tbuckley/cabot-search huggingface dataset:
Abstract 7101: Remodeling of cancer cells by chemotherapy
Authors: Gege Qian, Leah Schaffer, Kyung-Mee Moon, Leonard Foster, Trey Ideker, Mengzhou Hu, Sahar Alkhairy, Emma Lundberg
Journal: Cancer Research (2024)

Abstract Cisplatin is a commonly administrated chemotherapy drug for cancer treatment. Although the direct mechanism of cisplatin is largely well-defined, it is challenging to comprehensively assess its systemic effects. Cellular responses to perturbations are intricate processes involving modifications to protein complexes across diverse cellular compartments. Therefore, substantial research endeavors have been directed towards unraveling protein organization in cells. We recently built a multiscale integrated cell map, MuSIC, that combines fluorescence-stained images and interactions derived from affinity purification mass spectrometry to allow comprehensive characterization of cellular structure and functional networks of 5,254 proteins of the human bone osteosarcoma epithelial line (U2-OS). To exploit the biology of U2OS, we integrated dynamics into this map to determine the proteome reorganization upon cisplatin exposure. Thus, we developed a data-driven approach integrating high throughput size exclusion chromatography mass spectrometry (SEC-MS) data with large-scale cell maps built from static-state information to systematically map at all scales the remodeling of cell architecture in drug-treated cells. Here, we acquired drug-perturbed protein-protein interactions (PPIs) from the SEC-MS data by treating U2-OS with cisplatin. Integrating the differential interactions identified from SEC-MS PPIs with the scaffold large-scale hierarchy (MuSIC) allows retention of the upper cellular organization to systematically map drug impact on protein complexes in the cell. This pipeline serves as an explorative method to identify the drug-responsive organelles, alterations of hierarchical structures, and translocation of proteins. Apart from the well known alterations of DNA damage repair complexes, we also recapitulate remodeling in metabolism pathways, splicing, cAMP-dependent kinase activity, and histone modification. We identify 26 novel protein assemblies containing members that are previously associated with cisplatin biology. This pipeline exploits the potential of a well-established network by integrating the high throughput data modality, allowing for the screening of a range of chemical agents and stimuli to generate differential networks. Citation Format: Gege Qian, Leah Schaffer, Kyung-Mee Moon, Leonard Foster, Trey Ideker, Mengzhou Hu, Sahar Alkhairy, Emma Lundberg. Remodeling of cancer cells by chemotherapy [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 7101.
Abstract 489: Unlocking immune resistance and metastasis of PDAC via dual acting circularized nanodisc
Authors: Ahmed Elzoghby, Hagar Emam, Seungbin Yim, Cuiyan Xin, Mahmoud Nasr
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadliest forms of cancer. While major progress in immunotherapy has been made in recent years, it remains poorly effective in this malignancy. Two key players stand behind immune resistance of PDAC and inadequate efficacy of immunotherapy to suppress its metastasis. First, the immune-resistant pancreatic cancer stem cells (CSCs) evade immune surveillance acting as a source for tumor relapse and metastasis. This immune resistance stems from low immunogenicity of PDAC cells as well as the inaccessible CSCs that reside deep in the tumor core. Second, pancreatic cancer associated fibroblasts (CAFs) fuel metastasis of PDAC cells by suppressing their immune recognition and establishing pre-metastatic niche at distant organs to help their colonization. Our hypothesis is to overcome immune resistance of PDAC and inhibit early steps of its metastasis via simultaneous immunogenic eradication of immune resistant CSCs and switching immunosuppressive and pro-metastatic CAFs into quiescent ones. Therefore, we engineered ultrasmall circularized nanodiscs (cND) that encapsulate oncolytic peptide LTX-315 and fibroblast remodeling Notch signaling inhibitor. The engineered oncolytic LTX-315 loaded cND successfully induced immunogenic cell death (ICD) of both bulk PANC1 and pancreatic CSCs. Compared to non-treated and free LTX-315 treated cells, LTX-315 cND resulted in enhanced release of DAMPs including ATP and HMGB-1 as well as surface translocation of calreticulin. The ultrasmall size (9 nm) of cND enabled its deep tumor penetration to eradicate resistant CSCs, as revealed using 3D PDAC heterospheroids. In parallel, the Notch blocking cND promoted quiescence of the activated pancreatic stellate cells as denoted by downregulation of SMA, FAP and collagen. In KPC syngeneic PDAC mouse model, the dual oncolytic/Notch blocking cND combined with aPD-L1 therapy significantly suppressed tumor growth and prevented its metastasis to liver compared to vehicle-treated mice. Immunophenotyping study showed marked reduction in the abundance of CSCs and CAFs in the tumor treated with the cNDs. Moreover, the tumor infiltration of CD86+ MHCII+ dendritic cells and cytotoxic CD8+ T cells was enhanced after treatment with the cND. Overall, our dual strategy of targeting pancreatic CSCs and CAFs via oncolytic/Notch blocking cND boosted the anti-tumor and anti-metastatic efficacy of aPD-L1 therapy to eliminate primary PDAC tumor and suppress its metastasis. Citation Format: Ahmed Elzoghby, Hagar Emam, Seungbin Yim, Cuiyan Xin, Mahmoud Nasr. Unlocking immune resistance and metastasis of PDAC via dual acting circularized nanodisc [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 489.
Abstract 3160: PufA promotes proliferation, migration and tumorigenesis through NF-kB pathway in cholangiocarcinoma
Authors: Chiao-Ping Chen, Chun-Nan Yeh, Yi-Ru Pan, Yu-Tien Hsiao, Chih-Hong Lo, Chia-Hsien Lin, Chiao-En Wu
Journal: Cancer Research (2024)

Abstract Cholangiocarcinoma (CCA) exhibits a poor prognosis despite the recent advances in targeted therapy and immunotherapy. Therefore, exploring the novel mechanism of CCA tumorigenesis and identifying the effective targeted therapy is critical for advanced CCA to improve future treatment. A novel biogenesis factor of the 90S pre-ribosome named PufA, is higher expressed in tumors than normal tissue based on the TCGA databank implying the role of CCA tumorigenesis. Our results showed that PufA expression was significantly associated with larger tumor size, more lymph node metastasis, more tumor relapse, death, and unfavorable survivals in 205 patients with resectable CCA in Chang Gung Memorial Hospital. We demonstrated the inhibited effect of cell survival, migration ability, and the sphere-formation potential by silencing of PufA in CCA cell lines. Tumor growth is also suppressed in PufA knockdown xenograft mice. Mechanistic investigation showed that PufA was expression associated with nuclear factor kappa B p65 (RELA) activity and facilitated activity of the NF-κB transactivation. RELA, a transcription factor, is the principal regulator of the inflammatory response and is crucial for the homeostasis of the immune system and the expression of the immune checkpoint. Furthermore, decreased PufA levels also downregulated PD-L1 expression in CCA. Together, these findings suggested that the PufA-RELA axis could be a potential target for further application of targeted therapy in combination with immunotherapy. Citation Format: Chiao-Ping Chen, Chun-Nan Yeh, Yi-Ru Pan, Yu-Tien Hsiao, Chih-Hong Lo, Chia-Hsien Lin, Chiao-En Wu. PufA promotes proliferation, migration and tumorigenesis through NF-kB pathway in cholangiocarcinoma [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 3160.
Abstract 529: Investigating the synergistic effect of milciclib and PD0325901 in colorectal cancer therapy
Authors: Xinyu Pei, Anh Nguyen, Hannah Neiger, Wenjia Wang, William Bautista, Lily Wang, Alvan Cai, Valerie A. Gerriets, John K. Cusick, Yihui Shi
Journal: Cancer Research (2024)

Abstract Milciclib, characterized as a potent nanomolar inhibitor of multiple cyclin-dependent kinases, has recently emerged as a promising therapeutic agent in cancer treatment, particularly with its additional role as a spliceosome modulator. Our recent studies employing RNA sequencing technology revealed a comprehensive profile of Milciclib-induced transcriptional changes in colorectal cancer cells, identifying several key regulated pathways. In light of these findings, we explored a novel therapeutic strategy: combining Milciclib with specific inhibitors targeting pathways upregulated by Milciclib treatment. This hypothesis is based on the rationale that such a combination could exert a synergistic effect. We have assessed the efficacy of this combinational therapy and found that the combination of Milciclib and PD0325901 greatly potentiates the killing of colorectal cancer cells versus either treatment alone. PD0325901 has been extensively studied for its efficacy in targeting the MEK/ERK signaling pathway, a critical pathway in many cancers, including colorectal cancer. To further characterize the underlying molecular mechanisms contributing to the observed synergistic effect, we applied quantitative proteomic analysis of 8107 proteins in human colorectal cancer cells with the treatment of different doses of Milciclib and PD0325901 administered alone, or in combination. Our results demonstrate 49 proteins were significantly decreased in a dose-dependent manner, and that many of these proteins are key players regulating pathways associated with the cell cycle, apoptosis, gene expression, metabolism, WNT signaling, and the MEK/ERK signaling pathway. The discovery of the down-regulation of these proteins and pathways after treatment provides a molecular basis to elucidate the synergistic mechanism underlying Milciclib and PD0325901 combination therapy. In conclusion, our study establishes the combinatorial use of Milciclib and PD0325901 as a potential breakthrough in the treatment of colorectal cancer, offering a promising prospect for enhancing future patient outcomes. Citation Format: Xinyu Pei, Anh Nguyen, Hannah Neiger, Wenjia Wang, William Bautista, Lily Wang, Alvan Cai, Valerie A. Gerriets, John K. Cusick, Yihui Shi. Investigating the synergistic effect of milciclib and PD0325901 in colorectal cancer therapy [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 529.
Abstract 4256: Autologous organoids and T cell co-cultures as a powerful personalized platform for immunotherapy development
Authors: Claudia Beaurivage, BanuPriya Sridharan, Sumeyra Mucuk, Kimberly Nadwodny, Derek Poore, Anna Schepers, Farzin Pourfarzad, Sylvia F. Boj
Journal: Cancer Research (2024)

Abstract Recent advances in cancer immunotherapy have had a positive impact on the life expectancy of patients for an extensive range of clinical indications. With new treatment strategies and druggable targets being identified at an increasing pace, the number of patients eligible for cancer immunotherapy is expected to expand steadily. However, promising therapeutic developments face hurdles in translating preclinical findings into therapy since conventional 2D cancer models hold low clinical predictive value. We developed an innovative alternative, building on the discovery that adult stem cells proliferate and organize into three-dimensional organotypic structures when they are embedded into extracellular matrix. Patient-derived organoids are generated from normal and malignant tissues and stored as high-quality biobanks that yield highly reproducible results. HUB Organoids® recapitulate complex characteristics of the parental tissue, including molecular heterogeneity, as well as morphological and functional traits. Since cancer progression and response to immunotherapy are governed by immune cell interactions in the tumor microenvironment, we developed an assay in which colorectal (CRC) and non-small cell lung cancer (NSCLC) tumor organoids are co-cultured with paired tumor infiltrating lymphocytes (TIL) that are simultaneously expanded as a source of tumor reactive cells. Paired resources allow for the screening of immune-modulatory therapies under physiologic conditions, not depending on peptide-pulsing and alloreactivity. We quantify tumor organoid killing and TILs reactivity by combining imaging-based analysis of apoptotic cells with flow cytometry to measure cytokine release by cytotoxic TILs. Here, we show that our system is robust and reproducible with an establishment rate of 75%, allowing for expansion of TILs that preserve T cell receptor repertoires. First line expansion of both PDO and TIL components can be used to effectively build coculture models and probe the tumor and immune components, respectively. Our system offers a powerful tool for the development and validation of cancer immunotherapy and can help to stratify cancer patients for susceptibility to various types of immunotherapies. We certify that the research use of each of the HBS marked above was conducted according to the expectations of each institution. Citation Format: Claudia Beaurivage, BanuPriya Sridharan, Sumeyra Mucuk, Kimberly Nadwodny, Derek Poore, Anna Schepers, Farzin Pourfarzad, Sylvia F. Boj. Autologous organoids and T cell co-cultures as a powerful personalized platform for immunotherapy development [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 4256.
Abstract 1639: Telomere dynamics in aging and cancer by nanopore long-read sequencing
Authors: Tobias T. Schmidt, Carly Tyer, Preeyesh Rughani, Candy Haggblom, Jeff Jones, Xiaoguang Dai, Kelly A. Frazer, Fred H. Gage, Sissel Juul, Scott Hickey, Jan Karlseder
Journal: Cancer Research (2024)

Abstract Telomeres are the protective, nucleoprotein structure at the ends of linear eukaryotic chromosomes. The accurate measurement of both telomeric length and composition of individual telomeres in mammalian cells has been challenged by the length and repetitive nature of telomeres. With the advent of third generation sequencing technologies, it is now technically possible to sequence entire telomeres and map them to individual chromosome arms. Here, we report a reliable method to enrich, sequence and analyze human telomeres using Oxford Nanopore Technologies long-read sequencing. To enrich for telomeric sequences we combine the ligation of adapters complementary to the telomeric G-overhang with restriction enzyme digest to sequence the telomeric C-strand and part of the adjacent subtelomere. The subtelomeric information is harvested to map individual telomeric reads to specific chromosome arms and even alleles. We have measured bulk, chromosome-arm-specific telomere length dynamics during cellular aging of cultured primary cells and in a patient-derived aging cohort. To address the impact of the telomere maintenance mechanism on telomere length and composition, we have sequenced matched pairs of fibroblasts and induced pluripotent stem cells, as well as five well-established telomerase- and ALT-positive cancer cell lines. Our results suggest that based on nanopore telomere long-read sequencing ALT-positive cells can be easily discriminated from normal and telomerase-positive cancer cells. Further, telomere sequencing allows to evaluate the methylation status of the subtelomeric CpG islands adjacent to telomeres. In summary, nanopore telomere long-read sequencing allows to measure the length and composition of individual telomeres and their mapping to specific chromosome arms. Telomere long read sequencing methods will be valuable tools to study telomere biology during aging and cancer. Citation Format: Tobias T. Schmidt, Carly Tyer, Preeyesh Rughani, Candy Haggblom, Jeff Jones, Xiaoguang Dai, Kelly A. Frazer, Fred H. Gage, Sissel Juul, Scott Hickey, Jan Karlseder. Telomere dynamics in aging and cancer by nanopore long-read sequencing [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 1639.
Abstract 5439: Metastasis-enhancing protein KITENIN confers temozolomide resistance in glioblastoma with unmethylated MGMT via upregulation of cancer stem cell makers
Authors: Eun-Jeong Ahn, Yeong Jin Kim, Tae-Young Jung, Jae-Hyuk Lee, Joon Haeng Rhee, Kyung-Keun Kim, Sung Sun Kim, Nah Ihm Kim, Hangun Kim, Kyung-Sub Moon, Kyung-Hwa Lee
Journal: Cancer Research (2024)

Abstract Background: Elevated expression of cancer stem cell (CSC) markers is linked with progression, poor survival, and treatment resistance in glioblastoma (GBM). Our prior work identified KAI1 COOH-terminal interacting tetraspanin (KITENIN) as key to GBM progression. We investigated its influence on temozolomide (TMZ) resistance in GBM through modulation of CSC markers. Methods: We examined KITENIN and CSC markers in TMZ-resistant GBM cells and patient-derived GBM cells, and assessed therapeutic responses to TMZ in mice implanted with KITENIN-modulated GBM cells. The correlation of these markers with clinical outcomes was analyzed using our cohort and The Cancer Genome Atlas (TCGA) data. Results: High KITENIN expression correlated positively with elevated CSC marker levels in human GBM samples and KITENIN-modulated GBM cells. Inhibition of KITENIN using usnic acid reduced tumor progression by decreasing CSC marker expression. Our data and TCGA analyses linked co-directional increase of these factors with tumor recurrence and shorter survival in GBM patients with unmethylated MGMT. This increase was also observed in TMZ-resistant cell lines with unmethylated MGMT. Implantation of KITENIN-overexpressing cells led to TMZ resistance in our mouse model, associated with co-directionally increased CD44 and ALDH1A1 expression. The link between KITENIN and CD44/ALDH1A1 could be inhibited by DKC2511, a novel KITENIN inhibitor, and T5244, a c-Fos/AP-1 inhibitor. Conclusion: KITENIN might contribute to TMZ resistance in GBM patients with unmethylated MGMT, potentially through AP-1 activation and subsequent upregulation of CSC markers. Hence, targeting KITENIN could provide a novel strategy to overcome TMZ resistance in GBM patients with unmethylated MGMT. Citation Format: Eun-Jeong Ahn, Yeong Jin Kim, Tae-Young Jung, Jae-Hyuk Lee, Joon Haeng Rhee, Kyung-Keun Kim, Sung Sun Kim, Nah Ihm Kim, Hangun Kim, Kyung-Sub Moon, Kyung-Hwa Lee. Metastasis-enhancing protein KITENIN confers temozolomide resistance in glioblastoma with unmethylated MGMT via upregulation of cancer stem cell makers [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 5439.
Abstract 2006: Deciphering the interplay of β-catenin/YAP signaling and alveolar lineage plasticity during targeted therapy in non-small cell lung cancer
Authors: Yu-Ting Chou, Wei Wu, Daniel Kerr, Macey Slota, Trever Bivona
Journal: Cancer Research (2024)

Abstract Molecularly targeted therapies have significantly enhanced clinical outcomes by directly addressing oncogenic driver mutations in genes such as EGFR. However, despite the success of treatments targeting these mutations, long-term patient survival remains limited. This study investigates the molecular mechanisms underlying drug-tolerance in response to targeted therapies in non-small cell lung cancer (NSCLC). Using single-cell RNA sequencing of oncogene-driven human NSCLCs at the residual disease (RD) state during active targeted therapy, our investigation reveals an increase of an alveolar type I/II (AT1/2) mixed lineage program in surviving cancer cells, resembling an alveolar cell-like state. We observed increased WNT3A/4 ligands, FZD2 receptors, β-catenin signaling, and AT1/2 signatures at the RD stage. Consistent with clinical results, AT1/2 signatures and target genes of β-catenin and YAP are increased in drug-tolerant persister (DTP) cells in preclinical models. Additionally, we discovered that β-catenin and YAP form a stable nuclear protein complex in DTP cells. Disrupting β-catenin/YAP protein expression and stability in DTP cells by knocking down FZD2 or interrupting the destruction complex of β-catenin/YAP leads to re-sensitization to the EGFR inhibitor Osimertinib, suggesting a potential therapeutic approach. Furthermore, this therapeutic strategy decreased AT1/2 gene signatures. Our results highlight an interdependence between β-catenin and YAP, with both proteins playing crucial roles in sustaining DTP cells and promoting the alveolar cell like lineage plasticity. These findings shed light on the complex interplay between β-catenin/YAP signaling and alveolar signatures in the residual cancer state, offering mechanistic insights and potential therapeutic strategies to address drug tolerance and improve clinical outcomes. Citation Format: Yu-Ting Chou, Wei Wu, Daniel Kerr, Macey Slota, Trever Bivona. Deciphering the interplay of β-catenin/YAP signaling and alveolar lineage plasticity during targeted therapy in non-small cell lung 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 2006.
Abstract 5273: A novel immunogenic cell death that exploits the cancer-specific overexpression of Rad51
Authors: Maria Soloveychik, Charly Chahwan
Journal: Cancer Research (2024)

Abstract Overexpression of the Homologous Recombination (HR) DNA repair pathway is often correlated with poor prognosis and metastatic disease. SyntheX developed STX100, a small, stabilized peptide that is able to disrupt the function of Rad51 - a crucial component of HR. STX100 exhibits low nanomolar affinity to the target, cell permeability, and proteolytic stability. STX100 has acute mono-agent activity that is selective towards HR-overexpressing cancer cells. Interestingly, STX100-mediated cell killing is independent of canonical cell death mechanisms (apoptosis, necroptosis, pyroptosis, ferroptosis, etc.). Rather, the elevated abundance of Rad51 in cancer cells relative to healthy tissues underlies the selective cytotoxicity resulting from an acute calcium surge upon STX100-mediated target engagement. The mechanism translates to in vivo models, where a single dose can achieve sustained survival when administered locally as a mono-therapy or in combination with an immune checkpoint blockade agent. Citation Format: Maria Soloveychik, Charly Chahwan. A novel immunogenic cell death that exploits the cancer-specific overexpression of Rad51 [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 5273.