tbuckley/cabot-search huggingface dataset:
Abstract 4658: Genome wide CRISPR/Cas9 library screening identifies aurora kinase A as a regulator of elraglusib sensitivity in pancreatic cancer
Authors: Li Ding, Easton Maeder, Cheng Zhang, Taylor Weiskittel, Daniel Schmitt, Andrew Mazar, Hu Li, Daniel Billadeau
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a deadly malignancy with a dismal 5-year survival rate, highlighting the urgent need to improve drug response and overcome primary or acquired (secondary) resistance to conventional chemotherapy. Glycogen synthase kinase 3β (GSK-3β) is a target in PDAC and the GSK-3 inhibitor, elraglusib, has been shown to improve chemosensitivity of PDAC and survival in preclinical cancer models. In addition, data from phase II clinical trials in patients with previously untreated metastatic pancreatic cancer is demonstrating preliminary evidence of clinical benefit in patients receiving a combination of gemcitabine/nab-paclitaxel. While this early evidence is highly encouraging, the biological determinants of elraglusib response are unknown. Using genome wide CRISPR/Cas9 library screening, we identify aurora kinase A (AURKA), an oncogenic kinase with major roles in mitosis, as a critical regulator for elraglusib sensitivity. Elraglusib treatment activates AURKA by inducing a G2/M cell cycle arrest. We show that knocking out AURKA reduces the phosphorylation of polo like kinase 1 (PLK1), arresting cells in mitosis, and leading to mitotic catastrophe and significant apoptosis after elraglusib treatment. Strikingly, the AURKA inhibitor, alisertib, works synergistically with elraglusib to inhibit PDAC cell line growth and induce apoptosis. In summary, our results demonstrate that targeting AURKA is an effective approach to sensitize PDAC tumors to elraglusib. Citation Format: Li Ding, Easton Maeder, Cheng Zhang, Taylor Weiskittel, Daniel Schmitt, Andrew Mazar, Hu Li, Daniel Billadeau. Genome wide CRISPR/Cas9 library screening identifies aurora kinase A as a regulator of elraglusib sensitivity in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4658.
Abstract 6283: Tumor repressive effects of estrogen receptor β mRNA-based therapy in aggressive breast cancers
Authors: Kim Cuong Cap, Aireana Phillips, Karem A. Court Pinto, Kristina D. Zambo, Wei Qian, Jianying Zhou, Jenny Chang, Biana Godin, Christoforos Thomas
Journal: Cancer Research (2024)

Abstract Inflammatory breast cancer (IBC) and triple-negative breast cancer (TNBC) are the most aggressive forms of breast cancer due to their high propensity to develop distant metastases and the lack of specific effective targeted therapies. The failure of previous research to produce viable therapeutic targets combined with the absence of estrogen receptor α (ERα) in TNBC and the majority of IBC led us to explore the second ER (ERβ) as a molecule with targeting potential. We previously reported the anti-metastatic effects of ERβ in both TNBC and IBC. Considering the anti-tumor activity together with the decreased expression of ERβ in IBC and TNBC tumors, we employed an mRNA-based approach to induce tumor-specific upregulation of the receptor and restore its anti-metastatic activity. Our findings show that complexes of ERβ mRNA with lipid nanoparticles (LNPs) enable in vitro translation of a functional protein with strong anti-invasive activity. More importantly, direct administration of ERβ mRNA-LNPs in orthotopically grown IBC and TNBC tumors results in high tumor levels of the receptor and an evident inhibition of metastasis demonstrating for the first time the ability of ERβ mRNA to prevent progression of the disease. Our study may have important clinical implications by establishing ERβ mRNA as a novel and specific therapy intervention that either alone or in combination with existing treatments can substantially repress metastasis, eliminate associated mortality and benefit patients with aggressive breast cancer. Citation Format: Kim Cuong Cap, Aireana Phillips, Karem A. Court Pinto, Kristina D. Zambo, Wei Qian, Jianying Zhou, Jenny Chang, Biana Godin, Christoforos Thomas. Tumor repressive effects of estrogen receptor β mRNA-based therapy in aggressive breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6283.
Abstract 3285: Elevated expression of breast cancer stem cell marker alpha6-integrin is associated with reduced anti-estrogen efficacy in breast cancer
Authors: Gabriel Viteri, Shawnee Angeloni, Ubaldo Soto, Eileen J. Brantley
Journal: Cancer Research (2024)

Abstract Most women diagnosed with breast cancer have tumors expressing the estrogen receptor and are prescribed agents such as aromatase inhibitors or the anti-estrogens tamoxifen or fulvestrant. However, up to 40% of these patients will experience relapse due to endocrine therapy resistance even when these agents are used in combination with cyclin dependent kinase inhibitors. A small population of cells within tumors known as breast cancer stem cells are generally resistant to endocrine therapy and are believed to promote patient relapse. We previously found that breast cancer stem cell marker α6-integrin is expressed at elevated levels in cells that are resistant to the anti-estrogen tamoxifen. We thus hypothesized that elevated levels of α6-integrin confer resistance to anti-estrogens. Quantitative PCR analyses revealed that tamoxifen-resistant and fulvestrant-resistant mammospheres (breast cancer spheroids) exhibit increased α6-integrin expression as compared to antiestrogen-sensitive mammospheres. Cells with enforced α6-integrin expression were less responsive to tamoxifen and fulvestrant than control cells. Further, pharmacological or genetic inhibition of α6-integrin enhanced anti-estrogen efficacy. Our data suggest that targeting α6-integrin represents a viable strategy to overcome endocrine therapy resistance. Citation Format: Gabriel Viteri, Shawnee Angeloni, Ubaldo Soto, Eileen J. Brantley. Elevated expression of breast cancer stem cell marker alpha6-integrin is associated with reduced anti-estrogen efficacy in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3285.
Abstract 6201: Early-onset CRC, vitamin A deficiency, and stem cell origin of cancer
Authors: Bruce M. Boman, Victoria O. Hunsu, Caroline O. Facey
Journal: Cancer Research (2024)

Abstract The recent surge in early-onset CRC (EOCRC) has been attributed to a Westernized lifestyle, but the underlying molecular mechanism is largely unknown. In our cancer genetics clinic, we provide care for 10-20 young (&amp;lt;50 age) CRC patients per year. But, only a fraction (~15%) of these young CRC patients are found to have CRC-predisposing germline mutations which doesn’t provide a hereditary factor that can explain EOCRC. Other genetic studies have found that the spectrum of somatic alterations was largely comparable between EOCRC and adult-onset CRC, particularly common are mutations occurring in APC and other members of the WNT pathway. Since a genetic etiology has not turned-up, we are exploring possible lifestyle factors. We hypothesize that vitamin A (retinol) deficiency is a likely etiologic factor because vitamin A is an essential nutrient that is not made by the human body. Thus, young individuals might be prone to any cancer-initiating effects of a vitamin A deficient diet. Indeed, many population-based studies (including ones on well-nourished populations) have reported a high prevalence of vitamin A deficiency in pre-school-aged children. Since APC mutation commonly occurs in early-onset CRCs, we conjecture that vitamin A (retinol) metabolism and APC mutation-induced activation of WNT signaling may be co-factors in promoting EOCRC. Accordingly, we have been investigating whether there is a functional connection between WNT and vitamin A/retinoic acid (RA) signaling, and if APC mutation generates an imbalance in a WNT:RA-linked mechanism that contributes to CRC development by impeding retinoid-induced colonic stem cell (SC) differentiation. We previously reported that RA signaling mainly occurs in aldehyde dehydrogenase-positive (ALDH+) SCs and that APC mutation leads to overpopulation of ALDH+ SCs and incomplete differentiation during CRC development. Thus, our findings suggest that APC mutation attenuates RA signaling in ALDH+ SCs, which might explain how vitamin A deficiency contributes to EOCRC development. Citation Format: Bruce M. Boman, Victoria O. Hunsu, Caroline O. Facey. Early-onset CRC, vitamin A deficiency, and stem cell origin of cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6201.
Abstract 4635: RNF208: A novel diagnostic and prognostic biomarker for colorectal cancer and key regulator of malignant behavior
Authors: Fangyue Guo, Shanfeng Zhang, Pei Li
Journal: Cancer Research (2024)

Abstract Background: RNF208, a member of the RING finger protein family, has been implicated in ubiquitin-mediated degradation of Vimentin, regulating invasion in breast cancer, and serves as a prognostic factor in uveal melanoma. However, its diagnostic and prognostic value in colorectal cancer (CRC), as well as its role in regulating malignant behavior in CRC, remains unclear. This study aims to reveal the potential of RNF208 as a diagnostic and prognostic marker for CRC and its function in regulating malignant behavior in CRC through bioinformatics analysis and experimental validation. Methods: In this study, based on the ExoRbase2.0 human plasma exosome database (CRC=35; Healthy=118) and TCGA-COAD dataset (CRC=478; Healthy=41), we conducted bioinformatics analysis of the transcriptomic differences in plasma exosomes between CRC patients and normal individuals using ExoRbase2.0. Survival data from the TCGA-COAD dataset were integrated to select key molecules for CRC diagnosis and prognosis. Plasma samples from 39 CRC patients and 16 normal individuals were collected from hospital, and exosomes were isolated and purified using a reagent kit. qPCR was employed to validate the levels of RNF208 in plasma exosomes, confirming the results of bioinformatics analysis. Biological behavior was assessed through CCK-8 proliferation assays, flow cytometry experiments, and Transwell migration assays to investigate the relationship between RNF208 and malignant behavior in the HCT116 colorectal cancer cell line. Results: Bioinformatics analysis revealed a significant correlation between elevated RNF208 expression in plasma exosomes and the incidence of CRC, as well as poor prognosis. The qPCR results from clinical samples further confirmed this correlation, and ROC curves demonstrated high sensitivity and accuracy, suggesting RNF208's potential as a diagnostic and independent prognostic factor for CRC. CCK-8 experiments showed that RNF208 knockdown suppressed proliferation activity in HCT116 cells, flow cytometry indicated that RNF208 knockdown promoted apoptosis in HCT116 cells, and Transwell migration assays demonstrated that RNF208 knockdown inhibited the migration of HCT116 cells. Conclusion: RNF208 serves as a novel diagnostic and prognostic biomarker for colorectal cancer, promoting the proliferation and migration of colorectal cancer cells and contributing to the further deterioration of the disease. Citation Format: Fangyue Guo, Shanfeng Zhang, Pei Li. RNF208: A novel diagnostic and prognostic biomarker for colorectal cancer and key regulator of malignant behavior [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4635.
Abstract 7461: Obesity promotes breast cancer progression via complement 1q
Authors: Tao Zhang, Shimeng Liu, Myles Brown
Journal: Cancer Research (2024)

Abstract Obesity markedly impacts the onset and progression of various tumors. Yet, the mechanisms by which obesity-driven remodeling in macrophages modulates tumor progression are not yet fully elucidated. Using single-cell RNA sequencing and in vivo syngeneic murine models, we identified an enriched subset of macrophages expressing high levels of C1q complex genes in the adipose tissue of obese mice. Intriguingly, these C1q-positive macrophages are also prevalent within the tumor microenvironment. Our data suggest that obesity induces cell apoptosis in both adipocytes and tumor cells, and that macrophages engulf these apoptotic cells via a C1q-dependent pathway, thus promoting immunosuppression. Moreover, C1q deficiency in mice impairs tumor growth. Notably, C1q is upregulated in human breast cancer and is associated with poor prognosis. Our results suggest that targeting C1q could be an effective method for breast cancer treatment. Citation Format: Tao Zhang, Shimeng Liu, Myles Brown. Obesity promotes breast cancer progression via complement 1q [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7461.
Abstract 3279: MUC1 is necessary for the inflammatory memory response to osimertinib resistance in NSCLC cells
Authors: Naoki Haratake, Atrayee Bhattacharya, Ayako Nakashoji, Hiroki Ozawa, Mototsugu Shimokawa, Donald Kufe
Journal: Cancer Research (2024)

Abstract Emergence of resistance is an invariable outcome in cancer progression that may involve memory of cancer cells to treatment. The oncogenic MUC1-C protein confers pleotropic resistance of cancer cells to diverse cytotoxic and targeted agents by unclear mechanisms. We demonstrate that MUC1-C regulates the interferon (IFN) type I/II pathways in H1975 non-small cell lung cancer (NSCLC) cells selected for osimertinib resistance (H1975-OR). Targeting MUC1-C in H1975-OR cells suppressed STAT1 and inflammatory IFN signaling in association with reversing the osimertinib-resistant phenotype. Studies of H1975-OR cells selected for growth in the absence of osimertinib demonstrate that revertant H1975-RT cells retain MUC1-C-dependent memory necessary for recalling osimertinib resistance. Mechanistically, osimertinib treatment of H1975-RT cells activates the MUC1 gene at a (i) promoter-like signature (PLS) by MUC1-C and STAT1, and (ii) proximal enhancer-like signature (pELS) by PBAF and JUN/AP-1. Targeting MUC1-C in osimertinib-treated H1975-RT and MGH170 NSCLC MET-amplified cells isolated from a patient refractory to osimertinib treatment suppressed induction of STAT1 and downstream IFN-stimulated genes (ISGs) encoding MX1, OAS1 and ISG15. Targeting MUC1-C, STAT1, PBRM1/PBAF and JUN/AP-1 further confirmed their dependencies for reemergence of osimertinib resistance in H1975-RT and MGH170 cells. In support of these results, high MUC1-C protein expression analyzed by IHC is associated with shorter progression free survival for patients treated with osimertinib. These findings and the demonstration that MUC1-C is upregulated in NSCLC cells from patients refractory to osimertinib indicate that MUC1-C drives osimertinib resistance in NSCLC cells by promoting an inflammatory memory response. Citation Format: Naoki Haratake, Atrayee Bhattacharya, Ayako Nakashoji, Hiroki Ozawa, Mototsugu Shimokawa, Donald Kufe. MUC1 is necessary for the inflammatory memory response to osimertinib resistance in NSCLC cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3279.
Abstract 7414: Claire: a search engine leveraging deep databases for reliable detection of peptides, with a special focus on proteogenomic applications
Authors: Miroslav Hruska, Petr Dzubak, Marian Hajduch
Journal: Cancer Research (2024)

Abstract As the field of cancer diagnostics and treatment evolves, the significance of peptides characterized by post-translational modifications and amino acid substitutions is becoming increasingly prominent. These molecular alterations frequently offer critical insights into tumor biology, aiding the development of targeted therapies and methods for personalized medicine. However, despite ongoing advances in shotgun proteomics, the field still faces multiple challenges for the reliable detection of rare peptide forms, for instance, amino acid substitutions when the corresponding DNA or RNA sequencing is unavailable. As a response to these challenges, our group has developed Claire—a probabilistic search engine employing large peptide databases for detection. These databases, often on the terabyte scale, further incorporate the estimates of peptides' prior probabilities to improve detection accuracy and utilize several optimizations to allow fast interpretation of tandem mass spectra. Claire outperformed state-of-the-art software, such as MSFragger and TagGraph when evaluated on the protein-level detection of single nucleotide variants in the public NCI60 proteome dataset. Further, Claire's analysis of a range of NCI60 datasets revealed high protein-level mutational burdens in genomically unstable cancer cell lines and detected mislabeling and contamination across several omics datasets. In a clinical domain, Claire discerned the hypermutation status of colorectal cancer patients' tumors, identifying candidates suitable for immunotherapy. Protein-level variation in peripheral blood mononuclear cells also recognized individuals, monozygotic twins aside, revealing the pseudonymous nature of germline proteome datasets, and raising the need for their protection. From a computational perspective, Claire can be run as a standalone software in the Linux operating system, or its capabilities accessed remotely using an interface on our cloud computing infrastructure. Claire has thus shown remarkable potential in enhancing peptide detection, offers substantial advancements for both clinical and research applications, and allows direct incorporation of its capabilities into various computational workflows. Citation Format: Miroslav Hruska, Petr Dzubak, Marian Hajduch. Claire: a search engine leveraging deep databases for reliable detection of peptides, with a special focus on proteogenomic applications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7414.
Abstract 1842: Global proteomics reveals integrin signaling as a driver of infiltration in glioblastoma
Authors: Lennart J. van Winden, Rifat Shahriar Sajid, Okty Abbasi Borhani, Evelyn Rose Kamski-Hennekam, Nakita Gopal, Alberto Leon, Phedias Diamandis
Journal: Cancer Research (2024)

Abstract Background: Glioblastoma (GBM), a notably aggressive brain cancer, presents significant treatment challenges due to its propensity for deep, diffuse infiltration into healthy brain tissue. This trait enables GBM to resist and survive following surgery and conventional adjuvant therapies. Emerging evidence suggests that signaling between GBM stem cells (GSCs) may be instrumental in this invasive behavior. Our study aimed to unravel the intricacies of these intercellular communication networks within glioblastoma by employing comprehensive proteomic profiling across a diverse array of patient-derived GSC lines. Methods: We conducted our study using a sex-stratified cohort comprising 17 patient-derived GSC lines. Proteomic profiling encompassed analyses of both GSC lysates and conditioned media under various oxygen conditions (normoxia at 20% O2, hypoxia at 1% and 0.2% O2). Additionally, we incorporated the glioma cerebral organoid (GLICO) system, facilitating co-cultures of GSCs with human cerebral organoids. For in-depth proteomic analysis, we utilized advanced TMT-based liquid chromatography-tandem mass spectrometry (LC-MS/MS; Q-Exactive, Thermo Fisher). Results: Our findings corroborate that GSCs adhere to the tripartite model of proliferation, invasion, and hypoxic response. A salient discovery was the consistent enrichment of integrin signaling pathways in GSCs under hypoxic conditions. Specifically, we observed a significant association between upregulation in integrin signaling (BIOCARTA_INTEGRIN_PATHWAY) and elevated KRAS activity (SWEET_KRAS_TARGETS_UP: r=0.43, p&amp;lt;0.01), as well as hypoxic responses (WINTER_HYPOXIA_UP: r=0.76, p&amp;lt;0.0001) in GSCs. Notably, in the GLICO model, both integrin signaling and KRAS pathways were markedly upregulated in the presence of GSCs compared to cerebral organoids alone (p&amp;lt;0.05). Conclusions: This research highlights the pivotal role of integrin signaling in mediating the invasive attributes of glioblastoma. The data underscore the importance of further exploring key modulators within the integrin signaling pathway, presenting a promising avenue for the discovery of novel therapeutic targets in glioblastoma treatment. Citation Format: Lennart J. van Winden, Rifat Shahriar Sajid, Okty Abbasi Borhani, Evelyn Rose Kamski-Hennekam, Nakita Gopal, Alberto Leon, Phedias Diamandis. Global proteomics reveals integrin signaling as a driver of infiltration in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1842.