bluuebunny/crossref_metadata_2025 huggingface dataset:
Item Selection for a New Health-Related Quality of Life Measure for Parkinson’s Disease: The Preference-Based Parkinson’s Disease Index (PB-PDI)
Authors: Malouka Selina , Teshler Lizabeth , Mayo Nancy , Beauchamp Marla , Richardson Julie , Kuspinar Ayse
Published: January 2023

Background. Parkinson’s disease (PD) is a neurodegenerative condition, predominantly affecting older adults. Preference-based measures (PBMs) can be used to make decisions about the cost-utility of different treatments. There are currently no PBMs for health-related quality of life (HRQoL) for PD. A previous study identified important health domains for individuals with PD and developed an item pool from existing measures per domain. The current study aims to contribute to the development of a new disease-specific PBM of HRQoL for PD by reducing the current pool of items according to the preferences of individuals with PD. Methods. Fifty-three participants completed a visual analogue scale (VAS) of self-perceived health, the prototype PBM measure, and an item importance rating. To reduce the item pool, the following were calculated: (1) inter-item correlations; (2) impact of each item based on item performance and importance rating; (3) directionality of response options by comparing the VAS scores against each item. Results. Participants (male = 54.7%, age = 60.0 ± 10.2) had a median Hoehn and Yahr score of 2.5 (interquartile range = 1). Items supported for inclusion by this analysis were sleep, fatigue, tremor, mood, walking, memory, and dexterity. Items demonstrating a logical decrease in VAS score with each increasing severity level were sleep, memory, tremor, fatigue, and mood. Conclusion. This PBM will be critical for informing decisions about the cost-utility of PD treatments, guiding the resource allocation within our healthcare system. Future research will include cognitive debriefing with individuals with PD to refine item response options.
Transcriptome Analysis of Key Genes Involved in Color Variation between Blue and White Flowers of Iris bulleyana
Authors: Ma Lulin , Zhang Yiping , Cui Guangfen , Duan Qing , Jia Wenjie , Xu Feng , Du Wenwen , Wang Xiangning , Li Xiang , Chen Fadi , Wang Jihua
Published: January 2023

Iris bulleyana Dykes (Southwest iris) is an extensively distributed Iridaceae species with blue or white flowers. Hereby, we performed a systematic study, employing metabolomics and transcriptomics to uncover the subtle color differentiation from blue to white in Southwest iris. Fresh flower buds from both cultivars were subjected to flavonoid/anthocyanin and carotenoid‐targeted metabolomics along with transcriptomic sequencing. Among 297 flavonoids, 24 anthocyanins were identified, and 13 showed a strong down‐accumulation pattern in the white flowers compared to the blue flowers. Significant downregulation of 3GT and 5GT genes involved in the glycosylation of anthocyanins was predicted to hinder the accumulation of anthocyanins, resulting in white coloration. Besides, no significant altered accumulation of carotenoids and expression of their biosynthetic genes was observed between the two cultivars. Our study systematically addressed the color differentiation in I. bulleyana flowers, which can aid future breeding programs.
Evaluation and Comparison of Different Methods for Improving Fault Ride-Through Capability in Grid-Tied Permanent Magnet Synchronous Wind Generators
Authors: Mahmoud Mohamed Metwally , Atia Basiony S. , Esmail Yahia M. , Bajaj Mohit , Mbadjoun Wapet Daniel Eutyche , Ratib Mohamed Khalid , Biplob Hossain Md. , AboRas Kareem M. , Abdel-Rahim Abdel-Moamen M.
Published: January 2023

Several advantages make wind-driven permanent magnet synchronous generators (PMSGs) very promising in the wind energy market, especially their fault ride-through capabilities. With the high penetration levels of today, both the grid and wind power (WP) systems are being affected by each other. Due to grid faults, the DC-bus in PMSG systems typically experiences overvoltage, which can negatively affect the generator parameters and trip the system. However, advancements in power electronics, control systems, fault limiters, FACTS, and energy storage technology make it possible to find and design satisfactory solutions and approaches. The most recent FRTC-improving techniques are mainly modified or external techniques based on controllers in PMSG-based WP. This paper evaluates the in-depth schemes of FRTC, introducing the underlying theory and traits of the different approaches to highlight the advantages and drawbacks of each. Five scenarios of DC-link voltage under zero-grid voltage are carried out by using the MATLAB SIMULINK program to assess the FRTC methods. This study shows that external device-based approaches can be efficient, but some of them are expensive, thus updated controller methods are recommended to cut costs. Research findings of this study are expected to support the deployment of FRTC technologies, as well as provide valuable input into WP research on grid integration.
Research on Urban Road Network Evaluation Based on Fractal Analysis
Authors: Wen Wen , Zhang Wenhui , Deng Hongxing
Published: January 2023

The structure of the urban road network affects the mode of urban development and the position of urban social and economic activities, families, and employment centers. Therefore, it is necessary to consider the supply inequality of urban road network and its impact on urban development so as to form a sustainable and fair urban development model in cities. Based on the fractal analysis, this paper seeks the evaluation index of urban road network layout and internal structure characteristics to guide the optimization and adjustment of the urban road network, which is of great significance for guiding urban land use, effectively utilizing geospatial space, and promoting sustainable urban development, and attempts to apply the fractal analysis concept to evaluate the urban road network in Harbin, China. It is found that there is a good relationship between the length of the urban road network and the build-up area. Therefore, fractal analysis is used to reasonably determine the spatial demand of incremental road networks, considering the impact of road network increase on development mode. This paper argues that fractal analysis is an auspicious tool for the evaluation of urban road networks, including solving the problem of supply inequality in urban road networks, which is very suitable for the gradual construction of road networks in urban situations, especially in the development environment of road networks with scarce resources.
NFE2L2Mutations Enhance Radioresistance in Head and Neck Cancer by Modulating Intratumoral Myeloid Cells
Authors: Guan Li , Nambiar Dhanya K. , Cao Hongbin , Viswanathan Vignesh , Kwok Shirley , Hui Angela B. , Hou Yuan , Hildebrand Rachel , von Eyben Rie , Holmes Brittany J. , Zhao Junfei , Kong Christina S. , Wamsley Nathan , Zhang Weiruo , Major Michael B. , Seol Seung W. , Sunwoo John B. , Hayes D. Neil , Diehn Maximilian , Le Quynh-Thu
Published: January 2023

Radiotherapy (RT) is one of the primary treatments of head and neck squamous cell carcinoma (HNSCC), which has a high-risk of locoregional failure (LRF). Presently, there is no reliable predictive biomarker of radioresistance in HNSCC. Here, we found that mutations in NFE2L2, which encodes Nrf2, are associated with a significantly higher rate of LRF in patients with oral cavity cancer treated with surgery and adjuvant (chemo)radiotherapy but not in those treated with surgery alone. Somatic mutation of NFE2L2 led to Nrf2 activation and radioresistance in HNSCC cells. Tumors harboring mutant Nrf2E79Q were substantially more radioresistant than tumors with wild-type Nrf2 in immunocompetent mice, whereas the difference was diminished in immunocompromised mice. Nrf2E79Q enhanced radioresistance through increased recruitment of intratumoral polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) and reduction of M1-polarized macrophages. Treatment with the glutaminase inhibitor CB-839 overcame the radioresistance induced by Nrf2E79Q or Nrf2E79K. RT increased expression of PMN-MDSC–attracting chemokines, including CXCL1, CXLC3, and CSF3, in Nrf2E79Q-expressing tumors via the TLR4, which could be reversed by CB-839. This study provides insights into the impact of NFE2L2 mutations on radioresistance and suggests that CB-839 can increase radiosensitivity by switching intratumoral myeloid cells to an antitumor phenotype, supporting clinical testing of CB-839 with RT in HNSCC with NFE2L2 mutations.

Significance:

NFE2L2 mutations are predictive biomarkers of radioresistance in head and neck cancer and confer sensitivity to glutaminase inhibitors to overcome radioresistance.
A Phase I Dose-escalation Study of AZD3965, an Oral Monocarboxylate Transporter 1 Inhibitor, in Patients with Advanced Cancer
Authors: Halford Sarah , Veal Gareth J. , Wedge Stephen R. , Payne Geoffrey S. , Bacon Chris M. , Sloan Philip , Dragoni Ilaria , Heinzmann Kathrin , Potter Sarah , Salisbury Becky M. , Chénard-Poirier Maxime , Greystoke Alastair , Howell Elizabeth C. , Innes William A. , Morris Karen , Plummer Chris , Rata Mihaela , Petrides George , Keun Hector C. , Banerji Udai , Plummer Ruth
Published: January 2023

Purpose:

Inhibition of monocarboxylate transporter (MCT) 1–mediated lactate transport may have cytostatic and/or cytotoxic effects on tumor cells. We report results from the dose-escalation part of a first-in-human trial of AZD3965, a first-in-class MCT1 inhibitor, in advanced cancer.

Patients and Methods:

This multicentre, phase I, dose-escalation and dose-expansion trial enrolled patients with advanced solid tumors or lymphoma and no standard therapy options. Exclusion criteria included history of retinal and/or cardiac disease, due to MCT1 expression in the eye and heart. Patients received daily oral AZD3965 according to a 3+3 then rolling six design. Primary objectives were to assess safety and determine the MTD and/or recommended phase II dose (RP2D). Secondary objectives for dose escalation included measurement of pharmacokinetic and pharmacodynamic activity. Exploratory biomarkers included tumor expression of MCT1 and MCT4, functional imaging of biological impact, and metabolomics.

Results:

During dose escalation, 40 patients received AZD3965 at 5–30 mg once daily or 10 or 15 mg twice daily. Treatment-emergent adverse events were primarily grade 1 and/or 2, most commonly electroretinogram changes (retinopathy), fatigue, anorexia, and constipation. Seven patients receiving ≥20 mg daily experienced dose-limiting toxicities (DLT): grade 3 cardiac troponin rise (n = 1), asymptomatic ocular DLTs (n = 5), and grade 3 acidosis (n = 1). Plasma pharmacokinetics demonstrated attainment of target concentrations; pharmacodynamic measurements indicated on-target activity.

Conclusions:

AZD3965 is tolerated at doses that produce target engagement. DLTs were on-target and primarily dose-dependent, asymptomatic, reversible ocular changes. An RP2D of 10 mg twice daily was established for use in dose expansion in cancers that generally express high MCT1/low MCT4).
Abstract A003: Integrating noise into a signal: Luminal epithelial cells integrate variable responses to aging into stereotypical changes that underlie breast cancer susceptibility
Authors: Miyano Masaru , Sayaman Rosalyn W. , Senapati Parijat , Hinz Stefan , Seewaldt Victoria E. , Schones Dustin , LaBarge Mark A.
Published: January 2023

This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Short Talks from Proffered Abstracts section (PR006) of the Conference Proceedings.

Citation Format: Masaru Miyano, Rosalyn W. Sayaman, Parijat Senapati, Stefan Hinz, Victoria E. Seewaldt, Dustin Schones, Mark A. LaBarge. Integrating noise into a signal: Luminal epithelial cells integrate variable responses to aging into stereotypical changes that underlie breast cancer susceptibility [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A003.
Abstract A004: Identification and characterization of the cancer permissive environment in companion dogs
Authors: Modiano Jaime F. , Schulte Ashley J. , DaPauw Taylor A. , Khammanivong Ali , Kim Jong H. , Sarver Aaron L. , Cutter Gary R. , Lindquist Eric , Makielski Kelly M.
Published: January 2023

This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Short Talks from Proffered Abstracts section (PR008) of the Conference Proceedings.

Citation Format: Jaime F. Modiano, Ashley J. Schulte, Taylor A. DaPauw, Ali Khammanivong, Jong H. Kim, Aaron L. Sarver, Gary R. Cutter, Eric Lindquist, Kelly M. Makielski. Identification and characterization of the cancer permissive environment in companion dogs [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A004.
Abstract A014: Cytokines surge in the blood years prior to a cancer diagnosis in elderly individuals
Authors: Chen Guangbo , Zheng Hong , Rosenberg-Hasson Yael , Araya Saron , Padilla Cindy , Sarin Kavita , Dekker Cornelia L. , Grant Philip , Maecker Holden T. , Furman David , Shen-Orr Shai , Khatri Purvesh , Davis Mark M.
Published: January 2023

This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Short Talks from Proffered Abstracts section (PR002) of the Conference Proceedings.

Citation Format: Guangbo Chen, Hong Zheng, Yael Rosenberg-Hasson, Saron Araya, Cindy Padilla, Kavita Sarin, Cornelia L. Dekker, Philip Grant, Holden T. Maecker, David Furman, Shai Shen-Orr, Purvesh Khatri, Mark M. Davis. Cytokines surge in the blood years prior to a cancer diagnosis in elderly individuals [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A014.
Abstract A026: History of blood transfusion and the risk of developing hematologic cancers in the United States: A cross-sectional study using the NHANES database. [R]
Authors: Ebied Amr , Salemi Jason , Bakour Chighaf , Gillis Nancy
Published: January 2023

Blood transfusion has long been regarded as a determinant of cancer, plausibly because it influences inflammatory and immunological changes in the recipient's body. Recently, there has been evidence of a role of donor-derived malignancy in donors of autologous stem cell transplants, supporting the possible cancer-driving role of age-related clonal hematopoiesis. Given that routine blood transfusion is more ubiquitous than stem cell transplantation, we hypothesize an association between blood transfusion and the occurrence of hematologic malignancies. We conducted a secondary analysis using data from the 2017-2018 survey of the National Health and Nutrition Examination Survey (NHANES). A total of 4,917 participants were included in our final analytic sample, of whom 587 (11.9%) had ever received a blood transfusion. Out of the participants receiving a blood transfusion, six (1.1%) were diagnosed with hematologic cancer versus 9 (0.21%) from the non-transfusion group. Specifically, three (0.51%) participants from the transfusion group were diagnosed with leukemia versus 2 (0.046%) from the non-transfusion group. Using multivariable logistic regression, we have found that, after adjustment of other predictors, people with a history of blood transfusion were 4.08 (95%CI= 1.18-14.05), 2.09 (95%CI= 0.47-9.27), and 6.76 (95%CI= 1.13-40.44) times more likely to report a history of hematologic cancers, Hodgkin lymphoma, and leukemia, respectively than those who were never transfused. In conclusion, we found a possible significant association between blood transfusion and the risk of developing hematological cancers (particularly leukemia) in the United States. Prospective studies are needed to confirm the temporal sequence of blood transfusion and hematologic cancers in that regard.

Citation Format: Amr Ebied, Jason Salemi, Chighaf Bakour, Nancy Gillis. History of blood transfusion and the risk of developing hematologic cancers in the United States: A cross-sectional study using the NHANES database. [R] [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A026.
Abstract B004: Sugar Intake and premature aging in adult survivors of childhood cancer in the St. Jude Lifetime (SJLIFE) Cohort
Authors: Lan Tuo , Wang Mei , Williams AnnaLynn M. , Ehrhardt Matthew J. , Finch Emily R. , Lanctot Jennifer Q. , Jiang Shu , Krull Kevin R. , Armstrong Gregory T. , Hudson Melissa M. , Colditz Graham A. , Robison Leslie , Ness Kirsten K. , Park Yikyung
Published: January 2023

This abstract is being presented as a short talk in the scientific program. A full abstract is available in the Short Talks from Proffered Abstracts section (PR014) of the Conference Proceedings.

Citation Format: Tuo Lan, Mei Wang, AnnaLynn M. Williams, Matthew J. Ehrhardt, Emily R. Finch, Jennifer Q. Lanctot, Shu Jiang, Kevin R. Krull, Gregory T. Armstrong, Melissa M. Hudson, Graham A. Colditz, Leslie Robison, Kirsten K. Ness, Yikyung Park. Sugar Intake and premature aging in adult survivors of childhood cancer in the St. Jude Lifetime (SJLIFE) Cohort [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B004.
Abstract B015: Racial differences in epigenetic aging and its impact on expression of T-cell inhibitory receptors
Authors: Hsu Ping-Ching , Bauer Michael , Chiang Tung-Chin , Rogers Lora J. , Aydin A. Murat , Su L. Joseph , Koss Brian
Published: January 2023

Introduction: Accelerated aging is associated with lifetime stress and frailty, and has been reported in aging-related disease and mortality, including lung cancer, postmenopausal breast cancer, childhood cancer, and coronary heart disease. However, current knowledge on the impact of epigenetic aging in anti-tumor immunity remains limited. Pre-existing immune status heavily contributes to cancer diagnosis and the success of immunotherapy treatment, therefore, the relationship between epigenetic aging and immune function, and how it may lead to racial health disparity needs to be further explored. Methods: Genome-wide DNA methylation analysis were conducted in a feasibility test of 16 participants with equal number of African Americans (AAs) and European Americans (EAs), and epigenetic age (mAge) were calculated using R package methylclock for the established multi-tissue epigenetic clock algorithms which consists of 353 CpGs by Horvath. Correlation analysis was performed between mAge and in vitro T cell activation tests. Results: As expected, high correlation of calculated mAge versus chronological age was observed from 16 participants using the Horvath calculator, with higher mAge in AAs than EAs. Significant separation in DNA methylation profiles between AAs and EAs existed based on the top 1,000 CpG sites from the principal component analysis. To understand the effects of aging on T cell function, a series of functional assays were performed from different age groups, and significant (P<0.05) negative correlations of Age and mAge to flow cytometry defined naïve lymphocyte subsets were detected. Significant positive correlations between mAge and the expression of T-cell inhibitory receptors CTLA4 and TIGIT were observed in activated T cells from this sample population. Conclusion: The human immune system undergoes dramatic aging-related changes, which continuously progress and contribute to the decline in immune-mediated protection against infections and cancer. Our study serves as a proof-of-principle to highlight the degree of accelerated epigenetic aging and its impact on T cells function among different racial and age groups), which warrants further research that may shed more light into therapeutic cellular immune responses and mechanisms of immune-related adverse events in patients treated with immunotherapy for cancer.

Citation Format: Ping-Ching Hsu, Michael Bauer, Tung-Chin Chiang, Lora J. Rogers, A. Murat Aydin, L. Joseph Su, Brian Koss. Racial differences in epigenetic aging and its impact on expression of T-cell inhibitory receptors [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr B015.
Abstract IA001: DNA damage repair: Impact on aging and cancer and applications of nutritional interventions
Authors: Hoeijmakers Jan H
Published: January 2023

Rare DNA repair syndromes display strong cancer predisposition and/or premature aging, indicating that DNA damage underlies both, consistent with the notion that age is the most important risk factor for cancer. We have generated a series of DNA-repair-deficient mouse mutants, and discovered that defects in transcription-coupled repair cause accelerated, segmental aging and overprotect from cancer, whereas global genome repair defects are predominantly associated with cancer. When combined aging is dramatically accelerated, indicating a dose-dependent causal relationship. We also found that premature aging triggers a potent anti-aging ‘survival response’, which suppresses growth (IGF1) and enhances resilience and defenses, resembling the longevity response induced by dietary restriction (DR). Interestingly, subjecting progeroid mutants to actual DR tripled lifespan, and drastically retarded accelerated aging, most notably neurodegeneration. We also found that DR lowered DNA damage, explaining how DR counteracts aging and cancer and why DNA repair mutants overrespond to DR. Interestingly, expression profiles of progeroid mutants showed gradual decline of expression in a genelength-dependent manner, due to genome-wide accumulation of stochastic, transcription-blocking lesions, which affect long genes more than short ones. This transcription stress is also prominent in normal aging of many (post-mitotic) tissues and explains protein aggregation in dementias. DR largely alleviated transcription stress and hence prolongs genome function. I will present phenotypes of conditional DNA repair models targeting aging to selected organs, striking parallels with Alzheimer’s disease and the first remarkable results translating these concepts from mice to repair-deficient children. Our findings identify DNA damage as main cause of aging, establish repair-deficient mice as models for interventions to promote healthy aging, explain the molecular anti-aging, anti-cancer mechanism of DR and the aging component of proteinopathies based on transcription stress and promote counterintuitive DR-like interventions for progeroid syndromes, for preventing neurodegenerative diseases and ischemia reperfusion damage in surgery and for improving chemotherapy outcome and reducing side effects.

Citation Format: Jan H Hoeijmakers. DNA damage repair: Impact on aging and cancer and applications of nutritional interventions [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA001.
Abstract IA016: Epigenetics mechanisms of tissue aging
Authors: Sen Payel
Published: January 2023

Epigenetic alterations are one of the key hallmarks of aging. How epigenetic changes broadly affect euchromatin-heterochromatin balance, three-dimensional chromatin conformation, histone composition and global transcriptome in aging have been limitedly addressed. These outstanding questions are key to understanding the susceptibility of aged tissue to develop cancers, the incidence of which exponentially increases with age. Using murine liver as a model organ and an integrated multi-omics approach, we find that aged cells assume a repressed chromatin state characterized by condensed chromatin, broad heterochromatinization, and global suppression of the transcriptome. At the local level, there are site-specific chromatin openings with simultaneous derepression of genes. Our findings reveal a unique chromatin state in aging with opposing changes at the global and local levels.

Citation Format: Payel Sen. Epigenetics mechanisms of tissue aging [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA016.
Abstract IA022: Age-induced metabolic reprogramming: A bridge between the aging process and tumorigenesis
Authors: Gomes Ana P.
Published: January 2023

Lung cancer accounts for the largest number of cancer-associated deaths in the United States. While great strides have been made due to the introduction of immunotherapies and targeted therapies against oncogenic drivers, chemotherapies remain the standard of care for the majority of lung cancer patients. However, many patients do not respond to these treatments or relapse following an initial response. We postulate that part of the problem is the lack of consideration in preclinical research and clinical trials of the main driver of lung tumorigenesis, the aging process. Here, we show that the organismal metabolic reprogramming that occurs with aging endows cancer cells with pro-aggressive properties favoring progression into metastatic disease through, at least in part, the accumulation in the circulation of methylmalonic acid, a by-product of vitamin B12 deficiency. On the other hand, we also show that this age-induced organismal metabolic reprogramming makes lung tumors intrinsically more resistant to chemotherapies through the chronic upregulation of glucocorticoid hormones. Together, our work demonstrates a role for age-induced systemic metabolic reprogramming in shaping the tumorigenic process toward more aggressive, treatment-resistant disease and offers a rationale for using interventions that ameliorate the metabolic deregulation that occurs with age in the treatment of age-related cancers.

Citation Format: Ana P. Gomes. Age-induced metabolic reprogramming: A bridge between the aging process and tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA022.
Abstract A045: Examining the role of RNA:DNA hybrids (r loops) in glioblastoma multiforme cell motility and invasion
Authors: Morales Julio C. , Dang Tuyen T.
Published: January 2023

Glioblastoma multiforme (GBM) is a highly aggressive brain cancer. The standard course of treatment is a combination of radiation and chemotherapy. Even with the dual treatment, the 5-year survival rate of patients with GBM is between 4-10%. A possible cause of the low survival rate for GBM patients is the presence of motile neoplastic cells with efficient DNA repair abilities. Thus, the two major obstacles to treating GBMs is 1) the tumors inherent invasive nature and 2) the recurrent tumors ability to acquire treatment resistance. As such, gaining a better understanding of the mechanisms mediating GBM recurrence would allow us to design better treatment strategies for patients. We have found that the 5’-3’ exoribonuclease XRN2 is upregulated in GBMs as compared to normal and other brain cancer types. While XRN2 is traditionally associated with the process of transcription termination, our published work has defined a role for XRN2 in the DNA damage response. Our group has shown that loss of XRN2 sensitizes to a variety of DNA damaging agents but in particular ionizing radiation. Previously, we have shown that XRN2 is required for DNA repair, specifically double stranded break (DSB) repair. Loss of XRN2 impairs both the non-homologous end-joining and homologous recombination DSB repair pathways. Loss of XRN2 also results in increased spontaneous DSB formation, chromosomal aberrations and RNA:DNA hybrid (R-loop) formation. In addition to a role in the DNA damage response, we found that loss of XRN2 is required for GBM cell motility, invasion through a matrix and decreased tumor volume in mouse models. Interestingly, R-loop formation can affect gene expression by modulating the access of genes to transcription factors, miRNA transcription, and methylation status of genes. To gain a better understanding of how XRN2 modulates gene expression, we conducted RNA-Seq analyses of GBM cell lines with and without XRN2 expression and found that XRN2 can regulate genes involved in cell movement, cell development and cellular organization programs. Consistent with our findings that XRN2 impairs DNA damage and tumor invasion; XRN2 loss results in R-loop formation in promoters of genes important for tumor invasiveness and DNA repair such as FOXM1 and Cyclin B1. These data suggest that the regulation of R-loop formation is an important determinant in tumor progression.

Citation Format: Julio C. Morales, Tuyen T. Dang. Examining the role of RNA:DNA hybrids (r loops) in glioblastoma multiforme cell motility and invasion [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A045.
Abstract B010: The effects of tumor cell-secreted factors on endothelial cell junction phenotype
Authors: DeCastro Ariana Joy L. , Griffith Lauren , Stroka Kimberly
Published: January 2023

Triple negative breast cancer (TNBC) is subtype of breast cancer that has no expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC metastasizes to specific tissues such as brain and bone in a process termed organotropism. In this process, TNBC cells cross the vascular endothelium; transport across endothelial cells is, in part, regulated by cell-cell junctions. The TNBC cell secretome has been shown to contain factors such as vascular growth factor (VEGF) and matrix metalloproteinases (MMPs) that could play a role in altering endothelium permeability. Prior work by us has shown that VEGF in tumor conditioned media can alter endothelial cell junction phenotype in human brain microvascular endothelial cells. Given the various factors present in tumor conditioned media (TCM), we hypothesized that both VEGF and MMPs are present at distinct levels in conditioned media derived from brain- or bone-seeking TNBC cells and that these factors alter junction phenotype in human umbilical vein endothelial cells. We quantified levels of VEGF and MMPs 1 and 9 in tumor conditioned media from parental, brain-seeking, and bone-seeking MDA-MB-231 cells. Our results show that brain-seeking tumor cell conditioned media reduces VE-cadherin continuous junction coverage compared to conditioned media from parental or bone-seeking cells. VE-Cadherin junctions also have decreased junction widths in response to tumor conditioned treatment from brain-seeking MDAs. These results show that secreted factors from TNBC cells have a modest impact on endothelium junction integrity, and future work will quantify changes in endothelium permeability to test barrier function. This work will contribute to a further understanding of TNBC organotropic metastasis and more effective targeted therapeutics to prevent disease progression.

Citation Format: Ariana Joy L. DeCastro, Lauren Griffith, Kimberly Stroka. The effects of tumor cell-secreted factors on endothelial cell junction phenotype [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B010.
Abstract B013: Tumor-derived CCL5 recruits’ cancer-associated fibroblasts and promotes tumor cell proliferation in esophageal carcinomas
Authors: Dunbar Karen J. , Tang Qiaosi , Karakasheva Tatiana A. , Rustgi Anil K.
Published: January 2023

The tumor microenvironment (TME), at both the primary tumor and sites of metastases, is a key determinant in the success of metastatic colonization. Cancer-associated fibroblasts (CAFs) are a predominant cell type in the TME that, through deposition and remodeling of extracellular matrix (ECM) components, can mediate the TME and promote cancer progression. In addition to cancer progression and metastasis, CAFs have also been shown to mediate resistance to chemotherapy and radiotherapy. Therefore, there is a need to identify the factors which activate and recruit CAFs to solid tumors. Though cytokine arrays, we identified CC motif chemokine ligand 5 (CCL5) as a secreted factor which is increased upon co-culture of esophageal cancer cell lines and CAFs. Using CRISPR/Cas9 technology, we determined that CCL5 is predominantly tumor-cell derived and loss of tumor-cell derived CCL5 reduced esophageal carcinoma cell proliferation in vitro and in vivo. We propose that this reduction in cell proliferation is mediated by ERK1/2 signaling as loss of tumor-cell derived CCL5 reduces expression of p-ERK1/2 and cyclin D1, an ERK1/2 target gene which is essential for cell cycle progression. Interestingly, the loss of tumor-derived CCL5 also reduced the percentage of CAFs, identified by αSMA positivity, recruited to xenograft tumors in vivo. CCL5 is a ligand for the CC motif receptor 5 (CCR5), for which a clinically approved inhibitor exists called Maraviroc. We treated xenografts generated from esophageal carcinoma cell lines or patient derived tumor fragments with Maraviroc. Maraviroc treated xenografts had reduced tumor volume, CAF recruitment and ERK1/2 signaling. Thus, mimicking the effects of the genetic loss of CCL5. Analysis of the TCGA database, identified that high CCL5 or CCR5 expression is associated with poorer prognosis in low grade esophageal carcinomas. Together, we propose that this data highlights the importance of CCL5 in esophageal carcinomas with regards to CAF recruitment and tumor cell proliferation, and that the maraviroc in vivo experiments suggest that targeting the CCL5-CCR5 axis may have therapeutic potential in esophageal carcinomas.

Citation Format: Karen J. Dunbar, Qiaosi Tang, Tatiana A. Karakasheva, Anil K. Rustgi. Tumor-derived CCL5 recruits’ cancer-associated fibroblasts and promotes tumor cell proliferation in esophageal carcinomas [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B013.
Abstract B016: Pleiotrophin drives a pro-metastatic immune niche within the breast tumor microenvironment
Authors: Ganguly Debolina , Schmidt Marcel , Coleman Morgan , Ngo Tuong-Vi , Sorrelle Noah , Dominguez Adrian , Toombs Jason , Lewis Cheryl , Fang Yisheng , Mora Fatima , Ortega David , Wellstein Anton , Brekken Rolf
Published: January 2023

Metastatic cancer cells adapt to thrive in secondary organs. To investigate metastatic adaptation, we performed transcriptomic analysis of metastatic and non-metastatic murine breast cancer cells. We found that pleiotrophin (PTN), a neurotrophic cytokine, is a metastasis-associated factor that is expressed highly by aggressive breast cancers. Moreover, elevated PTN in plasma correlated significantly with metastasis and reduced survival of breast cancer patients. Mechanistically, we find that PTN activates NF-kB in cancer cells leading to altered cytokine production, subsequent neutrophil recruitment and an immune suppressive microenvironment. Consequently, inhibition of PTN, pharmacologically or genetically, reduces the accumulation of tumor associated neutrophils and reverts local immune suppression resulting in increased T cell activation and attenuated metastasis. Furthermore, inhibition of PTN significantly enhanced the efficacy of immune checkpoint blockade + chemotherapy in reducing metastatic burden in mice. These findings establish PTN as a previously unrecognized driver of a pro-metastatic immune niche and thus represents a promising therapeutic target for the treatment of metastatic breast cancer.

Citation Format: Debolina Ganguly, Marcel Schmidt, Morgan Coleman, Tuong-Vi Ngo, Noah Sorrelle, Adrian Dominguez, Jason Toombs, Cheryl Lewis, Yisheng Fang, Fatima Mora, David Ortega, Anton Wellstein, Rolf Brekken. Pleiotrophin drives a pro-metastatic immune niche within the breast tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B016.
Abstract B021: Piezo1 and ROCK2 promote fast amoeboid migration in confined environments
Authors: Caruso Alexa , Kar Neelakshi , Logue Jeremy
Published: January 2023

Cell migration through confined environments may induce a phenotypic transition to fast amoeboid (leader bleb-based) migration. However, the molecular mechanism(s) controlling this phenotypic transition remain poorly understood. Here, we show that regulation of intracellular calcium levels by the plasma membrane tension sensor, Piezo1, promotes the Leader Bleb-Based Migration (LBBM) of melanoma cells. Using a ratiometric assay, intracellular calcium is shown to rise with increasing levels of confinement. Chelation of extracellular and intracellular calcium by BAPTA and BAPTA-AM, respectively, inhibits LBBM. Moreover, in highly motile cells, we found intracellular calcium levels to be dramatically increased at the cell rear. Using the Piezo1 inhibitor, GsMTx4, and RNAi, we can inhibit the phenotypic transition to fast amoeboid (leader bleb-based) migration. Therefore, we wondered if Piezo1 through calcium/calmodulin activates Myosin Light Chain Kinase (MLCK) to promote actomyosin contractility and amoeboid migration. Using a microchannel based assay, we find that ROCK2 and not MLCK, promotes amoeboid migration. Altogether, our work reveals an unanticipated collaboration between Piezo1 and ROCK2 in amoeboid migrating melanoma cells.

Citation Format: Alexa Caruso, Neelakshi Kar, Jeremy Logue. Piezo1 and ROCK2 promote fast amoeboid migration in confined environments [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B021.
Abstract B024: TBX2highmiR-375-3plowRBPJhigh signaling drives prostate cancer bone metastatic phenotype via exosomes
Authors: Patel Girijesh Kumar , Dutta Sayanika , Khedmatgozar Hamed , Tripathi Manisha , Nandana Srinivas
Published: January 2023

Recent studies have shown that exosome secretion by prostate cancer (PCa) cells fosters multiple facets of PCa progression and metastasis, mediated in particular through exosomal micro RNAs (miRs) that dictate gene expression changes. However, the molecular mechanisms through which exosomal miRs orchestrate bone remodeling that facilitates the establishment of a pre-metastatic niche (PMN) at the distant metastatic site i.e. bone remain elusive. We have identified that TBX2, a transcription factor that we previously reported plays a key role in PCa metastasis, represses miR-375-3p thereby resulting in de-repression/upregulation of its target RBPJ, an effector of Notch signaling and an established driver of PCa metastasis. Further, the unbiased identification of miR-375-3p as the topmost miR repressed by TBX2, in combination with experiments that genetically manipulate miR-375-3p in the context of TBX2 modulation, point to a crucial biological function of miR-375-3p as a key mediator in RBPJ regulation exerted by TBX2. In addition, the study highlights a dual level of RBPJ regulation by TBX2/miR-375-3p signaling i.e. via: a) gene expression changes at the intra-cellular or autocrine level, and b) gene expression changes at the distant site of bone metastasis through inter-cellular/endocrine communication via exosomes. Further, the study implicates TBX2high primary PCa cells in directing bone remodeling activity at the distant metastatic site in a paracrine mode via exosomes in addition to our previously reported role of TBX2 in mediating bone remodeling in an autocrine mode that occurs following metastatic dissemination. Taken together, our study unravels the role of TBX2/miR-375-3p/RBPJ signaling in PCa bone metastatic progression.

Citation Format: Girijesh Kumar Patel, Sayanika Dutta, Hamed Khedmatgozar, Manisha Tripathi, Srinivas Nandana. TBX2highmiR-375-3plowRBPJhigh signaling drives prostate cancer bone metastatic phenotype via exosomes [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B024.
Abstract B049: Breast cancer-derived angiopoietin-like 7 regulates necrotic core formation and metastasis from the tumor interior
Authors: Yamamoto Ami , Huang Yin , Krajina Brad A. , McBirney Margaux , Doak Andrea E. , Wang Carolyn L. , Haffner Michael C. , Cheung Kevin J.
Published: January 2023

Necrosis in the tumor interior is a common feature of aggressive cancers that is associated with poor clinical prognosis and the development of metastasis. However, how the necrotic core promotes tumor cell dissemination and metastasis remains unclear. Foundational models for cancer metastasis research include mouse, zebrafish, and chick embryo, but identifying tumor cells in transit is painstaking. Here we used a rat model of breast cancer metastasis to increase detection of dissemination events. Owing to the large size and higher blood volume of rats, we collected 10 times more circulating tumor cells (CTCs) than from mice. In the rat model, tumor dissemination was temporally correlated with the emergence of necrosis in the tumor interior. These findings were corroborated by longitudinal study of CTC abundance and tissue necrosis markers in blood plasma from patients with metastatic breast cancer. Further, we observed that dilated blood vessels were located next to necrotic regions of the tumor and that their increase was concurrent with the initiation of intratumoral necrosis and increase in CTC abundance. Bulk RNA sequencing of mouse-to-rat xenograft tumor necrotic core compared to the non-necrotic rim revealed distinct tumor-specific and host-specific transcripts in the necrotic interior. We identified angiopoietin-like 7 (Angptl7) as a tumor-specific factor localized to the peri-necrotic zone. Functional studies showed that Angptl7 loss normalizes central necrosis, peri-necrotic dilated vessels, metastasis, and reduces circulating tumor cell counts to nearly zero. Mechanistically, Angptl7 promoted vascular permeability and supported vascular remodeling in the peri-necrotic zone. Taken together, these findings show that breast tumors actively produce factors controlling central necrosis formation and metastatic dissemination from the tumor core. Tumor dissemination events are localized spatially to dilated peri-necrotic vessels in the tumor interior, and tumor dissemination is dependent functionally on the expression of a factor, Angptl7, produced by peri-necrotic tumor cells. Our findings in breast cancer models, in conjunction with recent clinical observations, provide strong evidence for tumor dissemination from the tumor interior.

Citation Format: Ami Yamamoto, Yin Huang, Brad A. Krajina, Margaux McBirney, Andrea E. Doak, Carolyn L. Wang, Michael C. Haffner, Kevin J. Cheung. Breast cancer-derived angiopoietin-like 7 regulates necrotic core formation and metastasis from the tumor interior [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr B049.
Abstract IA009: Biology and vulnerabilities of circulating tumor cell clusters
Authors: Aceto Nicola
Published: January 2023

The metastatic spread of cancer occurs through the generation and hematogenous dissemination of circulating tumor cells (CTCs). Among these, CTC clusters have recently emerged as key players in the metastatic process. With a combination of microfluidic technologies and single cell-resolution molecular analysis applied to cancer patients and mouse models, we gained fundamental insights into the biology, vulnerabilities, and clinical implications of CTC clusters. For instance, we found that their physical features enable molecular changes that promote stemness and metastasis, allowing us to define new treatment concepts aimed at suppressing their metastatic potential. Further, we investigated CTC heterogeneity at the single cell level, revealing fundamental interactions that occur between CTCs and immune cells and that accelerate metastasis formation, as well as microenvironment signals that impact on CTC generation. More recently, we also gained important insights into CTC generation dynamics and signals that trigger intravasation. Together, our findings support a model whereby upon defined microenvironmental cues, CTCs form multicellular aggregates to expand their metastatic ability, providing a new rationale for targeting these interactions in cancer.

Citation Format: Nicola Aceto. Biology and vulnerabilities of circulating tumor cell clusters [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA009.
Abstract IA022: Cell archetypes in human brain metastases: Connecting programs in tumor cells with the microenvironment
Authors: Gonzalez Hugo , Mei Wenbin , Robles Isabella , Hagerling Catharina , Allen Breanna , Okholm Trine Hauge , Nanjaraj Ankitha , Verbeek Tamara , Kalavacherla Sandhya , Gogh Merel van , Georgiou Stephen , Daras Mariza , Phillips Joanna J. , Spitzer Matthew H. , Roose Jeroen P. , Werb Zena
Published: January 2023

Brain metastasis (BrM) is the most common form of brain cancer, characterized by neurologic disability and an abysmal prognosis. Unfortunately, our understanding of the biology underlying human BrMs remains rudimentary. Here, we present an integrative analysis of >100,000 malignant and non-malignant cells from 15 human parenchymal BrMs, generated by single-cell transcriptomics, mass cytometry, and complemented with mouse model- and in silico approaches. Specific single-cell interrogation of metastatic tumor cells provides a framework of 8 functional cell programs that coexist or anticorrelate. Collectively, these programs delineate two functional BrM archetypes, that co-exist within each metastatic tumor, one proliferative and the other inflammatory, that are evidently shaped through tumor-immune interactions. Our study provides a foundation to understand the molecular basis of BrM in patients with tumor cell-intrinsic and host environmental traits. For more details please refer to the original study: H. Gonzalez, et al. Cellular architecture of human brain metastases Cell, 185 (2022), pp. 729-745.

Citation Format: Hugo Gonzalez, Wenbin Mei, Isabella Robles, Catharina Hagerling, Breanna Allen, Trine Hauge Okholm, Ankitha Nanjaraj, Tamara Verbeek, Sandhya Kalavacherla, Merel van Gogh, Stephen Georgiou, Mariza Daras, Joanna J. Phillips, Matthew H. Spitzer, Jeroen P. Roose, Zena Werb. Cell archetypes in human brain metastases: Connecting programs in tumor cells with the microenvironment [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr IA022.