bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3611: Determining the regulation and role of mreg DC in tumor immunity
Authors: Mattiuz Raphael , Assad Nima , Hamon Pauline , Magen Assaf , Berichel Jessica Le , Merad Miriam 
Published: June 2022

Abstract
Therapeutic immunity against tumors is mainly determined by effector T cells. However, T cells are educated by antigen presenting cells, particularly dendritic cells (DC), that control their differentiation into effector T cells able to eliminate target tumor cells. While most studies focused on understanding T cell features leading to antitumor immunity, little is known about DC determinants required to promote effective antitumor T cell function. Yet several studies are revealing that high DC content in tumor lesions correlate with improved tumor outcome. To identify molecular program that modulate DC functionality in tissues we have profiled tumor-associated DC in mice and tumor lesions. We identified a DC molecular program that was shared between mice and human tumors that included maturation genes associated with T cell simulation and migration to the LN (Cd40, Cd80, Fscn, Ccr7), but also genes associated with immunoregulation (Socs1, Socs2, Socs3, Cd200, Pd-l1, Pd-l2, Fasl), we named mregDC (Maier et al., Nature 2020). We also found that mregDC molecular state is induced in DC1 and DC2 upon capture of tumor debris leading to hypothesize that the mregDC state identifies antigen-charged DC that migrate to lymphoid structures, including tertiary lymphoid structures and tumor draining lymph nodes to modulate tumor specific T cell immune responses. While the role of DC in the draining LN has been established the exact role played by DC in the tumor microenvironment (TME) remains unclear. To explore this question, we used multiplex imaging and spatial transcriptomics platforms to identify the distribution and spatial interactions of DC1, DC2 and mregDC within the TME of human NSCLC and HCC lesions during treatment with PD-1 blockade. We found that mregDC accumulate within the tertiary lymphoid structures together with activated T cell and B cell programs. We are continuing to generate additional data on mregDC interactions in human tumors tissues that respond or resist PD-1 blockade and should be able to provide additional information at the time of the meeting.
Citation Format: Raphael Mattiuz, Nima Assad, Pauline Hamon, Assaf Magen, Jessica Le Berichel, Miriam Merad. Determining the regulation and role of mreg DC in tumor immunity [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 3611.
Abstract 3639: Senescent stromal cells drive breast cancer tumorigenesis
Authors: Ye Jiayu (Jennifer) , Delgado Ana Paula , Powers Scott , Stewart Sheila 
Published: June 2022

Abstract
Age is the largest risk factor for the development of cancer, including breast cancer, which is the most frequent malignancy in women. Investigation into how age impacts breast cancer development suggests that both the accumulation of oncogenic mutations within incipient tumor cells and age-related stromal changes conspire to drive tumorigenesis. While numerous physiologic changes arise with age, we posit that the accumulation of p16INKA4 (p16) positive senescent cells, which express various cytokines, chemokines, and enzymes collectively referred to as the senescence-associated secretory phenotype (SASP) contribute to cancer progression. SASP factors not only directly promote the proliferation of tumor cells, but also create an immunosuppressive microenvironment that contributes to robust tumor growth. Immunosuppressive SASP factors are detectable in human breast cancer stroma and high p16 positivity in stromal cells strongly correlates with breast cancer recurrence regardless of subtype. To investigate the role of senescent stroma in mammary tumor development, we crossed MMTV-PyMT (PyMT) transgenic mice that spontaneously develop mammary tumors to INK-ATTAC (INK) mice, which allows selective elimination of p16-positive cells. Depletion of senescent stromal cells in PyMT/INK mice led to significantly delayed mammary tumor onset and changes in various tumor-infiltrating immune cell populations. Analyses of single-cell RNA-sequencing (scRNA-seq) datasets of murine and human mammary tumor/breast cancer samples revealed that senescence is restricted to a cancer-associated fibroblasts (CAFs) subpopulation, which expresses high levels of immune-related and extracellular matrix (ECM)-related SASP factors and shows decreasing abundance in PyMT/INK mice upon the depletion of senescent stroma. Together, these data suggest that senescent CAFs contribute to mammary gland tumorigenesis by modulating tumor immunity and remodeling ECM in the microenvironment.
Citation Format: Jiayu (Jennifer) Ye, Ana Paula Delgado, Scott Powers, Sheila Stewart. Senescent stromal cells drive breast cancer tumorigenesis [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 3639.
Abstract 3643: The role of HBP1 in controlling breast cancer dormancy reawakening
Authors: Gelman Irwin H. , Degan Seamus , Withers Henry G. , Venkata Subrahmanya Anirudh Kaligotla 
Published: June 2022

Abstract
At least 22% of breast cancer (BrCa) cases recur after 3 to 15 years, typically at metastatic sites such as the bone. Bone metastases derive from early disseminated tumor cells that become dormant because of interaction with specific cells that define the endosteal niche (EN) microenvironment. However, outside knowing that dormancy is driven by a p38MAPKhi, ERK1/2lo activation profile, our understanding of what factors regulate dormancy maintenance and reawakening is poor. We used a genomic shRNA screen to identify HBP1 as a suppressor of BrCa dormancy reawakening in a 3D-EN culture system. Our data indicate that under 3D-EN conditions, HBP1 is upregulated by p38MAPK, interacts with the metastasis suppressors, BRMS1 and BRMS1L, and with the histone modifiers, SIN3A and HDAC1-3. We hypothesize that HBP1 suppresses p38MAPK-mediated dormancy reawakening by complexing with BRMS1/BRMS1L/SIN3A to alter cell cycle gene expression through histone landscape remodeling. HBP1 suppresses the expression of cell cycle progression genes, such as MYC and CCND1, and concomitantly upregulates cyclin kinase inhibitors, p16 and p21. HBP1 RNA and protein levels are decreased in BrCa metastases relative to primary tumors, and this downregulation correlates with poorer overall survival. We are investigating whether the anti-histiminic drug, cyproheptadine, which upregulates HBP1 expression through the activation of p38MAPK, can suppress dormancy reawakening of BrCa cells in 3D-EN cultures and in in vivo models of bone dormancy using mouse mammary carcinoma D2A1 cell lines with varying abilities to form active or dormant metastatic bone colonization. Data will be shown addressing how cell-cell interactions and secretory factors between BrCa and bone EN cells facilitates dormancy signaling through a p38MAPK/HBP1/BRMS1 axis, and how drugs such as cyproheptadine agonize that pathway in order to prevent the reawakening that drives the growth of BrCa metastases in the bone, thereby increasing overall survival.
Citation Format: Irwin H. Gelman, Seamus Degan, Henry G. Withers, Subrahmanya Anirudh Kaligotla Venkata. The role of HBP1 in controlling breast cancer dormancy reawakening [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 3643.
Abstract 3647: Oncogenic Kras drives cancer-associated fibroblast heterogeneity and substate changes in pancreatic cancer
Authors: Thalappillil Jennifer S. , Caligiuri Giuseppina , Nadella Sandeep , Alagesan Brinda , Yordanov Georgi N. , Shakiba Mojdeh , Kaminow Benjamin , Hinds Juliene , Perez-Mancera Pedro A. , Preall Jonathan , Dobin Alexander , Park Youngkyu , Tuveson David A. 
Published: June 2022

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is currently the third-leading cause of cancer-related deaths in the United States with no effective or targeted therapies to improve outcomes. Two defining features of PDAC are the dense stroma composing the bulk of the tumor mass and mutations in KRAS, the primary oncogene in most PDAC patients. Advances in knowledge on both fronts have led to promising avenues for therapeutics: recently described heterogeneity within the cancer-associated fibroblast (CAF) population residing in the stroma offers insight into the lack of success with therapies only targeting CAFs; and mutant KRAS inhibitors directed at the G12C isoform have received accelerated FDA approval for treatment of locally advanced and metastatic non-small cell lung cancer. However, the nature of this CAF heterogeneity is not yet fully understood, and any effects of KRAS blockade on the stroma have not been evaluated with consideration of this heterogeneity in mind. To assess how loss of Kras affects CAF heterogeneity and plasticity, we employed a genetically engineered mouse model (GEMM) of PDAC harboring a reversible oncogenic KrasG12V allele conditionally expressed from the endogenous Kras locus. This FPC compound mouse (KrasFrt-LSL-G12V-Frt; p53LSL-R172H; PDX-CRE; Rosa26FlpOERT2) spontaneously develops pancreatic lesions and allows for irreversible excision of the mutant Kras allele upon the application of Tamoxifen. Using single-cell RNA sequencing (scRNAseq), fluorescence in situ hybridization, and functional in vitro and in vivo approaches, we found that oncogenic Kras ablation led to tumor regression and altered cancer cell gene programs, profoundly affecting the tumor microenvironment, specifically CAF heterogeneity. Mutant Kras loss leads to decreased Tgfb1 expression in the cancer cells, but surprisingly also to increased Il1a levels, correlating with a reduction in myofibroblastic CAFs (myCAFs) and an expansion in inflammatory CAFs (iCAFs), respectively. Our results suggest that mutant Kras drives paracrine signaling that shapes CAF heterogeneity and should be considered for the development of the most effective therapeutic strategies.
Citation Format: Jennifer S. Thalappillil, Giuseppina Caligiuri, Sandeep Nadella, Brinda Alagesan, Georgi N. Yordanov, Mojdeh Shakiba, Benjamin Kaminow, Juliene Hinds, Pedro A. Perez-Mancera, Jonathan Preall, Alexander Dobin, Youngkyu Park, David A. Tuveson. Oncogenic Kras drives cancer-associated fibroblast heterogeneity and substate changes in pancreatic 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 3647.
Abstract 3679: A qualitative analysis of coping with genetically exacerbated risk of breast and ovarian cancers among medically-underserved women with BRCA1/2 mutations
Authors: Tredway Kristi , Dibble Kate E. , Connor Avonne E. 
Published: June 2022

Abstract
Individuals testing positive for BRCA1/2 genetic mutations, or hereditary breast and ovarian cancer mutations, are 33-55% more likely than women without these mutations to develop breast and/or ovarian cancers before the age of 70. While research involving these genetic mutations continues to emerge, there remains unanswered questions regarding prophylactic experiences and subsequent impacts on mental health within subgroups of BRCA1/2-positive women. The purpose of this analysis was to explore the impact of BRCA1/2 mutations, prophylactic surgeries, and surveillance regimens within the scope of everyday life within a sample of BRCA1/2 positive women from medically-underserved backgrounds living in the United States (US). A sample of 211 US adult women who have tested positive for BRCA1/2 mutations within the past 5 years and who identify with one or more medically-underserved populations (racial, ethnic, or sexual minority, person with a physical disability, chronically-ill, those in poverty, immigrant populations) elucidated compelling qualitative data. A total of 169 (80.1%) women completed open-ended questions at the end of the online survey. Thematic analysis was utilized to identify themes and subthemes concerning mental health, sources of stress, and methods of stress relief. The focus of the current analysis is on the sources of stress identified by the respondents. Fourteen subthemes were identified. The four most common stressors were concerns about post-treatment recovery (19% of respondents), recurrence of a new cancer (15%), medical unknown of having a genetic mutation that increases the risk of cancer (14%), and having to schedule and plan for continual surveillance (12%). The next five subthemes ranged from 7-9% and include waiting for medical results, personal finances and covering medical expenses, impact of the COVID-19 pandemic, pre-operative anxiety, and worrying about insurance coverage. Our findings support previous research on cancer stressors for women while adding important qualitative elements for a richer understanding. Furthermore, since much of the research on the lived experiences of BRCA1/2 has been on highly-educated, non-Hispanic white women, few studies have focused entirely on medically-underserved populations, which was the entirety of our sample. This work adds an important intersectional lens in which to better understand the experiences of living with a BRCA1/2 mutation.
Citation Format: Kristi Tredway, Kate E. Dibble, Avonne E. Connor. A qualitative analysis of coping with genetically exacerbated risk of breast and ovarian cancers among medically-underserved women with BRCA1/2 mutations [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 3679.
Abstract 3747: RPS3 positively regulates nucleotide excision repair with respect to XP-D and skin cancers
Authors: Kim Joon , Park Yong-Joon , Kim Tae Sung , Ahn Woo Sung , Kim Hag Dong 
Published: June 2022

Abstract
Ribosomal protein S3 (rpS3) is a multifunctional protein working in translation, DNA repair, cancer, apoptosis etc. UV induced DNA damage is repaired by the nucleotide excision repair (NER) pathways; defects in these pathways lead to a genetic instability known as xeroderma pigmentosum (XP) eventually developing skin cancers. We discovered that rpS3 associates with transcription factor IIH (TFIIH) via an interaction with the xeroderma pigmentosum complementation group D (XPD) protein and complements its function in the NER pathway. Here, we showed that XP-D cells overexpressing rpS3 showed markedly increased resistance to UV through XPD and rpS3 interaction thus augmenting the helicase activity of XPD protein. Additionally, the knockdown of rpS3 caused reduced NER efficiency and the subsequent addition of rpS3 restored the helicase activity of the TFIIH complex in cells. We present data suggesting that rpS3 is involved in post-excision processing in NER, assisting TFIIH in expediting the repair process by increasing its turnover rate when DNA is damaged. We also propose that rpS3 is a novel accessory protein of the NER pathway and its recruitment to the repair machinery upon UV damage augments repair efficiency by enhancing XPD helicase function and increasing its turnover rate, thus facilitating DNA repair. In addition to this, manipulations of rpS3 gene could complement XP-D phenotype and prevent UV damage and skin cancer occurrence. Animal studies strongly indicate that these result could be applied not only for the development of cancer drugs but also for cosmeceuticals. [1] FASEB J. (2020) 34: 8102 [2] Cell & Mol Life Sci (2021) 78: 3591
Citation Format: Joon Kim, Yong-Joon Park, Tae Sung Kim, Woo Sung Ahn, Hag Dong Kim. RPS3 positively regulates nucleotide excision repair with respect to XP-D and skin cancers [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 3747.
Abstract 3773: Mitochondrial fusion is required to support higher rates of respiration in proliferating cancer cells
Authors: Wang Yahui , Yao Conghui , Stancliffe Ethan , Fowle-Grider Ronald , Wang Rencheng , Wang Cheng , Schwaiger-Haber Michaela , Shriver Leah P. , Weber Jason , Patti Gary J. 
Published: June 2022

Abstract
Proliferating cancer cells exhibit an elevated rate of glucose consumption and lactate excretion, a phenomenon described as the “Warburg effect”. Although increased glycolytic flux in proliferating cells is well established, metabolic changes associated with mitochondria still remain elusive. Here, using various inducible quiescence models and mass spectrometry-based metabolomics, we directly compared mitochondrial respiration and TCA cycle activity from the same cells in the proliferative and quiescent states. We found that mitochondrial respiration and TCA cycle flux is significantly increased during proliferation in both transformed and non-transformed cell lines. This increase was supported by mitochondrial fusion rather than mitochondrial biogenesis. Notably, as cells transitioned from a quiescent state to a proliferative state, the elongation of mitochondria occurred as quickly as 3 hours. Our results reveal that the Warburg effect, which was originally associated with dysfunctional mitochondria, does not necessitate decreased mitochondrial respiration. Rather, in many proliferating cancer cells, mitochondrial respiration is actually elevated, underscoring the importance of mitochondrial respiration during proliferation.
Citation Format: Yahui Wang, Conghui Yao, Ethan Stancliffe, Ronald Fowle-Grider, Rencheng Wang, Cheng Wang, Michaela Schwaiger-Haber, Leah P. Shriver, Jason Weber, Gary J. Patti. Mitochondrial fusion is required to support higher rates of respiration in proliferating cancer cells [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 3773.
Abstract 38: Racial disparities in prostate cancer mortality rates explained by differences in dietary and lifestyle factors
Authors: Rencsok Emily , Sodipo Michelle , Gerke Travis , Stopsack Konrad , Mucci Lorelei 
Published: June 2022

Abstract
Introduction: Black men have 2.1 times higher prostate cancer mortality rates than White men in the United States, yet the reasons for this disparity remain unclear. Several dietary and lifestyle factors may influence the risk of developing lethal prostate cancer. This study evaluated to what extent differences in the prevalence of modifiable risk factors by race could explain racial disparities in prostate cancer mortality.
Methods: Our study utilized data from the Health Professionals Follow-up Study (HPFS, N=51,529 men, 1986-2016) and the National Health and Nutrition Examination Study (NHANES, 2000-2010). First, we used data from NHANES to estimate the prevalence of three factors among Black and White men: smoking, vitamin D, and coffee. Then, using HPFS, we generated relative risk estimates for lethal prostate cancer for each factor. To estimate the relative prostate cancer burden associated with these risk factors, we calculated the population attributable fraction (PAF) for each factor by self-identified race, defined as the reduction in mortality that would be achieved if the population had been entirely unexposed, compared with the current exposure pattern. We then calculated the difference in the PAF between Black and white men to estimate the difference in mortality reduction between the two groups if all men had been entirely unexposed, assuming causality of risk factors and no effect modification by race.
Results: There were notable differences in the prevalence of several risk factors by race. For example, Black men had significantly lower levels of vitamin D[MLA1], were less likely to drink coffee, and had a higher prevalence of smoking compared to white men. We estimated that eliminating these risk factors among Black men could lead to a reduction in prostate cancer mortality that is 4-14% larger compared to eliminating these risk factors among white men.
Conclusions: Modifiable lifestyle and dietary factors are potentially responsible for a proportion of the racial disparity in prostate cancer mortality. Our future work will expand the modifiable factors as well as incorporating more contemporary comparisons of the prevalence of these factors to predict future disparities in prostate cancer.
Citation Format: Emily Rencsok, Michelle Sodipo, Travis Gerke, Konrad Stopsack, Lorelei Mucci. Racial disparities in prostate cancer mortality rates explained by differences in dietary and lifestyle factors [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 38.
Abstract 3808: Spatially resolved transcriptomics of cellular architecture in EGFR-mutated lung cancer
Authors: Kerr Daniel L. , Wu Wei , Tamaki Whitney , Urisman Anatoly , Chou Yu-Ting , Gui Philippe , Jablons David M. , Bivona Trever G. , Blakely Collin M. 
Published: June 2022

Abstract
Introduction: Single-cell RNA sequencing of dissociated tumors enables the profiling of cellular states in fine detail, but erases the cellular organization of the analyzed tissue. Spatially resolved transcriptomics (SRT) using 10X Genomics’ Visium platform combines histological staining and RNA sequencing by capturing each transcript across spatially barcoded microarrays. SRT yields gene-expression matrices resolved within 55-micron array spots, and creates opportunities to explore how lung biology is affected by lung adenocarcinoma and how tumor cells and the proximal microenvironment are modulated by targeted therapy.
Methods: SRT reactions (n=8) were performed on surgical specimens from human lung adenocarcinomas driven by kinase domain mutations of EGFR (exon 19 deletion, L858R point mutation, exon 20 insertion). SRT reactions analyzed primary lung cancer (n=5) or paired tumor-adjacent lung tissues (n=3).
Results: 28458 array spots were recorded across all samples, and array spots captured a median of 5800 total transcripts and a median of 2416 unique transcripts. Single marker gene expression and unsupervised clustering across array spots corresponded with histological annotations of lung structures and adenocarcinoma. Integration of single-cell RNA sequencing data from lung adenocarcinoma specimens permitted mapping and quantification of 15 major cell types, including cancer cells, T- and B- lymphocytes, macrophages, dendritic cells, fibroblasts, and endothelial cells. Compared with paired tumor-adjacent lung tissues, adenocarcinoma tissues contained fibroblast-enriched desmoplasia and B-cell enriched tertiary lymphoid structures. In a clinical case with resistance to Osimertinib, the standard tyrosine kinase inhibitor, gene signature analysis of cancer-containing array spots revealed enrichment of gap-junction, fatty acid metabolism, and kynurenine pathway signatures compared to treatment naïve array spots.
Conclusion: This pilot study demonstrates the feasibility of using SRT in lung adenocarcinoma. Paired with a single-cell atlas of lung adenocarcinoma during targeted therapy, this approach enables hypothesis-generation to investigate the alterations of tumor and tumor microenvironmental architecture in relation to targeted therapy.
Citation Format: Daniel L. Kerr, Wei Wu, Whitney Tamaki, Anatoly Urisman, Yu-Ting Chou, Philippe Gui, David M. Jablons, Trever G. Bivona, Collin M. Blakely. Spatially resolved transcriptomics of cellular architecture in EGFR-mutated lung 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 3808.