bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A034: 3D in-vitro model picturing cancer-stromal cell crosstalk & bone metastasis
Authors: Ghosh Shrinwanti 
Published: February 2024

Abstract
Breast cancer is presently the most prevalent malignancy and the second leading cause of tumor-related deaths among women. Approximately 75% of patients with advanced breast cancer will develop bone metastasis. Despite the significant improvement in treating primary breast cancer, the 5-year survival rate for metastatic breast cancer remains at 25%. While we recognize the critical importance of cancer cells and Tumor Microenvironment (TME) communication, the field still suffers from a lack of a proper model system to reconstitute 3D multi-cellular TME in-vitro, especially for bone metastasis. Most of the current 3D in-vitro breast cancer models are composed of cancer cells only and are unable to mimic the complex cellular homeostasis within the TME. To address this deficiency along with the tumor heterogeneity, we aimed to develop a unique 3D multi-cellular culture system using patient-derived (PD) cancer cells. In this study, we implemented the “hanging drop” method to create 3D Tumor Spheroids (TSs). This method was not only sufficient to build the 3D structure, but also significantly enhanced patient-derived cancer cell line establishment rate up to 75%. 3D TSs maintained their histopathological characteristics and original hormone receptor status. Over time, TSs exhibited intratumoral hypoxia leading to significant induction of VEGF expression and EMT showcasing the quality of the system. To investigate the complex interrelation between the tumor and TME, we cultured TSs with Endothelial Cells (ECs) and pericytes to introduce the vascular component. To probe these tumor-stromal interactions, we incorporated Cancer-Associated Fibroblasts (CAFs) into TSs and observed the successful growth of Multi-Cellular Tumor Spheroids (MCTSs) alongside the tubular structure. Analysis of our data revealed that the presence of stromal cells in TME enhanced tumor survival. In this study, we define how CAFs aid in the formation of vascular structures of ECs. Recent studies also have found that the effects of CAFs are significantly high in aggressive TNBC and HER2+ cell lines compared to HR+. The long-term goal of this current study is to explore bone-mimicking nano-clay-based 3D scaffold culture systems to investigate the development of metastatic tumors and to understand the influence of bone TME on cellular responses in-vitro.
Citation Format: Shrinwanti Ghosh. 3D in-vitro model picturing cancer-stromal cell crosstalk & bone metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A034.
Abstract B013: Understanding the anti-metastatic activity of estrogen receptor β in inflammatory breast cancer
Authors: Karagounis Ilias , Tastsoglou Spyros , Nagandla Harika , Ueno Naoto , Maity Amit , Hatzigeorgiou Artemis , Thomas Christoforos 
Published: February 2024

Abstract
Inflammatory breast cancer (IBC) is a highly metastatic breast carcinoma with high frequency of estrogen receptor a (ERα) negativity. We previously explored the second ER subtype, (ERβ) and reported expression in IBC tissues and correlation with reduced metastasis in patients. We have also seen decreased metastasis of IBC tumors in vivo when ERβ was expressed or activated by agonists. Mechanistically, we found that ablation of ERβ in IBC cells increased actin-based cell migration and activated gene expression that promote Rho GTP signaling and cytoskeleton reorganization. Because migratory cells undergo metabolic and epigenetic adaptations that enable them to evade immune surveillance and progress to metastasis, we have now followed an integrated approach to fully understand the role of ERβ as a driver of interconnected transcriptional programs that function to inhibit aggressive phenotypes. We have mapped ERβ binding sites in IBC cells and interrogated this information with gene expression data to identify downstream targets that prevent IBC cells from gaining metastatic traits. Through analysis of cells that express endogenous ERβ and upon its activation by agonists we have defined how a physiologically relevant receptor interacts with the cancer genome to adjust differentiation, metabolism and tumor host interactions to mitigate the metastatic propensity of IBC cells. We compared target genes in normal and malignant tissues and associated their expression with clinical outcomes to strengthen their biological relevance and evaluate their potential use as molecular targets. Our findings thus offer ample opportunities to advance our understanding about endocrine mechanisms that operate within the tumor microenvironment to regulate metastasis with the potential to discover novel targets for therapy intervention.
Citation Format: Ilias Karagounis, Spyros Tastsoglou, Harika Nagandla, Naoto Ueno, Amit Maity, Artemis Hatzigeorgiou, Christoforos Thomas. Understanding the anti-metastatic activity of estrogen receptor β in inflammatory breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B013.
Abstract B051: Breast cancer stem cells tolerate chromosomal instability during tumor progression via c-Jun/AXL stress signaling
Authors: Baba Shahnawaz A , Sun Qi , Mugisha Samson , Labhsetwar Shreyas , Klemke Richard , Desgrosellier Jay S 
Published: February 2024

Abstract
Chromosomal instability (CIN) is an important driver of tumor evolution and metastasis, yet its role in stemness remains unclear. Here, we describe CIN tolerance as a key attribute of stem-like cancer cells. We identified CIN as a critical stress induced during early tumor initiation that may pose a significant barrier limiting the growth of new tumors. While basal CIN levels were not sufficient to distinguish stem from non-stem cell types, CIN was upregulated in early-stage tumors from breast cancer stem cells in an activated signaling state, suggesting these cells could better tolerate this stress. Indeed, stem-like cell lines were more resistant to increased CIN compared to basal-like cells, despite similar baseline levels. Further, the CIN induced during early tumor initiation appears to be transient, as levels diminish in more established disease. Mechanistically, CIN resistance in stem-like cells is mediated by expression of the receptor tyrosine kinase AXL downstream of activated c-Jun stress signaling. Thus, CIN tolerance due to activation of c-Jun/AXL may be a defining feature of stemness, contributing to breast cancer progression.
Citation Format: Shahnawaz A Baba, Qi Sun, Samson Mugisha, Shreyas Labhsetwar, Richard Klemke, Jay S Desgrosellier. Breast cancer stem cells tolerate chromosomal instability during tumor progression via c-Jun/AXL stress signaling [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B051.
Abstract IA11: Using the Cancer Dependency Map
Authors: Hahn William C 
Published: February 2024

Abstract
Although molecular profiling of human tumors is now routine, the use of this data to guide therapy remains limited to a subset of patients. To complement genome characterization studies, we have used genome scale gain and loss of function approaches to identify genes required for cell survival and transformation. Specifically, we have performed both genome scale RNAi and CRISRP-Cas9 screens in hundreds of cancer cell lines to identify differentially essential genes and the context that specifies gene dependency. These studies now allow us to define a Cancer Dependency Map. Using these datasets and approaches, we have defined new categories of potential cancer targets in breast and other cancers. In particular, we have interrogated genes required for MYC-driven breast cancers and identified metabolic dependencies in breast cancers and identified a novel mechanism of estrogen receptor expression. These approaches promise to further operationalize precision cancer medicine.
Citation Format: William C Hahn. Using the Cancer Dependency Map [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr IA11.
Abstract IA26: Exploring breast cancer vulnerabilities through apoptotic pathways
Authors: Whittle James R , Vaillant François , Surgenor Elliot , Heitink Luuk , Muttiah Christine , Visvader Jane E , Lindeman Geoffrey J 
Published: February 2024

Abstract
Combined CDK4/6 inhibitor and endocrine therapy has rapidly become standard therapy for patients with early line relapsed estrogen receptor (ER)-positive, HER2-negative breast cancer. Although this combination has been shown to significantly improve progression free and overall survival, relapse is virtually inevitable. This may in part be due to the profound cytostatic effect of CDK4/6 inhibitors on tumors, which is associated with reduced apoptotic cell death. It seems likely that growth arrested and/or senescent tumor cells acquire resistance to therapy, leading to relapse. BH3 mimetics are an emerging class of drug that target pro-survival proteins such as BCL2, BCL-xL and MCL1. Venetoclax, a BH3 mimetic that has potent and specific activity against BCL2, has shown considerable promise in hematopoietic tumors such as CLL, but has yet to be fully explored in solid tumors. We have previously demonstrated safety and efficacy of combining tamoxifen with venetoclax for patients with metastatic ER-positive BCL2-positive disease using pre-clinical PDX models and a dose-finding phase 1 study [mBEP study, ISRCTN98335443], where most patients were CDK4/6 inhibitor therapy-naïve. In the post-CDK4/6 inhibitor setting, however, venetoclax did not improve clinical benefit rate or progression free survival when added to fulvestrant in the phase 2 study VERONICA [NCT03584009]. In that study a minority of tumours exhibited strong BCL2 expression and exploratory biomarker analysis revealed a trend towards improved progression free survival for patients with tumors exhibiting high BCL2 expression (IHC 3+), a BCL2:BCL-xL Histoscore ratio ≥1, or with PIK3CA wild-type status. Using pre-clinical models including patient derived xenografts of ER-positive breast cancer, we have shown that the addition of venetoclax to dual therapy comprising fulvestrant and the CDK4/6 inhibitor palbociclib elicits a superior and more durable tumor response, accompanied by increased apoptosis. These findings have formed the basis of a phase 1 clinical trial of palbociclib, letrozole and venetoclax [PALVEN, NCT03900884] in patients with early line relapsed ER and BCL2-positive metastatic breast cancer. In parallel, pre-clinical studies are underway to determine the effect of dual targeting BCL-xL and MCL1, as well as dual targeting of AKT and with a BH3 mimetic in CDK4/6 inhibitor refractory breast cancer cells.
Citation Format: James R Whittle, François Vaillant, Elliot Surgenor, Luuk Heitink, Christine Muttiah, Jane E Visvader, Geoffrey J Lindeman. Exploring breast cancer vulnerabilities through apoptotic pathways [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr IA26.
Abstract PR10: Mammary epithelial architecture modulates field cancerization
Authors: Messal Hendrik A , Cleyp0ol Cindy , Lutz Catrin , Hutten Stefan , Lips Esther , Jonkers Jos , Wesseling Jelle , Bleys Ronald , Simons Ben , Scheele Colinda , van Rheenen Jacco 
Published: February 2024

Abstract
The architecture of the human breast undergoes extensive remodelling throughout puberty, the menstrual cycle, pregnancy, and involution with a risk of accumulating genetic alterations and tissue changes. Cells with mutations in cancer driver genes are abundant in tissues of healthy individuals, but rarely develop into tumors. However, the underlying mechanisms that prevent tumor formation are largely unknown. We utilized tissue clearing and imaged 15 disease-free human breasts and cancer resections with subcellular resolution to unravel the 3D architecture of thousands of mammary ducts per individual. Surprisingly, our analysis revealed that disease-free breasts carry a high burden of microscopic tissue lesions indicating widespread abnormal cell behaviour. Distinct mammary trees from the same breast differed in the kind and frequency of lesions, which coevolved scattered along the ductal routes. Combining 3D imaging of FFPE archived breast cancer resections with spatial CNV-seq revealed that, in half the cases, disease-free ductal segments neighbouring early cancer lesions contain molecular alterations. To resolve the mechanisms that regulate mutation spread, we compared the clonal behavior of cells with oncogenic mutations and neutral mutations in the mouse mammary gland epithelium. From the analysis of the clonal dynamics, we find that local tissue remodeling during the estrous cycle leads to the elimination of the majority of mutant clones, while accelerating the expansion of surviving clones. Thus, oncogenic mutations can spread along entire ducts before signs of transformation become apparent. Our data provides understanding of the earliest stages of epithelial evolution preceding disease.
Citation Format: Hendrik A Messal, Cindy Cleyp0ol, Catrin Lutz, Stefan Hutten, Esther Lips, Jos Jonkers, Jelle Wesseling, Ronald Bleys, Ben Simons, Colinda Scheele, Jacco van Rheenen. Mammary epithelial architecture modulates field cancerization [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr PR10.
Abstract A011: Modeling the coevolution of native and CAR T-cells in large B cell lymphoma reveals a potential biomarker for response to therapy
Authors: Gatenbee Chandler D. , Robertson-Tessi Mark , Strobl Maximilian , Schenck Ryan O. , Ziccheddu Bachisio , Maura Francesco , Locke Frederick , Anderson Alexander R.A. 
Published: February 2024

Abstract
Application of CD19 targeted Chimeric Antigen Receptor (CAR) T-cell therapy to large B cell lymphoma (LBCL) has yielded unprecedented clinical outcomes in a cancer largely resistant to conventional chemotherapy. This is highlighted in the recent ZUMA-7 trial, where axicabtagene ciloleucel (axi-cel), a CAR T-cell therapy, yielded a complete response (CR) rate in 65% of patients, an improvement over the 32% CR rate when using standard chemotherapy. The ZUMA-7 trial highlights the potential of CAR T-cell therapy to treat traditionally resistant cancers, but work remains to be done to identify biomarkers predictive of response. Operating under the assumption that CAR T not only directly targets CD19+ tumor cells, but also enhances tumor kill by amplifying the native T-cell populations, we hypothesized that neoantigen burden (NAB) may serve as a useful biomarker to make predictions of response to CAR T. We explore this hypothesis by building upon traditional predator-prey mathematical models to simulate the evolution of LBCL under immune predation and treatment with CAR T-cell therapy. More specifically, in our model native T-cells prey upon tumor cells that carry their cognate neoantigen, and each T-cell has variable search rate proportional to the cognate neoantigen’s recognition potential, modeled using a type III functional response. Tumor cells may mutate during division, always gaining a neoantigen, but possibly also losing HLA function, paving the way for immune escape. In addition to modeling the direct killing of tumor by CAR T, we also explore the synergistic effect of CAR T on native T-cells by modeling increased amplification of, and killing by, native T-cells based on interactions with the CAR T-cell population. Preliminary simulations suggest a high NAB can indeed be predictive of CAR T response, although only if the tumor has not evolved an escape mechanism. Indeed, simulations suggest that high NAB can also be a signature of an immune escaped tumor, as neoantigens become neutral traits once the immune system is removed as a selective force. These results suggest that knowledge of a patients’ NAB and immune competency can be used to guide CAR T treatment decisions.
Citation Format: Chandler D. Gatenbee, Mark Robertson-Tessi, Maximilian Strobl, Ryan O. Schenck, Bachisio Ziccheddu, Francesco Maura, Frederick Locke, Alexander R.A. Anderson. Modeling the coevolution of native and CAR T-cells in large B cell lymphoma reveals a potential biomarker for response to therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr A011.
Waitlist Outcomes in Candidates With Rare Causes of Heart Failure After Implementation of the 2018 French Heart Allocation Scheme
Authors: Legeai Camille , Coutance Guillaume , Cantrelle Christelle , Jasseron Carine , Para Marylou , Sebbag Laurent , Battistella Pascal , Kerbaul François , Dorent Richard 
Published: February 2024

BACKGROUND:
In 2018, an algorithm-based allocation system for heart transplantation (HT) was implemented in France. Its effect on access to HT of patients with rare causes of heart failure (HF) has not been assessed.

METHODS:
In this national study, including adults listed for HT between 2018 and 2020, we analyzed waitlist and posttransplant outcomes of candidates with rare causes of HF (restrictive cardiomyopathy [RCM], hypertrophic cardiomyopathy, and congenital heart disease). The primary end point was death on the waitlist or delisting for clinical deterioration. Secondary end points included access to HT and posttransplant mortality. The cumulative incidence of waitlist mortality estimated with competing risk analysis and incidence of transplantation were compared between diagnosis groups. The association of HF cause with outcomes was determined by Fine-Gray or Cox models.

RESULTS:

Overall, 1604 candidates were listed for HT. At 1 year postlisting, 175 patients met the primary end point and 1040 underwent HT. Candidates listed for rare causes of HF significantly differed in baseline characteristics and had more frequent score exceptions compared with other cardiomyopathies (31.3%, 32.0%, 36.4%, and 16.7% for patients with hypertrophic cardiomyopathy, RCM, congenital heart disease, and other cardiomyopathies). The cumulative incidence of death on the waitlist and probability of HT were similar between diagnosis groups (
P
=0.17 and 0.40, respectively). The adjusted risk of death or delisting for clinical deterioration did not significantly differ between candidates with rare and common causes of HF (subdistribution hazard ratio (HR): hypertrophic cardiomyopathy, 0.51 [95% CI, 0.19–1.38];
P
=0.18; RCM, 1.04 [95% CI, 0.42–2.58];
P
=0.94; congenital heart disease, 1.82 [95% CI, 0.78–4.26];
P
=0.17). Similarly, the access to HT did not significantly differ between causes of HF (hypertrophic cardiomyopathy: HR, 1.18 [95% CI, 0.92–1.51];
P
=0.19; RCM: HR, 1.19 [95% CI, 0.90–1.58];
P
=0.23; congenital heart disease: HR, 0.76 [95% CI, 0.53–1.09];
P
=0.14). RCM was an independent risk factor for 1-year posttransplant mortality (HR, 2.12 [95% CI, 1.06–4.24];
P
=0.03).

CONCLUSIONS:
Our study shows equitable waitlist outcomes among HT candidates whatever the indication for transplantation with the new French allocation scheme.
LncRNA CHKB-DT Downregulation Enhances Dilated Cardiomyopathy Through ALDH2
Authors: Nie Xiang , Fan Jiahui , Dai Beibei , Wen Zheng , Li Huaping , Chen Chen , Wang Dao Wen 
Published: February 2024

BACKGROUND:
Human cardiac long noncoding RNA (lncRNA) profiles in patients with dilated cardiomyopathy (DCM) were previously analyzed, and the long noncoding RNA CHKB (choline kinase beta) divergent transcript (CHKB-DT) levels were found to be mostly downregulated in the heart. In this study, the function of CHKB-DT in DCM was determined.

METHODS:
Long noncoding RNA expression levels in the human heart tissues were measured via quantitative reverse transcription–polymerase chain reaction and in situ hybridization assays. A CHKB-DT heterozygous or homozygous knockout mouse model was generated using the clustered regularly interspaced palindromic repeat (CRISPR)/CRISPR-associated protein 9 system, and the adeno-associated virus with a cardiac-specific promoter was used to deliver the RNA in vivo. Sarcomere shortening was performed to assess the primary cardiomyocyte contractility. The Seahorse XF cell mitochondrial stress test was performed to determine the energy metabolism and ATP production. Furthermore, the underlying mechanisms were explored using quantitative proteomics, ribosome profiling, RNA antisense purification assays, mass spectrometry, RNA pull-down, luciferase assay, RNA–fluorescence in situ hybridization, and Western blotting.

RESULTS:

CHKB-DT levels were remarkably decreased in patients with DCM and mice with transverse aortic constriction–induced heart failure. Heterozygous knockout of CHKB-DT in cardiomyocytes caused cardiac dilation and dysfunction and reduced the contractility of primary cardiomyocytes. Moreover, CHKB-DT heterozygous knockout impaired mitochondrial function and decreased ATP production as well as cardiac energy metabolism. Mechanistically, ALDH2 (aldehyde dehydrogenase 2) was a direct target of CHKB-DT. CHKB-DT physically interacted with the mRNA of ALDH2 and fused in sarcoma (FUS) through the GGUG motif. CHKB-DT knockdown aggravated ALDH2 mRNA degradation and 4-HNE (4-hydroxy-2-nonenal) production, whereas overexpression of CHKB-DT reversed these molecular changes. Furthermore, restoring ALDH2 expression in CHKB-DT
+/
−
mice alleviated cardiac dilation and dysfunction.

CONCLUSIONS:
CHKB-DT is significantly downregulated in DCM. CHKB-DT acts as an energy metabolism-associated long noncoding RNA and represents a promising therapeutic target against DCM.