bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting the Synthetic Lethal Relationship between FOCAD and TUT7 Represents a Potential Therapeutic Opportunity for TUT4/7 Small-Molecule Inhibitors in Cancer
Authors: Triboulet Robinson , Sadykov Khikmet , Harvey Darren M. , Wilson David M. , Steinbaugh Michael J. , Mayo Christopher B. , Hawley Dillon , Madanjian Andrew , Fyfe Corey , Bracken Christina , Rivera-Rivera Izarys , Ericsson Anna , Snyder Andrew R. , Knutson Sarah K. , Stein Ross L. , Gibaja Veronica , Ghosh Shomir , Campbell Robert M. 
Published: September 2024

Abstract
Targeting synthetic lethal interactions among genes has emerged as a promising strategy for cancer therapy. This study explores the intricate interplay among terminal uridylyltransferase 4 (TUT4) and terminal uridylyltransferase 7 (TUT7), the 3′-5′ exoribonuclease DIS3L2, and the superkiller (SKI) complex–interacting factor focadhesin (FOCAD) in the context of cancer vulnerability. Using CRISPR and public functional genomics data, we show impairment of cell proliferation upon knockout of TUT7 or DIS3L2, but not TUT4, on cancer cells with FOCAD loss. Moreover, we report the characterization of the first potent and selective TUT4/7 inhibitors that substantially reduce uridylation and demonstrate in vitro and in vivo antiproliferative activity specifically in FOCAD-deleted cancer. FOCAD deficiency posttranscriptionally disrupts the stability of the SKI complex, whose role is to safeguard cells against aberrant RNA. Reintroduction of FOCAD restores the SKI complex and makes these cells less sensitive to TUT4/7 inhibitors, indicating that TUT7 dependency is driven by FOCAD loss. We propose a model in which, in the absence of FOCAD, TUT7 and DIS3L2 function as a salvage mechanism that degrades aberrant RNA, and genetic or pharmacologic inhibition of this pathway leads to cell death. Our findings underscore the significance of FOCAD loss as a genetic driver of TUT7 vulnerability and provide insights into the potential utility of TUT4/7 inhibitors for cancer treatment.
Abstract A015 FGF8 promotes non-canonical KRAS/MAPK pathway in favorable histology Wilms' tumor
Authors: Su Yongdong , Skinner Katie T. , Cooper Garrett W. , Kang Sumin , Yin Hong , Yustein Jason T. , Hong Andrew L. 
Published: September 2024

Abstract
Favorable Histology Wilms tumor (FHWT) is the most common pediatric kidney cancer and those with relapsed FHWT continue to have poor prognoses. A challenge in the field of FHWT research is the lack of faithful preclinical in vitro models for both primary and relapsed tumors. This prevents us from understanding the biology of FHWT and introducing new targeted therapies into FHWT clinical trials. We recently established 10 FHWT cell lines, including one from a relapsed case, which faithfully recapitulated the genome and transcriptome of the primary tumor. However, challenges persist in maintaining the long-term growth of these cell lines, limiting our insight into the functional study of FHWT. Through comparison of the transcriptome of the FHWT primary tumor samples to their respective cell lines, we identified upregulation of fibroblast growth factor 8 (FGF8) expression in primary tumors. We then performed functional genomics to study the role of FGF8 in FHWT. We found that the splice variants, FGF8b or FGF8f, are required for the maintenance of FHWT cells. Re-introducing these two splice variants using either exogenous addition or endogenous overexpression led to increased viability and passaging of FHWT cell line models by an average of 100% and 30%, respectively. Further, we found that overexpressing FGF8b or FGF8f led to increased clonogenicity and invasion in vitro and led to tumor formation in vivo. Our mechanistic studies suggest that FGF8 drives a stemness and proliferation program through a non-canonical KRAS/MAPK pathway: FGF8b and FGF8f overexpression activates MEK1/2 without activating Erk1/2 while still promoting ETV1 and ETV4, leading to increased cell proliferation. Abrogation of MAPK pathway in vitro using MEK inhibitors led to decreased viability in cells overexpressing FGF8b and FGF8f. Together, our study highlights the oncogenic effect of FGF8 in FHWT and links FHWT to an unexpected non-canonical MAPK pathway.
Citation Format: Yongdong Su, Katie T. Skinner, Garrett W. Cooper, Sumin Kang, Hong Yin, Jason T. Yustein, Andrew L. Hong. FGF8 promotes non-canonical KRAS/MAPK pathway in favorable histology Wilms' tumor [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A015.
Abstract A056 Intertumoral epigenetic heterogeneity in response to a novel therapy in Ewing sarcoma
Authors: Isenhart Emily , Gupta Ajay , Ohm Joyce 
Published: September 2024

Abstract
Like many pediatric cancers, Ewing sarcoma (EwS) is a genomically quiet disease. Driven by an oncogenic fusion protein, usually EWSR1-FLI1, the epigenome of this genetically homogenous cancer is a driver of clinical outcomes, where heightened epigenetic heterogeneity within tumors is associated with metastatic disease. While prognosis for localized disease is moderate, outcomes are dismal for patients who present with advanced, relapsed, or refractory disease and there is a lack of targeted therapies in this setting. We have previously described a targeted combination therapy harnessing DDK and WEE1 inhibition exploits elevated endogenous replication stress in EwS to force cells into mitotic catastrophe in vitro. While our experiments evaluating the efficacy of this combination in vivo have been extremely encouraging, the data have shown that individual mice receiving the same treatment have variable patterns of outgrowth after treatment cessation, with some mice demonstrating moderate increases in tumor volume and some mice demonstrating little to no tumor outgrowth. This differential response to therapy is most likely to occur through epigenetic dysregulation. Thus, we aim to interrogate intertumoral epigenetic heterogeneity and examine epigenetic profiles associated with treatment response using samples from in vivo studies. Samples were analyzed from a CDX model using TC32 cells injected subcutaneously. Reduced representation bisulfite sequencing was performed on a control arm (n = 5) and the following three treatment arms, where the DDK inhibitor is TAK-931 (simurosertib) and the WEE1 inhibitor is MK1775 (adavosertib): 1) Irinotecan + Temozolomide (n=9), 2) Irinotecan (full dose) + DDKi + WEE1i (n=7), 3) Irinotecan (half dose) + DDKi + WEE1i (n=9), for a total of 30 samples. Our analysis of this data evaluates epigenetic changes between treatment conditions and increases our understanding of epigenetic heterogeneity in EwS.
Citation Format: Emily Isenhart, Ajay Gupta, Joyce Ohm. Intertumoral epigenetic heterogeneity in response to a novel therapy in Ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A056.
Abstract A079 Mechanisms of chemotherapy resistance in rhabdomyosarcoma
Authors: Mathavarajah Sabateeshan , Wang Yueyang , Wei Yun , Antelo Diego , Langenau David M. 
Published: September 2024

Abstract
Background: Rhabdomyosarcoma (RMS) is a childhood cancer that originates from soft tissue and shares features with skeletal muscle. RMS patients are treated with a combination of radiation, surgical resection, and chemotherapy (VAC; vincristine, actinomycin D and cyclophosphamide). Unfortunately, 30% of patients eventually develop relapsed tumors due to resistance to VAC or radiation, of whom have an abysmal 17% five-year survival rate. To date, the mechanisms underlying resistance to VAC is poorly understood in RMS tumors, which are desperately needed for devising new therapeutic avenues to target VAC chemoresistance and improve the outcomes for these patients. Methods: We have recently generated long-term VAC-resistant RMS cell lines (from RD and Rh41 parental lines) to model chemoresistance. These cell lines were acclimated to high dose VAC over a 3-month period. Afterwards, single clones were isolated from these chemoresistant cell lines and assessed for upregulation of the PIK3CA/AKT/ABC transporter pathway by Western blot analysis. Results: We find that within the pool of resistant clones, there are two distinct pathways that are upregulated to promote VAC-resistance, one that elevates the PIK3CA/AKT/ABC transport pathway to rapidly efflux drugs from RMS cells. Astonishingly, this same drug resistance pathway is activated in both fusion-positive and fusion-negative RMS. The upregulated ABC transporters are well known drug efflux pumps and include ABCB1/MDR1, ABCC1/MRP1 and ABCG2/BCRP. We next show that the increased transcription of these ABC transporters occurs through an AKT-dependent mechanism – akin to that described by our group for an investigational chemotherapy that combines DNA damaging agent temozolomide with Olaparib PARP-inhibitor (OT). Using an inhibitor of PIK3CA signaling, Alpelisib, we show that we can resensitize these chemoresistant cell lines to VAC and OT. Conclusions: VAC-resistance occurs in part through PIK3CA/AKT signaling to promote drug efflux. The PIK3CA/AKT pathway can be therapeutically targeted to resensitize tumors to VAC. Future studies will focus on determining the mechanisms of drug resistance in tumors that fail to upregulate the PIK3CA/AKT/ABC transport pathway.
Citation Format: Sabateeshan Mathavarajah, Yueyang Wang, Yun Wei, Diego Antelo, David M. Langenau. Mechanisms of chemotherapy resistance in rhabdomyosarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr A079.
Abstract B026: Infant ALL without KMT2A rearrangements harbor clinically relevant alterations and share common origins with childhood ALL
Authors: Zatzman Matthew , Seelisch Jennifer , Comitani Federico , Fuligni Fabio , Davidson Scott , Yuki Kyoko E. , Edwards Lisa-Monique , Brunga Ledia , Guest Erin , Hunger Stephen P. , Loh Mignon L. , Raetz Elizabeth A. , Chen John , Bartram Jack , Hitzler Johann K. , Brown Patrick A. , Gupta Sumit , Shlien Adam 
Published: September 2024

Abstract
Infant acute lymphoblastic leukemia (ALL) is characterized by high frequency of rearrangements in KMT2A (KMT2Ar), associated with poor outcomes. Infants lacking KMT2Ar typically have superior outcomes, but remain understudied. Here, we use whole genome and transcriptome sequencing to define driver mutations and transcriptional phenotypes in non-KMT2Ar infant ALL. Based on two index cases, we initially suspected that some infants with high-risk clinical features harbored clinically undetected non-canonical alterations to the KMT2A gene; however, we find no such evidence in our data. Instead, we find that these infants acquire other clinically relevant features such as Ph-like expression signatures, fusions impacting ZNF384, TCF3, ETV6::RUNX1, PAX5 or NUTM1, and events in known tumor genes such as CDKN2A, NOTCH1, and others. By mapping transcriptional profiles between infant and childhood B-ALL, we find that - in the absence of KMT2Ar - infant ALL resembles well defined childhood B-ALL subtypes, sharing the same genetic drivers. NUTM1 fusions are particularly enriched in infants compared to older children, and are associated with decreased MHC-Class II expression and B-cell developmental signaling pathways. Ph-like transcriptional signatures were apparent in several infants and confirmed by machine learning driven classification. Overall, our data support a common developmental origin of ALL without KMT2Ar in infants and children.
Citation Format: Matthew Zatzman, Jennifer Seelisch, Federico Comitani, Fabio Fuligni, Scott Davidson, Kyoko E. Yuki, Lisa-Monique Edwards, Ledia Brunga, Erin Guest, Stephen P. Hunger, Mignon L. Loh, Elizabeth A. Raetz, John Chen, Jack Bartram, Johann K. Hitzler, Patrick A. Brown, Sumit Gupta, Adam Shlien. Infant ALL without KMT2A rearrangements harbor clinically relevant alterations and share common origins with childhood ALL [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B026.
Spatially Resolved Whole-Transcriptomic and Proteomic Profiling of Lung Cancer and Its Immune Microenvironment According to PD-L1 Expression
Authors: Koh Jaemoon , Lee Dongjoo , Kim Sehui , Song Seung Geun , Han Bogyeong , Jeong Hyein , Kim Young A , Keam Bhumsuk , Lee Se-Hoon , Kim Kwangsoo , Jeon Yoon Kyung , Chung Doo Hyun 
Published: September 2024

Abstract
The expression of PD-L1 on tumor cells (TC) is used as an immunotherapy biomarker in lung cancer, but heterogeneous intratumoral expression is often observed. To better understand heterogeneity in the lung cancer tumor microenvironment, we performed proteomic and whole-transcriptomic digital spatial profiling analyses of TCs and immune cells (IC) in spatially matched areas based on tumor PD-L1 expression and the status of the immune microenvironment. We validated our findings using IHC, data from The Cancer Genome Atlas, and immunotherapy cohorts. ICs in areas with high PD-L1 expression on TCs showed more features, indicative of immunosuppression and exhaustion, than ICs in areas with low PD-L1 expression on TCs. TCs highly expressing PD-L1 within immune-inflamed areas showed upregulation of proinflammatory processes, whereas TCs highly expressing PD-L1 within immune-deficient areas showed upregulation of various metabolic processes. Using differentially expressed genes of TCs between the immune-inflamed and immune-deficient areas, we identified a prognostic gene signature for lung cancer. In addition, we found that a high ratio of CD8+ cells to M2 macrophages predicted favorable outcomes in patients with PD-L1–expressing lung cancer after immune checkpoint inhibitor therapy. Overall, this study demonstrates that TCs and ICs have distinct spatial features within the lung tumor microenvironment that are related to tumor PD-L1 expression and IC infiltration.
Spatial Transcriptomic Approach to Understanding Coronary Atherosclerotic Plaque Stability
Authors: Gastanadui Maria G. , Margaroli Camilla , Litovsky Silvio , Richter Robert P. , Wang Dezhi , Xing Dongqi , Wells J. Michael , Gaggar Amit , Nanda Vivek , Patel Rakesh P. , Payne Gregory A. 
Published: September 2024

BACKGROUND:
Coronary atherosclerotic plaques susceptible to acute coronary syndrome have traditionally been characterized by their surrounding cellular architecture. However, with the advent of intravascular imaging, novel mechanisms of coronary thrombosis have emerged, challenging our contemporary understanding of acute coronary syndrome. These intriguing findings underscore the necessity for a precise molecular definition of plaque stability. Considering this, our study aimed to investigate the vascular microenvironment in patients with stable and unstable plaques using spatial transcriptomics.

METHODS:
Autopsy-derived coronary arteries were preserved and categorized by plaque stability (n=5 patients per group). We utilized the GeoMx spatial profiling platform and Whole Transcriptome Atlas to link crucial histological morphology markers in coronary lesions with differential gene expression in specific regions of interest, thereby mapping the vascular transcriptome. This innovative approach allowed us to conduct cell morphological and spatially resolved transcriptional profiling of atherosclerotic plaques while preserving crucial intercellular signaling.

RESULTS:

We observed intriguing spatial and cell-specific transcriptional patterns in stable and unstable atherosclerotic plaques, showcasing regional variations within the intima and media. These regions exhibited differential expression of proinflammatory molecules (eg, IFN-γ [interferon-γ], MHC [major histocompatibility complex] class II, proinflammatory cytokines) and prothrombotic signaling pathways. By using lineage tracing through spatial deconvolution of intimal CD68
+
(cluster of differentiation 68) cells, we characterized unique, intraplaque subpopulations originating from endothelial, smooth muscle, and myeloid lineages with distinct regional locations associated with plaque instability. In addition, unique transcriptional signatures were observed in vascular smooth muscle and CD68
+
cells among plaques exhibiting coronary calcification.

CONCLUSIONS:
Our study illuminates distinct cell-specific and regional transcriptional alterations present in unstable plaques. Furthermore, we characterize spatially resolved, in situ evidence supporting cellular transdifferentiation and intraplaque plasticity as significant contributors to plaque instability in human coronary atherosclerosis. Our results provide a powerful resource for the identification of novel mediators of acute coronary syndrome, opening new avenues for preventative and therapeutic treatments.
Roles of Atrial Arrhythmias in Triggering Torsade de Pointes in Patients With Acquired Long QT Syndrome
Authors: Takasugi Nobuhiro , Endo Susumu , Takasugi Mieko , Tochibora Ryota , Yoshida Akihiro , Watanabe Takatomo , Kawaguchi Tomonori , Yamada Yoshihisa , Kanamori Hiromitsu , Ushikoshi Hiroaki , Okura Hiroyuki 
Published: September 2024

BACKGROUND:
Little is known about the role of atrial arrhythmias (AAs) in triggering Torsade de Pointes (TdP) in patients with long QT syndrome (LQTS). The aim of this study was to examine the contribution of AAs to the development of TdP in acquired LQTS patients.

METHODS:

The initiation patterns of 81 episodes of TdP obtained from 34 consecutive acute acquired LQTS patients (14 men, median age, 69 years; median QTc, 645.5 ms) with documented TdP were analyzed. The initiation mode of TdP was divided into 3 categories: (1) preceding short-long sequence (SLS); (2) sudden R-on-T phenomenon without preceding SLS; and (3) increased atrial rate. The patients were divided into 2 groups based on the presence or absence of AAs-induced TdP; AAs-induced (n=18) and non-AAs-induced (n=16) groups. The association of clinical/ECG characteristics and TdP frequency after initiating conventional therapy with AAs-induced TdP was evaluated. The groups were compared using the Mann-Whitney
U
test or Fisher exact test.

RESULTS:

AAs-induced group comprised 52.9% (18/34) of the patients studied. TdP was preceded by AAs-initiated SLSs in 41.2% (14/34) of the patients and was directly induced by R-on-T AAs (AAs coincidentally encountered a vulnerable repolarizing region during the T wave) in 23.5% (8/34). AAs triggered 48 (59.3%) of the 81 TdP episodes. AAs initiated SLSs in 67.8% (40/59) of the SLS-induced TdP episodes. R-on-T AAs accounted for 23.5% (19/81) of the TdP episodes. AAs-induced group experienced TdP after initiating therapy more frequently than non-AAs-induced group (2.5 versus 1 event,
P
=0.008). AAs-induced group exhibited macroscopic T-wave alternans more frequently than non-AAs-induced group (6 versus 0 event,
P
=0.02).

CONCLUSIONS:
AAs play a key role in triggering TdP in more than half of patients with acute acquired LQTS and can increase TdP frequency after initiating therapy. Thus, AAs are not benign but rather can be life-threatening in patients with acute acquired LQTS.
EPAS1 Attenuates Atherosclerosis Initiation at Disturbed Flow Sites Through Endothelial Fatty Acid Uptake
Authors: Pirri Daniela , Tian Siyu , Tardajos-Ayllon Blanca , Irving Sophie E. , Donati Francesco , Allen Scott P. , Mammoto Tadanori , Vilahur Gemma , Kabir Lida , Bennett Jane , Rasool Yasmin , Pericleous Charis , Mazzei Guianfranco , McAllan Liam , Scott William R. , Koestler Thomas , Zingg Urs , Birdsey Graeme M. , Miller Clint L. , Schenkel Torsten , Chambers Emily V. , Dunning Mark J. , Serbanovic-Canic Jovana , Botrè Francesco , Mammoto Akiko , Xu Suowen , Osto Elena , Han Weiping , Fragiadaki Maria , Evans Paul C. 
Published: September 2024

BACKGROUND:
Atherosclerotic plaques form unevenly due to disturbed blood flow, causing localized endothelial cell (EC) dysfunction. Obesity exacerbates this process, but the underlying molecular mechanisms are unclear. The transcription factor EPAS1 (HIF2A) has regulatory roles in endothelium, but its involvement in atherosclerosis remains unexplored. This study investigates the potential interplay between EPAS1, obesity, and atherosclerosis.

METHODS:

Responses to shear stress were analyzed using cultured porcine aortic EC exposed to flow in vitro coupled with metabolic and molecular analyses and by en face immunostaining of murine aortic EC exposed to disturbed flow in vivo. Obesity and dyslipidemia were induced in mice via exposure to a high-fat diet or through Leptin gene deletion. The role of
Epas1
in atherosclerosis was evaluated by inducible endothelial
Epas1
deletion, followed by hypercholesterolemia induction (adeno-associated virus-PCSK9 [proprotein convertase subtilisin/kexin type 9]; high-fat diet).

RESULTS:
En face staining revealed EPAS1 enrichment at sites of disturbed blood flow that are prone to atherosclerosis initiation. Obese mice exhibited substantial reduction in endothelial EPAS1 expression. Sulforaphane, a compound with known atheroprotective effects, restored EPAS1 expression and concurrently reduced plasma triglyceride levels in obese mice. Consistently, triglyceride derivatives (free fatty acids) suppressed EPAS1 in cultured EC by upregulating the negative regulator PHD2. Clinical observations revealed that reduced serum EPAS1 correlated with increased endothelial PHD2 and PHD3 in obese individuals. Functionally, endothelial EPAS1 deletion increased lesion formation in hypercholesterolemic mice, indicating an atheroprotective function. Mechanistic insights revealed that EPAS1 protects arteries by maintaining endothelial proliferation by positively regulating the expression of the fatty acid-handling molecules CD36 (cluster of differentiation 36) and LIPG (endothelial type lipase G) to increase fatty acid beta-oxidation.

CONCLUSIONS:
Endothelial EPAS1 attenuates atherosclerosis at sites of disturbed flow by maintaining EC proliferation via fatty acid uptake and metabolism. This endothelial repair pathway is inhibited in obesity, suggesting a novel triglyceride-PHD2 modulation pathway suppressing EPAS1 expression. These findings have implications for therapeutic strategies addressing vascular dysfunction in obesity.