bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5681: Metabolic targeting of NRF2 potentiates the efficacy of TRAP1 inhibitor GTPP in colorectal cancer
Authors: Tsai Hong-Yuan , Chen Ru , Shroyer Noah , Pan Sheng 
Published: June 2022

Abstract
Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial homolog of HSP90 chaperones. It plays an important role in protection against oxidative stress and apoptosis by regulating reactive oxidative species (ROS) and may also exert the cytoprotective activities by regulating mitochondrial permeability transition pore opening. Recent studies have suggested that TRAP1 may regulate metabolism and mitochondrial homeostasis in cancer. To further elucidate the mechanistic role of TRAP1 in regulating tumor cell survival, we used cellular models to investigate cellular effects and signaling pathways regulated by TRAP1 in several colon cancer cell lines. Inhibition of TRAP1 by a small molecule inhibitor, Gamitrinib-triphenylphosphonium (GTPP), in colon cancer cells led to ROS production, ER stress, reduction of cell viability and induction of cell death. Interestingly, we observed wide-range of responses to TRAP1 inhibition among these colon cancer cell lines. In GTPP sensitive cell lines (SW48), GTPP induced upregulation of GRP78, CHOP and cleavage form PARP proteins. In contract, in GTPP resistant cells (DLD1 and RKO), GTPP treatment highly induced activation of antioxidant gene NRF2, leading to better cell survival under oxidative environment. NRF2 target genes HO1 and NQO1 were upregulated in GTPP-treated DLD1 cells, making these cells more resistant to GTPP treatment. Using reporter assay, we further found that transcriptional activation of antioxidative responds element (ARE) was increased in GTPP-treated DLD1 and RKO cells (GTPP resistant), but not in SW48 cells (GTPP sensitive). Combination of NRF2 inhibitor ML385 and GTPP led to excessive ROS production and exacerbated GTPP-induced cell death in GTPP resistant cells. These new findings for the first-time link TRAP1 and NRF2 in a common pathway regulating ROS production in colon cancer. Taken together, dual targeting of TRAP1 and NRF2 may potentially overcome the tumor cell resistance through disruption of mitochondrial redox homeostasis.
Citation Format: Hong-Yuan Tsai, Ru Chen, Noah Shroyer, Sheng Pan. Metabolic targeting of NRF2 potentiates the efficacy of TRAP1 inhibitor GTPP in colorectal cancer [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 5681.
Abstract 5682: Accelerated biological age is a driver of cancer susceptibility in genetic high risk breast tissue
Authors: Miyano Masaru , Shalabi Sundus , Sayaman Rosalyn W. , Stampfer Martha , Seewaldt Victoria E. , LaBarge Mark A. 
Published: June 2022

Abstract
During aging in the human mammary gland, luminal epithelial cells lose lineage fidelity by expressing markers normally expressed in myoepithelial cells. We hypothesize that loss of lineage fidelity is a general manifestation of epithelia that are susceptible to cancer initiation. We show that histologically normal breast tissue from younger women who are susceptible to breast cancer because they harbor a germline mutation in BRCA1, BRCA2, or PALB2 genes, exhibit hallmarks of accelerated aging. These include proportionately increased luminal epithelial cells that acquired myoepithelial markers, decreased proportions of myoepithelial cells, and a basal differentiation bias or failure of differentiation of cKit+ progenitors. High-risk luminal and myoepithelial cells are transcriptionally enriched for genes of the opposite lineage, inflammatory, and cancer-related pathways. Genetically high risk luminal epithelial cells also show evidence of accelerated age, by as much as four decades compared to their chronological age, using a breast specific biological clock comprised of measurements of methylation and expression of the luminal-specific ELF5 transcription factor. We have identified breast aging hallmarks that reflect a convergent biology of cancer susceptibility, regardless of the specific underlying genetic or age-dependent risk, or the associated breast cancer subtype.
Citation Format: Masaru Miyano, Sundus Shalabi, Rosalyn W. Sayaman, Martha Stampfer, Victoria E. Seewaldt, Mark A. LaBarge. Accelerated biological age is a driver of cancer susceptibility in genetic high risk breast tissue [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 5682.
Abstract 5684: Protein homeostasis modulation is critical for cancer cell survival upon chaperone mediated proteotoxic stress
Authors: Sannino Sara , Brodsky Jeffrey L. 
Published: June 2022

Abstract
Cancer cells survive under extreme environments that alter protein homeostasis, thereby provoking cellular stress responses, such as the unfolded protein response (UPR) and the integrated stress response (ISR). These pathways increase the expression of molecular chaperones to prevent the accumulation of toxic proteins in the cell. One molecular chaperone in particular, Hsp70, plays a central role in both cellular protection and the response to proteotoxic insults. This is perhaps most evident in cancer cells, some of which overexpress Hsp70 and thrive even when harboring high levels of misfolded, aggregated, and/or unassembled protein complexes. In an effort to define how cells compensate for compromised proteostasis, we examined the adaptive response in breast cancer cells after challenge with a specific Hsp70 inhibitor. We first showed that established breast cancer cell lines bin into classes based on their sensitivity to the drug. We next discovered that resistant cells have higher autophagy levels compared to the more sensitive lines. Moreover, gene and protein expression studies and imaging methods showed that autophagy was further induced by Hsp70 inhibition in resistant breast cancer cells. Consistent with the fact that Hsp70 normally targets aberrant proteins for degradation, our data indicated that resistance to compromised Hsp70 activity arose from elevated levels of autophagy. We next showed that Hsp70 inhibition specifically triggers the ISR pathway. Unexpectedly, protection against the Hsp70 inhibitor was dependent on the ISR sensor, GCN2, which is most commonly associated with the amino acid starvation response. In contrast, sensitive cells succumbed to Hsp70 inhibition by activating the PERK pathway. These data reveal an unexpected route through which cancer cells can adapt to chaperone targeted-proteotoxicity and position GCN2 and autophagy as critical compensatory mechanisms for cancer cells when proteostasis is compromised.
Citation Format: Sara Sannino, Jeffrey L. Brodsky. Protein homeostasis modulation is critical for cancer cell survival upon chaperone mediated proteotoxic stress [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 5684.
Abstract 5692: Tissue specificity of chromosome aneuploidy correlates with BRCA-associated cancer risk
Authors: Wang Xinfeng , Jun Tomi , Sun Nan , He Jie , Huang Kuan-lin 
Published: June 2022

Abstract
Pathogenic germline variants of BRCA1 and BRCA2 disproportionally elevated the risk of specific cancer types (ex. breast [BRCA] and ovarian [OV] cancer) compared to tumors arising from other tissues. The reason underlying the strong tissue-specificity for BRCA-associated cancer risk remains largely unknown. Under the two-hit hypothesis, BRCA-mediated oncogenesis is thought to originate from a cell where the germline BRCA1/2 variant underwent loss of heterozygosity (LOH) of the wildtype BRCA allele, resulting in homologous recombination DNA repair deficiencies. Notably, tumor aneuploidy and loss of chromosome arms also show strong tissue specificity across cancer types. The apparent tissue specificities of BRCA-associated cancer risk and chromosome aneuploidy, together with deletion-induced LOH underlying the two-hit hypothesis, pose an intriguing possibility that they may be linked. Using genomic data from the TCGA PanCanAtlas and ICGC PCAWG projects, we calculated the frequencies of deletions of the chromosomal arms where the BRCA1/2 genes are located (17q for BRCA1; 13q for BRCA2) across different cancer types in tumors with no whole-genome doublings (WGD). Among TCGA cases, OV and BRCA showed significantly higher frequencies of 17q deletion (32.75% and 8.05%, respectively) than other cancer types (ranked 2/30 and 5/30, permutation p-value = 0.030 and 0.024), and relatively higher frequencies of 13q deletion (32.75% and 21.92%, respectively) compared to other cancers (ranked 5/32 and 8/32, p-value = 0.101 and 0.078). As expected, cancer types showing high fractions of BRCA1/2 deletions overlap with those showing 17q/13q deletions and often include BRCA and OV. Subsequently, we determined how often BRCA1/2 deletion co-occurred and thus may be caused by the corresponding 17q/13q deletions, showing that BRCA1 deletion carriers who also had chr17q deletion accounted for 40.76% in OV and 25.93% in BRCA patients, compared to 33.33% in all other cancer types while BRCA2 deletion carriers who also had chr13q deletion accounted for OV (53.97%) and BRCA (58.60%) patients, compared to 49.83% in all other cancer types. In addition, we validated our findings in non-overlapping cases of the ICGC PCAWG projects. Consistent with TCGA results, OV and BRCA showed higher frequencies of 17q and 13q deletion compared to other cancer types. To conclude, we identified a correlation between cross-cancer difference in arm-level and focal chromosome aneuploidy affecting BRCA1/2 and BRCA-associated cancer risk, and how chromosome aneuploid may give rise to tissue-specific risks of cancer remain to be investigated.
Citation Format: Xinfeng Wang, Tomi Jun, Nan Sun, Jie He, Kuan-lin Huang. Tissue specificity of chromosome aneuploidy correlates with BRCA-associated cancer risk [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 5692.
Abstract 5695: Roles of cGAS in DNA damage response
Authors: Chen Weidong , An Hyun-Jung , Lee Ga-Eun , Cho Yong-Yeon 
Published: June 2022

Abstract
Cytosolic double strand DNAs released from the nucleus or mitochondria produce diverse cellular signals mediated by cyclic GAM-AMP synthase (cGAS) to modulate cell proliferation, metastasis, apoptosis, and necroptosis. However, the role of cGAS has not been fully elucidated when cells are stimulated with DNA damage response such as ultraviolet (UV). In this study, we found that DNA damage by treatment of cisplatin or UVB induced cGAS protein levels. We further found that cisplatin and UVB increased not only endogenous cGAS protein levels, but also ectopic expressed cGAS protein levels. The cGAS protein increase was showed positive correlation with H2AX phosphorylation at Ser139 (γH2AX). Moreover, although UVB stimulation suppressed cell proliferation in both stably expressing mock control (SK-MEL-2-mock) and cGAS in SK-MEL-2 (SK-MEL-2-cGAS) cells, suppression ratio in SK-MEL-2-cGAS cells was reduced compared to SK-MEL-2-mock cells. These results suggested that cGAS may have a potential to cell protection when the cells are stimulated with DNA damage. This hypothesis was supported by that cell proliferation of SK-MEL-2-cGAS cells were 2 folds faster than that of SK-MEL-2-mock cells after UVB stimulation. We further found that living cell population of SK-MEL-2-cGAS cells, which were 80% in no UVB stimulation, was reduced to 37% at 24 h and 34% at 48 h after 2 mJ/cm2 UVB stimulation, while SK-MEL-2-mock cells were reduced to 37% at 24 h and 20% at 48 h after 2 mJ/cm2 UVB stimulation. On the other hand, total cell death about 40% at 24 h and 65% at 48 h in SK-MEL-2-mock cells was reduced about 25% at 24 h and 36% at 48 h in SK-MEL-2-cGAS cells after 2 mJ/cm2 UVB stimulation. Taken together, we concluded that cGAS may play an important role to protect the cells from DNA damage.
Citation Format: Weidong Chen, Hyun-Jung An, Ga-Eun Lee, Yong-Yeon Cho. Roles of cGAS in DNA damage response [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 5695.
Abstract 5696: Effect of extracellular matrix stiffness on cancer cells radiation response
Authors: Lacombe Jerome , Muccio Melinda , Zenhausern Frederic 
Published: June 2022

Abstract
Over the past decade, it has become clear that the mechanical cues of extracellular matrix (ECM) are a major regulator of the cancer biology. In particular, ECM stiffness has shown an important role in chemoresistance modulation. However, despite the central role of radiotherapy in cancer management, little is known about the effect of ECM stiffness on cancer cells radiation response. In this study, we used polyacrylamide collagen-coated hydrogel model to reproduce a soft (0.7 kPa) and a stiff (70 kPa) matrix. The model was validated by atomic force microscopy force spectroscopy and biological analyses through cellular morphology, proliferation and YAP/TAZ mechanotransduction pathway that all confirmed the accuracy of our model. Then, lung cancer cells seeded on both soft and stiff hydrogels were irradiated, and the level of DNA damages were compared between the two conditions. First, alkaline comet assay revealed the total amount of DNA damages were higher in cells grown on a rigid ECM at 1 h post-irradiation than cells seeded on a soft matrix. Second, γH2AX/53BP1 foci assay showed that the number of DNA double strand breaks were also higher in cells grown on a rigid environment. However, the level of DNA damage was identical at 24 h post-irradiation for both stiffness, suggesting that a more efficient DNA damage repair response could take place for cells seeded in stiff matrix. In order to explain these observations, analyses on chromatin structure and nucleus shape were then performed. Data showed that cells cultured on stiff matrix displayed a larger nucleus, less condensed chromatin, and a decreased expression level of class I HDACs genes. Moreover, it was found that the level of total reactive oxygen species (ROS) and superoxide ion was also higher in cells grown on a rigid environment 24 h post-irradiation. Altogether these data suggest that a high stiffness may increase early DNA damages after irradiation, partially by remodeling chromatin that could expose DNA to radiation-induced genotoxic agents such as ROS. Additional investigations are required to understand better the mechanisms that could explain such differences, but these preliminary data highlighted the potential role of mechanical stress in cellular radiation response and paved the way to new therapeutic target for radiotherapy management.
Citation Format: Jerome Lacombe, Melinda Muccio, Frederic Zenhausern. Effect of extracellular matrix stiffness on cancer cells radiation response [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 5696.
Abstract 5708: The DNA methylation landscape of prostate cancer brain metastases
Authors: Gallon John , Rodriguez-Calero Antonio , Maletti Sina , Ng Charlotte , Rubin Mark , Piscuoglio Salvatore 
Published: June 2022

Abstract
Introduction: Improved survival in prostate cancer through more effective therapies has also led to an increase in the diagnosis of metastases to infrequent locations such as the brain. In the largest cohort of prostate cancer brain metastases (PCBM) yet studied, we investigated the DNA methylation landscape of PCBM.
Methods: Using Illumina EPIC arrays, we profiled the DNA methylation landscapes of 95 metastatic samples from 42 patients, with multi-regional analysis of the metastases from 31 patients. We compared DNA methylation profiles from metastases to the primary prostate cancer (PCa) samples of 18 of these patients. Multi-regional data was obtained for 15 of these. We performed unsupervised analyses of DNA methylation profiles across sample types, and identified differentially methylated CpG sites and regions (DMRs) between PCBM and PCa samples, and PCBM/PCa samples and normal prostate tissue. We integrated our data with targeted-RNA sequencing and whole exome sequencing (WES).
Results: We highlight the epigenetic heterogeneity present in different regions of the PCBM from patients for which multi-regional data were available. While substantial DNA methylation changes were detected in PCa compared to normal prostate tissue, epigenetic dysregulation was strikingly more pronounced in PCBM samples. DNA methylation changes in PCBM involved striking hypermethylation particularly enriched at CpG islands, and associated with activity of the PRC2 complex. We observed a marked distinction of the methylation profiles of SPOP mutant and TMPRSS2-ERG samples. SPOP mutant samples acquired substantially more epigenetic aberrations, particularly enriched at CpG islands which were hypermethylated genome-wide compared to TMPRSS2-ERG PCBM samples, as well as SPOP mutant PCa samples. These changes were strongly associated with the activity of EZH2 and MYC, both of which were overexpressed specifically in SPOP mutant PCBM. TMPRSS2-ERG samples showed fewer DNA methylation changes, but those detected were associated with targets of the SP1 transcription factor.
Conclusion: We show that epigenetic heterogeneity is present in different regions of PCBM. While the distinct methylation landscapes of SPOP mutant and TMPRSS2-ERG PCa has been previously reported, we show that metastasis-specific DNA methylation changes emerge in each of these settings. These observations suggest that the acquisition of DNA methylation changes may be an important feature of PCBM, and may help to improve our understanding of the processes driving the occurrence of these rare metastases.
Citation Format: John Gallon, Antonio Rodriguez-Calero, Sina Maletti, Charlotte Ng, Mark Rubin, Salvatore Piscuoglio. The DNA methylation landscape of prostate cancer brain metastases [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 5708.
Abstract 5726: Splicing-based classifier for gastric cancer identifies epithelial-mesenchymal transition subtypes associated with survival
Authors: Jun Yukyung , Suh Yun-Suhk , Park SungHee , Lee Jieun , Kim Jong-Il , Lee Sanghyuk , Lee Wan-Ping , Anczuków Olga , Yang Han-Kwang , Lee Charles 
Published: June 2022

Abstract
Alternatively spliced RNA isoforms are a hallmark of tumors, but their nature, prevalence, and clinical implications in gastric cancer are unknown. We systematically profiled the splicing landscape of 83 gastric tumors and matched normal mucosa. We identified and experimentally validated eight splicing events that can classify all gastric cancers into three subtypes: Epithelial-splicing, Mesenchymal-splicing, and Hybrid-splicing. These subtypes were associated with distinct molecular signatures and epithelial-mesenchymal transition markers. Subtype-specific splicing events were enriched in motifs for splicing factors RBM24 and ESRP1, which were upregulated in Mesenchymal-splicing and Epithelial-splicing tumors, respectively. A simple classifier based only on RNA levels of RBM24 and ESRP1, and which is thus readily implementable in the clinic, is sufficient to distinguish gastric cancer subtypes and predict patient survival in multiple independent patient cohorts
Citation Format: Yukyung Jun, Yun-Suhk Suh, SungHee Park, Jieun Lee, Jong-Il Kim, Sanghyuk Lee, Wan-Ping Lee, Olga Anczuków, Han-Kwang Yang, Charles Lee. Splicing-based classifier for gastric cancer identifies epithelial-mesenchymal transition subtypes associated with survival [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 5726.
Abstract 5731: Structure-based development of a novel MYC inhibitor for neuroendocrine prostate cancer
Authors: Foo Jane , Ton Anh-Tien , Singh Kriti , Ban Fuqiang , Morin Helene , Lee Joseph , LeBlanc Eric , Lallous Nada , Cherkasov Artem 
Published: June 2022

Abstract
Background: MYC oncoproteins are important drivers of human cancers. More specifically, NMYC is amplified and overexpressed in neuroendocrine prostate cancer (NEPC). NMYC elicits its oncogenic effects by forming a heterodimer with MAX. This complex binds to regulating elements and activates the transcription of MYC target genes that play roles in tumor growth and progression. It is well known that members of the MYC family of proteins make compelling targets for cancer treatments. However, to this date, no tangible drug candidates have been developed into the clinics for MYC. In previous studies utilizing a rational computer-aided drug discovery (CADD) approach, we identified VPC-70551 as our most active hit. Subsequent optimization with the VPC-70551 scaffold has led to the identification of a new series of compounds. Using in silico drug screening followed by functional validation, we identified a small molecule inhibitor, VPC-70619, that exhibits higher microsomal stability and is better absorbed and tolerated orally than most MYC inhibitors described in the literature.
Method: We used a transcriptional reporter assay to determine the effect of VPC-70619 on MYC-mediated transcription. To validate on-target effect, we evaluated the effect of VPC-70619 treatment on MYC-positive (LASCPC-01, NCIH660, LNCaP N-MYC, 22Rv1 N-MYC) and MYC-negative (HO15.19) cancer cells. We also evaluated the effect of VPC-70619 on MYC/MAX interaction by PLA and on DNA binding by BLI. The direct binding between recombinant MYC/MAX protein complex and VPC-70619 was evaluated by MST.
Results: VPC-70619 inhibited MYC transcriptional activity in dose dependent manner and the proliferation of MYC-positive cell lines. VPC-70619 did not interfere with MYC/MAX interaction however it blocked the complex interaction with DNA. We confirmed the direct binding of VPC-70619 to the purified MYC/MAX complex by using MST.
Conclusion: This project presents the identification of a new MYC inhibitor that blocks the transcriptional activity of this oncogene and elucidates the molecular mechanism of action of this inhibitor. Our findings help prelude the development and discovery of more effective treatments for NEPC patients.
Citation Format: Jane Foo, Anh-Tien Ton, Kriti Singh, Fuqiang Ban, Helene Morin, Joseph Lee, Eric LeBlanc, Nada Lallous, Artem Cherkasov. Structure-based development of a novel MYC inhibitor for neuroendocrine prostate cancer [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 5731.