bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2402: SMAD4 represses PDAC metastatic colonization through binding FOSL1 enhancer regions
Authors: Rennhack Jonathan P. , Dai Chao , Aguirre Andrew , Doench John , Root David , Hahn William C. 
Published: June 2022

Abstract
Less than 5% of patients diagnosed with pancreatic ductal adenocarcinomas (PDAC) survive more than 5 years, largely due to therapeutic resistance and metastatic disease. Half of all PDAC patients have been shown to have loss of SMAD4, which has been shown to correlate with metastasis. Here we functionally demonstrate that SMAD4 is a key suppressor of metastatic colonization of PDAC. Using an in vitro and in vivo multi-component RNA-seq analysis on isogenic human PDAC cell lines, we defined SMAD4-dependent gene expression changes. Specifically, we identified genes that were suppressed in the presence of SMAD4. These genes could contribute to tumor metastasis. To test this, we performed a pooled open reading frame (ORF) overexpression lung colonization assay with the identified genes. We found that expression of the transcription factor FOSL1 is sufficient for metastatic colonization. Mechanistically, SMAD4 directly binds and modulates the activity of the FOSL1 enhancer. Taken together, these studies demonstrate a direct role for SMAD4 in regulating metastatic colonization and identify FOSL1 as a direct SMAD4-regulated gene involved in distant site colonization.
Citation Format: Jonathan P. Rennhack, Chao Dai, Andrew Aguirre, John Doench, David Root, William C. Hahn. SMAD4 represses PDAC metastatic colonization through binding FOSL1 enhancer regions [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 2402.
Abstract 2404: Role of TPD52L2 in cell migration and triple negative breast cancer progression
Authors: Parizadeh Seyedamirabbas , Geley Stephan , Reiterer-Farhan Veronika , Farhan Hesso 
Published: June 2022

Abstract
The Golgi apparatus plays an important role in cell migration and the establishment of epithelial polarity. A dispersed (or fragmented) Golgi ribbon is often seen in stressed cells and in various pathologies, including neurodegeneration or cancer, but whether and how a fragmented Golgi apparatus affect cellular function is poorly defined. Previously our lab has performed and analyzed published RNAi screens to identify genes required to maintain the Golgi ribbon. These candidate genes were filtered for altered expression patterns in breast cancer patients and for their association with survival data. The selected genes reevaluated by RNAi in BT549 breast cancer cells to assess the effect on Golgi fragmentation. One of the most effective hits was TPD52L2, a poorly characterised gene that encodes a membrane-associated protein that is overexpressed in various types of cancer. The aim of this project is to investigate the role of TPD52L2 in cell migration and cell invasion in breast cancer in order to understand the role of Golgi fragmentation in tumorigenesis. In random cell migration assays in dense and sparse seeding conditions, TPD52L2 depleted cells showed an altered actin cytoskeleton and were found to migrate faster in dense seeding without any change in directional persistence. These findings suggest that TPD52L2 not only is required to maintain an intact Golgi structure but also plays an important role in cellular motility and potentially metastasis.
Citation Format: Seyedamirabbas Parizadeh, Stephan Geley, Veronika Reiterer-Farhan, Hesso Farhan. Role of TPD52L2 in cell migration and triple negative breast 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 2404.
Abstract 2450: Investigating the intrinsic and extrinsic factors regulating breast cancer dormancy
Authors: Ren Qihao , Khoo Weng Hua , Ye Jiayu , Faget Douglas V. , Croucher Peter I. , Stewart Sheila A. 
Published: June 2022

Abstract
Unfortunately, breast cancer can recur in patients upwards of 25 years after an initial diagnosis and “cure”. It was once thought that recurrence occurred within patients that harbored dormant breast disseminated tumor cells (DTCs) in distant organs that were not present in patients that did not recur. Interestingly, a significant percent of patients harbor DTCs, yet many do not recur, raising the critical question, what differentiates patients that experience a recurrence versus those who live with dormant DTCs for the rest of their lives? It is likely the answer lies in both cell intrinsic as well as extrinsic factors. Nevertheless, the extreme rarity of dormant DTCs has been the major obstacle to their study. To overcome this challenge, we developed an efficient system to isolate and study rare dormant tumor cells from metastatic organs. Using this system and single cell RNA-sequencing (scRNA-seq), we identified a group of genes differentially expressed in dormant breast cancer cells present in both bone and lung. While modulation of these genes individually had no impact on the metastatic behavior of breast cancer cells, we found that as a group, these genes predicted the dormancy phenotype in murine breast cancer models. Importantly, expression of these genes in primary human breast cancer tumors correlated with disease-free survival, suggesting these genes have predictive value in determining which patients are likely to recur. Moreover, we explored extrinsic mechanisms that impact dormancy and found that the chemotherapy reagent doxorubicin (Doxo) drastically changed the microenvironment in vivo, which allowed dormant breast cancer cells to grow robustly within the visceral fat and this was further exacerbated by a high fat diet. Further, we found that Doxo treatment induces significant adipose tissue dystrophy and macrophage infiltration, which may contribute to dormant metastatic outgrowth. Our study provides novel insight into breast cancer dormancy, and also reveals microenvironmental changes that impact dormant breast cancer cell outgrowth.
Citation Format: Qihao Ren, Weng Hua Khoo, Jiayu Ye, Douglas V. Faget, Peter I. Croucher, Sheila A. Stewart. Investigating the intrinsic and extrinsic factors regulating breast cancer dormancy [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 2450.
Abstract 2588: M1774, a novel potent and selective ATR inhibitor, shows antitumor effects as monotherapy and in combination
Authors: Zimmermann Astrid , Dahmen Heike , Grombacher Thomas , Pehl Ulrich , Blaukat Andree , Zenke Frank T. 
Published: June 2022

Abstract
The protein kinase ataxia telangiectasia- mutated and Rad3-related (ATR) is an important component of the DNA Damage Response (DDR) and a key mediator of the replication stress response (RSR). ATR is recruited to and activated by single-stranded DNA, which commonly forms as a consequence of replication stress (RS). ATR activation and signaling coordinates a multifaceted response to RS, however if left unresolved, replication forks may collapse, form double-strand breaks (DSB), lead to chromosomal rearrangements and eventually cell death. Several chemotherapeutic agents act by increasing RS in tumor cells, by directly damaging the DNA and/or depleting cellular resources required for DNA replication. Increased RS may also result from activation of oncogenes that drive dysregulated replication, a hypoxic environment, or from defects in other repair pathways even in the absence of exogenous DNA damaging insults. Inhibition of ATR activity in cancer cells disables the RSR, potentially enhancing the cytotoxicity of DNA damaging interventions and causing efficacy as monotherapy against tumors with reliance on ATR activity. M1774 is a potent inhibitor of ATR protein kinase with high selectivity towards other protein kinases. A broad range of antiproliferative activities (ranging from ~20 nM to &gt;1 µM) was observed in a cancer cell line panel in vitro. M1774 showed pronounced synergy in combination with several DNA-damaging drugs and inhibitors of the DNA damage response. In vivo efficacy studies confirmed the combination potential suggested from in vitro studies. Pronounced combination benefit with complete tumor growth inhibition/regression was observed in combination with different chemotherapies or targeted DDR pathway inhibitors. Furthermore, M1774 showed pronounced activity as monotherapy in tumor models with gene mutations that result in a reliance on ATR activity. Clinical evaluation is ongoing to investigate M1774 as monotherapy and in combination with niraparib in patients with advanced solid tumors (DDRiver Solid Tumors 301, NCT04170153).
Citation Format: Astrid Zimmermann, Heike Dahmen, Thomas Grombacher, Ulrich Pehl, Andree Blaukat, Frank T. Zenke. M1774, a novel potent and selective ATR inhibitor, shows antitumor effects as monotherapy and in combination [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 2588.
Abstract 2621: Growth hormone receptor antagonist sensitizes melanoma and hepatocarcinoma to drug treatments via downregulation of ABC transporters in vivo
Authors: Qian Yanrong , Basu Reetobrata , Mathes Samuel , Kulkarni Prateek , Davis Emily , Berryman Darlene , List Edward , Duran Silvana , Kopchick John J. 
Published: June 2022

Abstract
Knockdown of the growth hormone receptor (GHR) in melanoma cells downregulates ATP-binding cassette (ABC) transporters and sensitizes them to multiple drug treatments in vitro. The goal for this study is to understand whether a GHR antagonist (GHA) could suppress different types of cancers by sensitizing tumors to drug treatments in vivo through the downregulation of ABC transporters. Sera from GHA transgenic mice inhibited the proliferation of mouse melanoma cells (B16F10) in culture and suppressed expression of multiple ABC transporters. When B16-F10 cells were intradermally inoculated into GHA mice, tumor size was markedly reduced, as was STAT5 activation and ABCG1, ABCG2 levels. We then tested the effect of the GHA on the efficacy of cisplatin in vivo. GHA sensitized melanomas to cisplatin, leading to the smallest tumors among all groups. GHKO mice showed the same effect. We further extended this investigation to hepatocellular carcinoma (HCC). GHA mice were subcutaneously inoculated with mouse HCC (Hepa1 6 cells) and subsequently treated with sorafenib. The HCC tumors in GHA mice were markedly sensitive to sorafenib treatment compared to the same in wild-type mice. RNA analysis showed that when HCC was exposed to the combined treatment, relatively decreased ABC transporters expression was found. Immunohistochemical staining showed that phosphorylation of STAT5 and ABCB1 were downregulated in HCC tissues, suggesting that GHA in vivo downregulates ABC transporters in HCC, and therefore sensitizes them to sorafenib. Clinical data derived from HCC patients using the TCGA database showed that multiple ABC transporters in both types of cancer correlate with GHR levels; that is, when GHR levels are relatively high, patient survival is significantly decreased. Additionally, higher ABCC1 levels also lead to significantly decreased survival rate in HCC patients. Collectively, the results indicate that a GHA is effective in sensitizing both melanoma and HCC to available treatments in vivo and may be used as a therapeutic strategy for higher efficacy of tumor clearance.
Citation Format: Yanrong Qian, Reetobrata Basu, Samuel Mathes, Prateek Kulkarni, Emily Davis, Darlene Berryman, Edward List, Silvana Duran, John J. Kopchick. Growth hormone receptor antagonist sensitizes melanoma and hepatocarcinoma to drug treatments via downregulation of ABC transporters in vivo [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 2621.
Abstract 2640: Targeted CUL4A inhibition synergizes with cisplatin to yield long-term survival in models of head and neck squamous cell carcinoma through a DDB2-mediated mechanism
Authors: Jones Trace M. , Espitia Claudia M. , Ooi Aikseng , Bauman Julie E. , Carew Jennifer S. , Nawrocki Steffan T. 
Published: June 2022

Abstract
Patients with late-stage and human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) continue to have a very poor prognosis. The development of more effective novel therapies that improve overall survival and overcome drug resistance is an urgent priority. We, and others, have reported that HNSCC tumors significantly overexpress NEDD8 and exhibit high sensitivity to the first-in-class NEDD8 activating enzyme (NAE) inhibitor pevonedistat. Here, we report that disruption of NEDD8-mediated protein turnover with pevonedistat dramatically augments cisplatin-induced DNA damage and apoptosis in HNSCC models. Further analysis revealed that the specific pevonedistat target, CUL4A, played an essential role in driving the synergy of the pevonedistat and cisplatin combination. Targeted inhibition of CUL4A resulted in significant downregulation in Damage Specific DNA binding protein 2 (DDB2), a DNA-damage recognition protein that promotes nucleotide excision repair and resistance to cisplatin. Silencing of CUL4A enhanced cisplatin-induced DNA damage and apoptosis in a manner similar to that of pevonedistat demonstrating that targeted inhibition of CUL4A may be a novel approach to augment cisplatin therapy. Administration of pevonedistat to mice bearing HNSCC tumors significantly decreased DDB2 expression in tumor cells, increased DNA damage and potently enhanced the activity of cisplatin to yield tumor regression and long-term survival of all animals. Our findings provide strong rationale for clinical investigation of CUL4A inhibition with pevonedistat as a novel strategy to augment the efficacy of cisplatin therapy for patients with HNSCC and identify loss of DDB2 as a key pharmacodynamic mediator controlling sensitivity to this regimen.
Citation Format: Trace M. Jones, Claudia M. Espitia, Aikseng Ooi, Julie E. Bauman, Jennifer S. Carew, Steffan T. Nawrocki. Targeted CUL4A inhibition synergizes with cisplatin to yield long-term survival in models of head and neck squamous cell carcinoma through a DDB2-mediated mechanism [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 2640.
Abstract 2653: Synthetic, small molecule glycosaminoglycan mimetics induce novel anti-cancer activity through preferential targeting of a growth factor receptor
Authors: O'Hara Connor , Morla Shravan , Ongolu Ravikumar , Patel Nirmita , Boothello Rio , Patel Bhaumik , Desai Umesh 
Published: June 2022

Abstract
Glycosaminoglycans (GAGs), such as heparan sulfate (HS), have been implicated in tumor initiation, progression and metastasis. Earlier we have shown that a defined GAG sequence of six residues, but not four or eight residues, inhibits colorectal cancer stem cells (CSCs) by inducing activation of p38 MAPK. To transform this sequence into a drug-like molecule, we developed a synthetic mimetic of the GAG sequence, labeled as G2.2, which was also found to selectively target CSCs over bulk adherent tumor cells. Unfortunately, G2.2’s oral bioavailability was low. To improve upon its drug-like properties, we pursued a hypothesis-driven analog design to derive three lipid-modified analogs (LMAs). Across a panel of &gt; 15 patient-derived colorectal cancer (CRC) cell lines, which could be stratified according to their clinically-relevant consensus molecular subtypes, LMAs showed enhanced potency while retaining selectivity against CSCs in spheroid inhibition assays. Both G2.2 and LMAs displayed better inhibition of cell lines with mesenchymal phenotypes and metabolic dysregulation. Microarray-based screening against more than a dozen receptor tyrosine kinases led to identification of IGF1R as a potential receptor of the synthetic GAG mimetics. To ascertain these screening results, biophysical studies were performed to clarify preferred soluble and/or cell surface target receptors. In line with microarray results, G2.2 preferentially bound to IGF1R in comparison to its soluble ligand IGF-1. G2.2 also preferred IGF1R as compared to an alternative receptor FGFR1. Further, LMAs bound to IGF1R with improved affinities as compared to parent mimetic G2.2, which could explain anti-CSC inhibition results. Unexpectedly, detailed fluorescence titrations revealed that IGF1R affinity of LMAs is minimally impacted by salt concentration, suggesting that these GAG mimetics utilize non-ionic forces in binding, which support the selectivity of target engagement. Overall, this work proves a powerful proof of concept that synthetic GAG mimetics, such as G2.2 and LMAs, present a unique class of anti-cancer therapeutics with high potential for selective elimination of the tumor initiating subpopulation of CRC cells in patient tumors.
Citation Format: Connor O'Hara, Shravan Morla, Ravikumar Ongolu, Nirmita Patel, Rio Boothello, Bhaumik Patel, Umesh Desai. Synthetic, small molecule glycosaminoglycan mimetics induce novel anti-cancer activity through preferential targeting of a growth factor receptor [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 2653.
Abstract 2668: Targeting of ERK and HDAC in the treatment of uveal melanoma
Authors: Musi Elgilda , Dao Kim-Hien , Hindley Chris , Schwartz Gary K. 
Published: June 2022

Abstract
Uveal melanoma is one of the most common intraocular malignancies of the adult eye. GNAQ/GNA11 genetic alterations are present in 85% of cases resulting in activation of the MAPK pathway. Single agent approaches targeting the MAPK pathway and histone deacetylases (HDACs) have shown very modest activity in uveal melanoma. We hypothesize that a combination strategy may be an effective, novel therapeutic approach in uveal melanoma. We examined the activity of ASTX029, a novel dual-mechanism ERK inhibitor, which inhibits both the catalytic activity of ERK and its phosphorylation by MEK, and belinostat, a pan-HDAC inhibitor, in one GNAQQ209L- (92.1) and GNAQQ209P- (OMM1.3) and two GNA11Q209L-mutant (MP41, OMM1) uveal melanoma cell lines. The uveal melanoma cell lines were sensitive to ASTX029 with IC50 values between 50 to 100nM and to belinostat with IC50 values between 100 to 250nM. Combination index analysis of ASTX029 and belinostat by the Chou-Talalay method indicated synergism, with CI values ranging from 0.34 to 0.97. We explored other drug candidates for combinatorial approaches including the BCL-2 inhibitor navitoclax, but no combination effect was observed. After 48h of combination treatment with ASTX029 and belinostat, we examined the biochemical effects by western blot which demonstrated a sustained decrease in levels of p-ERK with the combination treatment. Western blot analysis confirmed reduction of downstream markers of MAPK pathway activity including cell cycle markers p-RB (780), cyclin D1 and c-myc with combination treatment. Apoptosis was evident from an increase in the subG1 population by flow cytometry analysis, which correlated with BIM induction and PARP cleavage on western blot. We also observed increased surface expression of immunological markers HLA-A, B, C (MHC Class 1), PD-L1, gp100 and MART-1. These results support that a combination strategy targeting ERK and HDAC in uveal melanoma should be investigated further.
Citation Format: Elgilda Musi, Kim-Hien Dao, Chris Hindley, Gary K. Schwartz. Targeting of ERK and HDAC in the treatment of uveal melanoma [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 2668.
Abstract 268: Role of aquaporins in mechanotransduction and extracellular vesicle-mediated cancer cell communication in complex physical microenvironments
Authors: Smith Ian , Moses Allison , Kronstadt Stephanie , Jay Steven , Stroka Kimberly 
Published: June 2022

Abstract
Introduction: Metastasis is driven by the migration of cancer cells to different areas of the body, but the mechanisms that induce cell movement are still poorly understood. Aquaporins (AQPs), transmembrane water transport proteins, have been linked to tumor growth, metastasis, and more invasive phenotypes. However, the exact mechanisms behind AQP dysregulation and its role in mediating cancer migration remain unknown. Physical cues and extracellular signals from the tumor microenvironment have been implicated in the progression of cancer; yet the role AQPs play in sensing and signaling have yet to be elucidated. Recent studies have shown the paracrine signaling within the tumor microenvironment is mediated in part by cell secreted extracellular vesicles (EVs). EVs are membrane-delimited nanoparticles capable of protecting and transporting protein and nucleic acid cargo for intercellular communication. EV mediated paracrine signaling has been shown to participate in various steps of tumor progression. Cells are also able to sense complex mechanical signals from the tumor microenvironment to direct more invasive cellular responses. Understanding the role AQPs play in sensing and signaling within the tumor microenvironment can provide a more holistic view of the way AQPs influence cancer progression.
Materials and Methods: To study the role of AQP containing EVs and AQPs influence on mechanotransduction to facilitate cancer cell migration, this study has employed 3D in vitro models, including microfluidic devices, to recapitulate relevant in vivo conditions in concert with confocal microscopy to understand cell behaviors. EVs were isolated via tangential flow filtration. AQP levels were down regulated with siRNA complex or upregulated via AQP5-GFP plasmids.
Results: Knocking down AQPs with siRNAs, confirmed with western blotting, was shown to reduce cellular migration on 2D surfaces and in confining microenvironments. We have also found that AQPs can enhance the integrin mediated mechanotransduction pathway, which has been implicated in cell proliferation and migration. Effects of integrin mediated mechanotransduction were reversed by suppressing AQP expression. Finally, we have made the exciting discovery that cancer cells secrete extracellular vesicles that contain AQPs. These EVs could be released into the tumor microenvironment to enhance tumor migration. Further work is being conducted to elucidate the AQP-EV relationship.
Citation Format: Ian Smith, Allison Moses, Stephanie Kronstadt, Steven Jay, Kimberly Stroka. Role of aquaporins in mechanotransduction and extracellular vesicle-mediated cancer cell communication in complex physical microenvironments [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 268.