tbuckley/cabot-search huggingface dataset:
Abstract IA015: Comprehensive in vivo phenotyping of fusion-driven pediatric sarcomas
Authors: Genevieve Kendall
Journal: Cancer Research (2025)

Abstract Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma that has molecular features of immature skeletal muscle. The most aggressive forms of rhabdomyosarcoma are driven by two genes that are inappropriately juxtaposed to form a fusion-oncogene. These fusion-oncogenes consists of transcription factors, various chromatin regulators, and kinases that obtain gain-of-function activities. Fusion-positive rhabdomyosarcomas have no targeted therapies. Patients are treated general chemotherapy, surgery, and radiation and survivors of childhood cancer have an increased risk of adverse health impacts, secondary cancers, and premature death. There is a critical need to delineate the biology of fusion-driven pediatric rhabdomyosarcoma and leverage this biology into therapeutic opportunities. This has been challenging to investigate given the lack of animal models, cell lines, and patient-derived xenograft models, and is the motivation and rationale for our research. Through a collaborative effort with clinical sequencing of patient tumors by the NCI-COG-NCH Molecular Characterization Initiative, we have developed new personalized medicine zebrafish models of fusion-driven rhabdomyosarcomas. We have used our established fusion-oncogene modeling pipeline to incorporate a subset of pediatric RMS fusion-oncogenes into the zebrafish genome and assess their oncogenic potential and molecular features. This pipeline generates zebrafish tumors that recapitulate the human disease by integrating the human fusion-oncogene into the zebrafish genome with a transposase-based system. By modeling multiple fusion-oncogenes in vivo, we can elucidate shared biology and therapeutic vulnerabilities, including how fusion-oncogenes interface and misappropriate developmental pathways. Moreover, these studies can uncover putative tumor origins by overlaying transcriptional and chromatin accessibility profiles with developmental cell states. Currently, our group is focused on fusions with similar partners and domains for targeted therapeutic approaches that are likely applicable across a subset of rare cancers. More broadly, this modeling strategy could be implemented to identify potential shared dependencies across rhabdomyosarcoma subtypes or sarcoma in general. Citation Format: Genevieve Kendall. Comprehensive in vivo phenotyping of fusion-driven pediatric sarcomas [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr IA015.
Abstract B008: Targeting DNA damage responsive pathways in cancer therapy
Authors: Junjie Chen
Journal: Cancer Research (2025)

Abstract DNA double strand breaks (DSBs) result in activation of several key DNA damage response (DDR) kinases including ATM, ATR, and DNA-PK. These protein kinases not only promote DNA damage-induced checkpoint control, but also facilitate DSB repair in humans. Thus, these DDR kinases have become promising drug targets for cancer therapy. However, the benefits of targeting DDR kinases remain to be realized, in part due to the lack of predictive biomarkers. By undertaking CRISPR screens with inhibitors targeting key DDR kinases, we obtained a global and unbiased view of genetic interactions with DDR inhibition. Additionally, we compared the synergistic effects of combining different DDR inhibitors and found that ATM and PARP inhibitors showed remarkable synergy, which depends on the dominant negative function of ATM inhibition. Moreover, to provide comprehensive and unbiased perspective of DDR signaling pathways, we performed 30 fluorescence-activated cell sorting–based genome-wide CRISPR screens with antibodies recognizing distinct endogenous DNA damage–signaling proteins to identify new regulators involved in DNA damage response (DDR). We discovered that proteasome-mediated processing is an early and prerequisite event for cells to trigger camptothecin- and etoposide-induced DDR signaling. Furthermore, we identified PRMT1 and PRMT5 as new modulators that regulate ATM protein level. Additionally, we discovered that GNB1L is a master regulator of DDR signaling via its role as a co-chaperone for PIKK proteins. Collectively, these screens offer a rich resource for further investigation of DDR, which may provide insight into strategies of targeting these DDR pathways to improve therapeutic outcomes. More recently, we have adopted dTAG technology for the investigation of many essential DDR and replication proteins, which provide mechanistic insights into the roles of these essential proteins in genome maintenance. Additionally, we have expanded FACS-based screens for the studies of other cancer-associated pathways and explored key biological processes critical for cancer progression in vivo. These studies will facilitate the development of better therapies for cancer patients. Citation Format: Junjie Chen. Targeting DNA damage responsive pathways in cancer therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B008.
Abstract B003: cGAS inhibits TP53 and prevents DLBCL cell lines from ferroptosis death
Authors: Rui Wang, Bingzong Li
Journal: Cancer Research (2025)

Abstract Although the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been well recognized as the sensor of cytosolic DNA and plays a critical role in regulating anti-tumor immunity and cell death, whether and how cGAS plays a role in tumorigenesis and tumor progression is not well understood. Here we show that high level of cGAS was associated with poor prognosis in DLBCL patients. Using CRISPR-cas9 cGAS knockout DLBCL cell lines, we find that cGAS inhibition leads to a significant decrease of cell viability, cell growth and proliferation rate, and a significant increase of ferroptosis with mitochondrial and lipid ROS accumulation. These phenotypes can be largely rescued with ferroptosis inhibitors ferrostatin-1 (Fer-1) and liproxstatin-1 (Lip-1). Pharmaceutically inhibition of cGAS with a cGAS inhibitor G140 exhibited the same phenotype. Furthermore, we find that this cGAS induced ferroptosis resistance is not STING dependent. In vivo mouse xenograft models also showed a decrease of tumor growth with cGAS knockout. Mechanically, cGAS inhibits tumor suppressor TP53 protein expression and prevents DLBCL cell lines from undergoing ferroptosis. cGAS knockout leads to a rescue of TP53 and a decrease of MDM2, which sensitizes cells to ferroptosis. Our findings uncover a new mode of tumor promotion based on cGAS regulation of p53-MDM2, ROS responses and ferroptosis. Collectively, this previously unrecognized role for cGAS in cancer progression suggests that cGAS can serve as potential targets for new cancer interventions. Citation Format: Rui Wang, Bingzong Li. cGAS inhibits TP53 and prevents DLBCL cell lines from ferroptosis death [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B003.
Abstract IA020: Measuring single-cell mass: Biological insights and clinical translation
Authors: Scott Manalis
Journal: Cancer Research (2025)

Abstract Advancements in measuring the biophysical properties of single cells with both high precision and throughput have furthered our understanding of biological processes and facilitated the development of innovative clinical biomarkers. These biomarkers offer a comprehensive assessment of cell state with utility for both research and clinical contexts. This presentation will: (i) demonstrate the capability of single-cell mass measurements for guiding therapy in cancer treatment; and (ii) present a novel approach to quantify the fractional water content of single cells which serves as a proxy for molecular crowding. Our findings suggest that, unlike mass, proliferating cells maintain strict regulation over their water content. However, biological processes or perturbations that impact proliferation can lead to dramatic changes in water content. Thus, water content emerges as a crucial indicator of cell state, with potential implications for disease diagnosis and monitoring. Citation Format: Scott Manalis. Measuring single-cell mass: Biological insights and clinical translation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr IA020.
Abstract B004: cGAS promote DLBCL survival through STAT3 and NF-κB signaling
Authors: Rui Wang, None shuling Liu
Journal: Cancer Research (2025)

Abstract The innate immunity cGAS–STING signaling has been extensively studied to boost lymphocytes infiltration for tumor inhibition/eradication. However, DLBCL cells often cope with, take advantage, and get addicted to chronic STAT3 and NF-κB inflammatory state for survival. Little is known whether this chronic STAT3 and NF-κB inflammatory state in DLBCL is cGAS or STING dependent. In this study, we examined the relationship of cGAS–STING and STAT3, NF-κB in DLBCL. Different from STING low or negative, cGAS is usually highly expressed in many cancer types. Here we discovered a cancer promoting role of cGAS in DLBCL through IL6-STAT3 and NF-κB signaling. Firstly, we showed that cGAS was highly expressed in both ABC and GCB subtypes of DLBCL. Secondly, we discovered that it is cGAS, not STING knockout, that induced cell cycle arrest, decreased proliferation rate and induced apoptosis in DLBC cell lines in vitro. cGAS knockout lead to decreased tumor growth in xenograft tumor models in vivo. Furthermore, data from TCGA show that cGAS was closely correlated with many tumor-promote genes. Pan-cancer analysis reveal that cGAS is overexpressed and predicts poor prognosis in many cancer types. Mechanically, it is cGAS, not STING knockout, that lead to downregulation of STAT3 and NF-κB signaling both in vitro and in vivo. Suppression of cGAS consequently deprives DLBCL from this pro-inflammatory niche for growth, which showed a therapeutic target in DLBCL treatment. Citation Format: Rui Wang, shuling Liu. cGAS promote DLBCL survival through STAT3 and NF-κB signaling [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B004.
Abstract B019: Cyclin E1 amplification promotes chromosomal instability and distinct vulnerabilities in gastroesophageal adenocarcinoma
Authors: ZHONG WU, Ankur Nagaraja, Chunyang Bao, Jin Zhou, Adam Bass
Journal: Cancer Research (2025)

Abstract Background: Gastroesophageal adenocarcinomas (GEA) are characterized by chromosomal instability (CIN) predominantly consisting of high amplitude focal amplifications of oncogenes, including Cyclin E1. An initial pan-cancer analysis revealed that CCNE1 is one of the top genes whose expression correlates with focal CIN. Objective: We proposed a causal role for excess CCNE1 as a driver of CIN and gastroesophageal tumorigenesis, and investigated the therapeutic vulnerabilities of CCNE1 amplification/overexpression. Design: We engineered a novel CCNE1-overexpressing mouse gastric organoid model with Trp53 deletion and studied the functional effects on tumor initiation and progression. Whole genome sequencing of tumors was performed to characterize the effects of CCNE1 overexpression on genomic instability. To identify dependencies of CCNE1-amplified GEA, we executed a CRISPRi functional genomic screen. Top genetic dependencies were translated into potential pharmacologic vulnerabilities and tested in monotherapy and combination. Results: CCNE1 overexpression accelerated tumor initiation and progression of mouse gastric organoids with Trp53 deletion. These tumors demonstrated increased chromosomal complexity, mainly focal amplifications. Our functional genomic screen identified specific genetic dependencies of CCNE1-amplified GEA, including CCNE1/CDK2 as the strongest hits, and SKP2 as a novel dependency likely through its function as a p27 degrader. Pharmacologic inhibition of CDK2 was insufficient and antagonistic with concurrent inhibition of the DNA damage response via targeting the ATR/CHEK1 axis. However, staggered inhibition of these distinct vulnerabilities demonstrated efficacy. Conclusions: Our study identifies CCNE1 as a driver of CIN in GEA and builds a foundation for further exploration of therapies for CCNE1-amplified GEA characterized by genomic instability. Citation Format: ZHONG WU, Ankur Nagaraja, Chunyang Bao, Jin Zhou, Adam Bass. Cyclin E1 amplification promotes chromosomal instability and distinct vulnerabilities in gastroesophageal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B019.
Abstract B022: Decipher actionable tumor suppressor defects for personalized cancer medicine
Authors: Feiyu Chen, Di Zhao
Journal: Cancer Research (2025)

Abstract Chromatin remodeling proteins contribute to DNA replication, transcription, repair, and recombination. The chromodomain helicase DNA-binding (CHD) family of remodelers plays crucial roles in embryonic development, neurogenesis, and carcinogenesis. As the founding member, CHD1 is capable of assembling nucleosomes, remodeling chromatin structure, and regulating gene transcription. Dysregulation of CHD1 at genetic, epigenetic, and post-translational levels is common in prostate cancer and other malignancies. Through interacting with different genetic alterations, CHD1 possesses the capabilities to exert oncogenic or tumor-suppressive functions in context-dependent manners. In the past decade, my study uncovered the novel cell-intrinsic and -extrinsic roles of CHD1 during prostate cancer development, progression, and therapy resistance (Nature 2017, Cancer Discover 2020, Cancer Research 2022, Nature Cancer 2024). Cancer genome studies have uncovered a unique subtype of prostate cancer characterized by speckle-type BTB/POZ protein (SPOP) mutations, which stabilize AR and its co-activators and have been associated with prolonged responses to androgen deprivation therapies and favorable prognoses. Loss of CHD1 frequently co-occurs with SPOP mutations; however, how concurrent CHD1 loss impacts SPOP-mutated prostate cancer remains unclear. Most recently, by generating the first-in-the-field genetically engineered mouse models, we provided genetic evidence supporting that CHD1 loss accelerates SPOP-mutated prostate cancer progression and confers resistance to castration in this context. We uncover a non-canonical epigenetic function of CHD1 and demonstrate that CHD1 reprograms lipid metabolism by governing SREBPs. CHD1 loss–induced lipid reprogramming supplies intratumoral androgen biosynthesis and retains AR transcriptional activity in SPOP-mutated prostate tumors upon castration. Furthermore, the mechanistic studies facilitate the development of a novel biomarker-driven combinatorial therapy for castration-resistant prostate cancer harboring CHD1 loss and SPOP mutations. These findings advance our understanding of an emerging prostate cancer subtype and mechanism of action and provide novel therapeutic strategies for men with advanced prostate cancer. *This research article has been accepted by Nature Cancer for publication. Citation Format: Feiyu Chen, Di Zhao. Decipher actionable tumor suppressor defects for personalized cancer medicine [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr B022.
Abstract A028: Harnessing patient derived models to understand tumor evolution in metastatic breast cancer
Authors: Zannel Blanchard, Sandra D Scherer, Zhengtao Chu, Chieh-Hsiang Yang, Emilio Cortes-Sanchez, Bryan E Welm, Alana L Welm
Journal: Cancer Research (2025)

Abstract In the United States, more than 280,000 women are diagnosed with breast cancer every year, with more than 90% of breast cancer deaths caused by metastatic disease. 20-30% of breast cancer patients will develop metastasis, despite receiving state-of-the-art therapies. Once metastases are detected, the disease becomes incurable. Developing therapeutic interventions that eliminate metastasis represents a significant challenge in the field, as breast tumors evolve and develop resistance, ultimately undermining a tumor’s response to therapy. Underlying this resistance is the complex heterogeneity of tumors, which includes different disease subtypes, diverse patient biology, and unpredictable therapeutic responses. To date, there is very limited use of models for breast cancer research that accurately reflect the dynamic way tumors evolve in patients and how heterogeneity contributes to this process. Though cell lines have been useful to elucidate several mechanisms of drug resistance and response, their findings have failed to translate to accurate predictions of efficacy in clinical settings. The development of patient-derived models of cancer (PDMC), including patient-derived xenografts (PDX) have advanced the field by providing model systems with high fidelity to the tumor of origin, thereby providing opportunities to identify fundamental characteristics that underlie tumor evolution, patient drug response and resistance. This study hypothesizes that PDXs can model lethal disease and recapitulate tumor evolution in response to therapy, allowing us to leverage this data to predict patient responses, and improve patient outcomes. Longitudinal samples from metastatic breast cancer patients, representing various disease stages and subtypes will be used to uncover mutational, transcriptomic and epigenetic alterations that may contribute to metastatic disease progression. This study will also lead to a better understanding of mechanisms that contribute to resistance, such as cellular plasticity, by examining the evolutionary trajectories of cell populations during tumor evolution. These pioneering studies aim to establish PDMCs as more accurate representations of metastatic breast cancer evolution, while unravelling links between heterogeneity and therapy response in metastatic disease, with the hope of ultimately improving breast cancer patient outcomes. Citation Format: Zannel Blanchard, Sandra D Scherer, Zhengtao Chu, Chieh-Hsiang Yang, Emilio Cortes-Sanchez, Bryan E Welm, Alana L Welm. Harnessing patient derived models to understand tumor evolution in metastatic breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A028.
Abstract A019: UALCAN Mobile app, an update to the cancer multi-omic data analysis application
Authors: Sooryanarayana Varambally, David Rubey, Darshan Shimoga Chandrashekar, Ahmedur Rahman Shovon, Gopi Chand Puli, Santhosh Kumar Karthikeyan, Upender Manne, Chad J. Creighton, Sidarth Kumar
Journal: Cancer Research (2025)

Abstract Cancer is a major cause of death worldwide. Various genomic and proteomic alterations in cells results in initiation of cancer, disease progression, and tumor metastasis. Large scale molecular data has been generated recently that can help identify these molecular changes. These genomic, transcriptomic, proteomic and epigenetic data can be utilized to evaluate and identify cancer biomarkers and sub-class specific precision targets. In order to analyze the large scale data, user friendly tools are needed. We had earlier developed UALCAN, an integrative pan-cancer cancer data analysis platform that allows users to evaluate the expression of each genes, microRNAs and long-noncoding RNAs and identify changes between normal and cancer tissues. Previously, we have described the development and release of the UALCAN Mobile application (app) that provides cancer transcriptomic data from The Cancer Genome Atlas (TCGA) to evaluate gene expression based on cancer subtypes. Here, we describe the update to the UALCAN mobile, which now provides data analysis option for epigenetic changes due to DNA promoter methylation and Clinical Proteomic Tumor Analysis Consortium (CPTAC) cancer proteomic data. This app, which is suitable for tablets and mobile devices, provides access to large cancer molecular datasets at the fingertips of the researchers. To find changes in expression of causative genes and to identify biomarkers and therapeutic targets, app will be extremely valuable. The app is free and can be downloaded from both iOS/Apple and Android play store. Citation Format: Sooryanarayana Varambally, David Rubey, Darshan Shimoga Chandrashekar, Ahmedur Rahman Shovon, Gopi Chand Puli, Santhosh Kumar Karthikeyan, Upender Manne, Chad J. Creighton, Sidarth Kumar. UALCAN Mobile app, an update to the cancer multi-omic data analysis application [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A019.