive the release of a pro-inflammatory secretome that activates the TME to promote progression. This secretome was enriched with immune recruiting cytokines and members of the transforming growth factor beta (TGFβ) superfamily. Both healthy and cancer associated fibroblasts (CAFs) were hyperactivated in response to the inflamed secretome with induction of the inflammatory marker, alpha smooth muscle actin (αSMA). Pharmacologic inhibition of TGFβ receptor type I (TGFβRI) using SB431542 or clinically relevant TEW-7197, diminished CAF αSMA phenotype, disrupted TGFβ and phospo-SMAD2/3 signaling, and blunted CAF expression of tumor promoting extracellular matrix and adhesion molecules. Invasion of melanoma spheroids was enhanced ~2.5-fold in CAF coculture transwells. However, treatment with MEK inhibitor AZD6244 and TEW-7197 only limited invasion of mixed melanoma and CAF multi-cell spheroids in vitro. Prompted by this, the extracellular matrix of patient-derived and melanoma xenograft tumors was analyzed for inflammatory protein expression. Micrometastatic foci were flanked by peri-tumor αSMA+ CAFs and enriched for inflammatory Tenascin-C (TNC) at the invasive front. The analysis of human melanoma tissue microarrays corroborated the experimentally observed expression of αSMA CAFs and TNC which statistically increase with malignant tumor grade. Conversely, the anti-invasive Decorin (DCN), decreased in malignant melanoma while collagen-1 increased during late stage tumor fibrosis. These findings prompted the use of ex vivo human skin organ cultures (SOCs) to define how cell matrix impacted melanoma. Addition of DCN to the SOC eliminated melanoma vertical invasion whereas pathological TNC promoted progression. Thus, a BRAFV600E resistant patient-derived metastatic cell line was used to establish intrasplenic xenografts that were treated after one week using AZD6244 and TEW-7197. Both monotherapy and combination therapy were well tolerated and resulted in reduced splenic tumor burden, αSMA staining, and halted metastasis to the liver.
Citation Format: Andrew M. Bradshaw, Erica Kuo, Jelena Grahovac, Kyle Sylakowski, Cindy Sander, Howard Edington, John M. Kirkwood, Alan Wells. The therapeutically inflamed tumor microenvironment drives melanoma progression [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 3169.