tbuckley/cabot-search huggingface dataset:
Abstract 6430: Gene expression signature quantifies the cellular contribution of the tumor <i>vs.</i> the microenvironment in determining colorectal cancer prognosis and therapeutic outcome
Authors: Mingli Yang, Timothy J. Yeatman, Michael V. Nebozhyn, Michael J. Schell, Lance Pflieger, Andrey Loboda, Warren J. Pledger, Ramani Soundararajan, Michelle Maurin, Heiman Wang, Jetsen Rodriguez Silva, Ashley Alden
Journal: Cancer Research (2024)

Abstract Accumulating evidence has suggested that cancer progression and therapeutic response may depend on not only tumor cells but also their tumor microenvironment (TME). However, their contributory roles are complex and not well understood. Here we report an analysis of 2373 human colorectal cancer (CRC) tumors representing all stages, leading to identification of a 20-gene signature capable of quantifying the cellular contribution of the tumor vs. the TME in determining colorectal cancer prognosis and therapeutic outcome. We classified these tumors into the consensus molecular subtypes (CMS1-4) with distinct, variable TME cellular features defined by CIBERSORT deconvolution analysis of bulk gene expression data. Surprisingly, all the 10 positive signature genes (portending worse survival) were strongly correlated with the TME-rich CMS1 and CMS4 tumors. By contrast, all the 10 negative signature genes (portending better survival) were highly related to the TME-poor CMS2 and CMS3 tumors. A single cell expression analysis from an independent database further revealed that strikingly, all the 10 positive genes were principally expressed by the immune/stromal TME whereas all the 10 negative genes were predominantly expressed in epithelial tumor cells. These data suggest that the TME has an equally important role as do tumor cells in determining CRC prognosis and support targeting the TME to improve survival. Moreover, distinct gene expression from tumor cells versus the TME also showed a differential impact on therapeutic outcome. Retrospective analyses on two independent clinical trial datasets show that the 20-gene signature score significantly predicted progression free survival in metastatic CRC patients treated with cetuximab, an FDA-approved EGFR inhibitor therapy. These data suggest a potential for the 20-gene signature as a predictive biomarker to identify “sensitive” versus “resistant” subpopulations of CRC patients to improve outcome of EGFR-targeted therapy. Citation Format: Mingli Yang, Timothy J. Yeatman, Michael V. Nebozhyn, Michael J. Schell, Lance Pflieger, Andrey Loboda, Warren J. Pledger, Ramani Soundararajan, Michelle Maurin, Heiman Wang, Jetsen Rodriguez Silva, Ashley Alden. Gene expression signature quantifies the cellular contribution of the tumor vs. the microenvironment in determining colorectal cancer prognosis and therapeutic outcome [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 6430.
Abstract 4123: Attenuating breast cancer metastasis with BCL-XL-targeting PROTACs
Authors: Madison E. Carelock, Peiyi Zhang, Mo Jiao, Umasankar De, Zeng Jin, Rachel M. Stump, Sarah G. Williams, Guangrong Zheng, Weizhou Zhang
Journal: Cancer Research (2024)

Abstract B-cell lymphoma X-large (BCL-XL) emerges as a significant player in cancer progression. In our recent findings, we unveil the efficacy of proteolysis-targeting chimeras (PROTACs) directed against BCL-XL, demonstrating their capacity to not only eliminate cancer cells but also target tumor-induced regulatory T cells (TI-Tregs). Notably, BCL-XL's role in promoting breast cancer metastasis extends beyond its anti-apoptotic function. We posit that BCL-XL-targeting PROTACs (BCL-XL-Ps) hold promise for treating metastatic breast cancer. Their potential lies in directly eliminating circulating tumor cells during vulnerable stages and/or triggering anti-cancer immunity through Treg cell depletion. Our experiments underscore the potency of IAP-based PROTACs in facilitating BCL-XL degradation via the ubiquitin-proteasome system (UPS) while mitigating on-target platelet toxicity. Treatment of breast cancer-bearing mice with these compounds demonstrates a tangible reduction in breast cancer metastasis to the lungs. Additionally, our studies reveal a significant depletion of tumor-infiltrating Tregs in mice treated with BCL-XL-Ps. While affirming BCL-XL as a viable therapeutic target for breast cancer metastasis, further exploration into the mechanisms behind BCL-XL-P targeting is imperative. Our future endeavors will be devoted to unraveling whether our BCL-XL-Ps effectively target both tumor-intrinsic BCL-XL, potentially inducing tumor cell death, and tumor-infiltrating Tregs, thereby fostering an adaptive immune response against the tumor cells. Citation Format: Madison E. Carelock, Peiyi Zhang, Mo Jiao, Umasankar De, Zeng Jin, Rachel M. Stump, Sarah G. Williams, Guangrong Zheng, Weizhou Zhang. Attenuating breast cancer metastasis with BCL-XL-targeting PROTACs [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 4123.
Abstract 4719: Modulation of HR-HPV viral protein E7 by SHetA2 in cervical cancer
Authors: Justin Garland, Showket Hussain, Doris M. Benbrook
Journal: Cancer Research (2024)

Abstract Introduction: The purpose of this study is to determine the effect of the chemotherapeutic sulfur heteroarotinoid A2 (SHetA2) on high-risk human papillomavirus (HR-HPV) proteins and the modulation of cell survival and proliferation in cervical cancer. Cervical cancer is caused by persistent HR-HPV infection. HR-HPV tumorigenesis is driven by its early 6 and 7 (E6, E7) oncoproteins, which increase cell proliferation and survival. Cellular pathways regulated by E6 and E7 are counter-regulated by the investigational new drug SHetA2, which is currently in phase 1 clinical trial for advanced and recurrent cancers. SHetA2 disrupts complexes of 70-kDa heat shock protein (HSP70) family members, hsc70, GRP78, and mortalin, with their client proteins. We hypothesized that SHetA2 reduces E6 and E7 levels and their binding to HSP70 chaperones in association with the reduction of cervical cancer cells and tumor growth. Methods: SHetA2 effects on specific genes and proteins in HR-HPV-positive cervical cancer cell lines and xenograft tumors were assessed by western blot, quantitative polymerase chain reaction, immunofluorescence ligation assays, and coimmunoprecipitation assays. Results: SHetA2 significantly reduced E6 and E7 mRNA, and protein levels of E7 and the E7-regulated p16, but not E6 in cervical cancer cells and xenograft tumors. MG132 inhibition of proteasome function attenuated the E7 reduction. HSP70/hsc70 proteins bound E7 and SHetA2 disrupted these complexes. Conclusions/Implications: SHetA2 reduces E7 proteins in cervical cancer cells through a mechanism that involves proteasomal degradation in association with disruption of HSP70/E7 complexes, p16 reduction, and decreased cell and tumor growth. This is the first demonstration of HSP70/E7 complexes. SHetA2-induced release of E7 from HSP70s could be causing increased susceptibility of E7 to proteasomal degradation. This data supports the development of SHetA2 and HSP70 inhibitors for cervical cancer. Citation Format: Justin Garland, Showket Hussain, Doris M. Benbrook. Modulation of HR-HPV viral protein E7 by SHetA2 in cervical 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 4719.
Abstract 3011: The loss of an orphan nuclear receptor NR2E3 augments Wnt/β-Catenin signaling via epigenetic dysregulation that links to the Sp1-β catenin-p300 interactions in hepatocellular carcinoma
Authors: Yuet-Kin Leung, Sung-Gwon Lee, Jiang Wang, Shuk-Mei Ho, Nancy Rusch, Chungoo Park, Kyounghyun Kim
Journal: Cancer Research (2024)

Abstract Hepatocellular carcinoma (HCC) stands as the fourth leading cause of global cancer-related mortality due to late-stage detection, tumor heterogeneity, and drug resistance. The pivotal role of epigenetic factors in HCC development and progression necessitates the identification of critical epigenetic regulators. The orphan nuclear receptor NR2E3 (Nuclear receptor subfamily 2 group E, Member 3), primarily associated with retinal development, has emerged as a potential tumor suppressor. Earlier studies showed that the loss of NR2E3 leads to epigenetic repression of the estrogen receptor α (ER) through the involvement of Lysine Specific histone Demethylase 1 (LSD1). NR2E3 also forms a transcriptional complex with Sp1, governing the aryl hydrocarbon receptor (AHR) expression, a crucial factor in liver xenobiotic metabolism. In vivo, NR2E3 ablation results in p53 inactivation and severe liver injuries when exposed to liver toxicants, highlighting its role in activating p53. Nonetheless, the precise tumor suppressive and epigenetic role of NR2E3 in HCC remains unclear. HCC patients expressing low NR2E3 exhibit unfavorable clinical outcomes, aligning with heightened activation of the Wnt/β-catenin signaling pathway. The murine HCC models utilizing NR2E3 knockout mice show accelerated liver tumor formation and progression accompanied by enhanced activation of the Wnt/β-catenin signaling pathway and inactivation of the p53 signaling pathway. At a cellular level, losing NR2E3 increases the acquisition of aggressive cancer cell phenotype and tumorigenicity and upregulates vital genes in the Wnt/β-catenin pathway with enhanced chromatin accessibility. This event is mediated through the increased formation of active transcription complex involving Sp1, β-catenin, and p300, a histone acetyltransferase, on the promoters of target genes. Correspondingly, treatment of p300 inhibitor C646 decreased the expression of critical genes in the Wnt/β-catenin signaling pathway. These findings demonstrate that the loss of NR2E3 promotes Wnt/β-catenin signaling activation at cellular, organismal, and clinical levels. In summary, NR2E3 is a novel tumor suppressor that maintains epigenetic homeostasis, thereby preventing activation of Wnt/β-catenin signaling that promotes HCC formation. Citation Format: Yuet-Kin Leung, Sung-Gwon Lee, Jiang Wang, Shuk-Mei Ho, Nancy Rusch, Chungoo Park, Kyounghyun Kim. The loss of an orphan nuclear receptor NR2E3 augments Wnt/β-Catenin signaling via epigenetic dysregulation that links to the Sp1-β catenin-p300 interactions in hepatocellular carcinoma [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 3011.
Abstract 4956: A fast and efficient bioinformatics analysis workflow for processing reads from single-cell multiomics assays captured on a microwell-based platform
Authors: Raghavendra Padmanabhan, Brent Weichel, Amie Radenbaugh, Yuefu Jiang, Charles Weeks, Thomas McCarthy, Youngsook Kim, Anthony Berno, Devon Jensen
Journal: Cancer Research (2024)

Abstract Here, we present a significant update: version 2.0 of our sequencing analysis, it is a comprehensive primary analysis workflow that is up to 7X faster and consumes 2X less disk space than the previous release. We used it to process a library with 20,000 human PBMCs sequenced to a depth of 1.2 billion reads in 2.5 hours of wall-clock time. The pipeline can be used with reads from single-cell whole transcriptome, targeted mRNA, surface antigens (AbSeq), TCR/BCR and Sample Tag libraries captured on the BD Rhapsody™ System platform. The major processing steps include Quality Filtering, Cell Barcode Identification, Read Alignment, Feature Assignment, UMI Error Correction, Identification of Putative Cells, Sample De-Multiplexing, Dimensionality Reduction for Visualization and VDJ Contig Assembly and Annotation. Output files and metrics are available in easy-to-digest formats, including an html report with dynamic visualization. Integrated outputs in Seurat and Scanpy formats combine expression matrices and all cell annotation metadata (e.g., predicted cell type, sample assignment, TCR/BCR sequence and gene segments). These pre-generated files are ready to load into popular single-cell analysis tools. The pipeline uses CWL as the workflow manager and makes use of custom code written in C++ and Python along with various open-source packages for data processing. The pipeline can also process reads from non-human species and includes built-in support for specifying and building custom reference genome indices. In support of high-throughput multiomic discovery studies enabled by the BD Rhapsody™ HT Xpress System, this pipeline has been tested with datasets containing more than 800,000 putative cells and 14.5 billion reads. For Research Use Only. Not for use in diagnostic or therapeutic procedures. BD, the BD Logo and BD Rhapsody are trademarks of Becton, Dickinson and Company or its affiliates. © 2023 BD. All rights reserved. NPM-2535 (v1.0) 1023 Citation Format: Raghavendra Padmanabhan, Brent Weichel, Amie Radenbaugh, Yuefu Jiang, Charles Weeks, Thomas McCarthy, Youngsook Kim, Anthony Berno, Devon Jensen. A fast and efficient bioinformatics analysis workflow for processing reads from single-cell multiomics assays captured on a microwell-based platform [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 4956.
Abstract 1583: Neutrophil pro-tumorigenic role in progression and therapy resistance in pancreatic ductal adenocarcinoma
Authors: Reegan Sturgeon, Esther Johnson, Caitlin Molczyk, Paran Goel, Parker Tinsley, Lauren Abrahams, Michael Maher, Rakesh K. Singh
Journal: Cancer Research (2024)

Abstract Pancreatic cancer (PC) continues to be a challenge for today’s therapeutics, with a meager 5-year survival rate of 12%. Due to the pancreas’ location, patients often receive diagnosis late, leaving them with limited treatment options. Often, they fail to respond to chemotherapy regimens or develop resistance to those therapies. Tumor-promoting inflammation is a hallmark of cancer, contributing to tumor cells’ survival and proliferation. Infiltrating leukocytes and pro-inflammatory cytokines released into the tumor microenvironment (TME) often cause this inflammation. My lab has previously linked increases in pancreatic ductal adenocarcinoma (PDAC) progression and chemotherapy resistance to inflammation and the CXCR2 pathway. In the present study, we examined the role of neutrophil recruitment in PDAC progression using patient samples and KRAS-dependent KC and KPC murine models. Our data suggest a positive association between tumor-associated neutrophils (TANs) and PDAC progression. In vitro, we observed neutrophil-PDAC interaction enhancing the survival of both neutrophils and PDAC cell lines. Moreover, this survival was mediated by cellular aggressiveness and therapy resistance. Concerning survival, we saw increased expression of anti-apoptotic genes in the neutrophils upon PDAC cancer cell conditioned media treatment. We also observed modulated expression of immunoregulatory molecules. Our data suggest that increased recruitment of TANs supports PDAC progression and survival, and PDAC cell-neutrophil interaction modulates neutrophil survival and immunoregulatory phenotype. Citation Format: Reegan Sturgeon, Esther Johnson, Caitlin Molczyk, Paran Goel, Parker Tinsley, Lauren Abrahams, Michael Maher, Rakesh K. Singh. Neutrophil pro-tumorigenic role in progression and therapy resistance in pancreatic ductal adenocarcinoma [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 1583.
Abstract 2082: Identification of nonsense-mediated decay inhibitors that alter the tumor immune landscape
Authors: Ashley L. Cook, ojit Sur, Laura Dobbyn, Evangeline Watson, Joshua D. Cohen, Blair Ptak, Bum Seok Lee, Suman Paul, Emily Hsiue, Maria Popoli, Bert Vogelstein, Nickolas Papadopoulos, Chetan Bettegowda, Kathy Gabrielson, Shibin Zhou, Kenneth Kinzler, Nicolas Wyhs
Journal: Cancer Research (2024)

Abstract Despite exciting developments in cancer immunotherapy, its broad application is limited by the paucity of targetable antigens on the tumor cell surface. As an intrinsic cellular pathway, nonsense-mediated decay (NMD) conceals neoantigens through the destruction of the RNA products from genes harboring truncating mutations. We developed and conducted a high throughput screen, based on the ratiometric analysis of transcripts, to identify critical mediators of NMD. This screen revealed disruption of kinase SMG1’s phosphorylation of UPF1 as a potent disruptor of NMD. This led us to design a novel SMG1 inhibitor, KVS0001, that elevates the expression of transcripts and proteins resulting from truncating mutations in vivo and in vitro. Most importantly, KVS0001 concomitantly increased the presentation of immune-targetable HLA class I-associated peptides from NMD-downregulated proteins on the surface of cancer cells. KVS0001 provides new opportunities for studying NMD and the diseases in which NMD plays a role, including cancer and inherited diseases. Citation Format: Ashley L. Cook, ojit Sur, Laura Dobbyn, Evangeline Watson, Joshua D. Cohen, Blair Ptak, Bum Seok Lee, Suman Paul, Emily Hsiue, Maria Popoli, Bert Vogelstein, Nickolas Papadopoulos, Chetan Bettegowda, Kathy Gabrielson, Shibin Zhou, Kenneth Kinzler, Nicolas Wyhs. Identification of nonsense-mediated decay inhibitors that alter the tumor immune landscape [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 2082.
Abstract 5050: Germline variants in <i>CDKN2A</i> wild-type melanoma prone families
Authors: Stian Knappskog, Gjertrud T. Iversen, Marie Loeng, Amalie L. Holth, Per E. Lonning, Jurgen Geisler
Journal: Cancer Research (2024)

Abstract The presence of germline pathogenic variants in CDKN2A is a well-established underlying cause of familial malignant melanoma. While pathogenic variants in several other genes have also been linked to melanoma development, many familial cases remain unexplained. We analyzed for pathogenic germline variants in a panel of 360 cancer related genes in a set of 56 Norwegian melanoma prone families. The index cases and families were selected based on familial history of melanoma and/or multiple primary melanomas in the same individual, along with previous negative tests for pathogenic CDKN2A variants. We found 6 out of 56 index individuals to carry germline pathogenic or likely pathogenic variants. These variants were found in BRCA2, MRE11, ATM, MSH2, CHEK2 and AR. In addition, one family member with a melanoma diagnosis (not index case) carried a pathogenic variant in MAP3K6. In genes typically linked to xeroderma pigmentosum, we found a high fraction of variants previously considered benign and/or as variants of uncertain significance. In particular the XPCL48F variant was found in 8 out of 56 indexes, thus, the allele fraction (0.07) was significantly higher than in comparable healthy populations (p-values from 0.007 to 0.014). Similarly, we found presumed benign or uncertain variants in MC1R to be significantly enriched or numerically higher in index cases versus comparable healthy populations (p-values from 0.009 to 0.1). The common MC1RArg151Cys variant was highly enriched in our cohort (p=0.001).In conclusion, we found that several melanoma prone families harbored pathogenic variants in genes not usually linked to melanoma. Citation Format: Stian Knappskog, Gjertrud T. Iversen, Marie Loeng, Amalie L. Holth, Per E. Lonning, Jurgen Geisler. Germline variants in CDKN2A wild-type melanoma prone families [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 5050.
Abstract 1917: HER2-FGFR1 interaction induced by bispecific molecules: A novel strategy for treating breast cancer
Authors: Mateusz Adam Krzyscik, Kalina Hristova
Journal: Cancer Research (2024)

Abstract Breast cancer poses a significant global health challenge, demanding effective therapies targeting specific receptors. In our prior study, we engineered molecules capable of binding to both HER2 and FGFR1, pivotal receptors in breast cancer progression. By combining the high-affinity Affibody ZHER2:2891 for HER2 with a modified, stable form of FGF2 binding to FGFR1, we created the bispecific protein (AfHER2-lFGF2). This innovative molecule could simultaneously recognize HER2 and FGFR1, exhibiting enhanced cell penetration. When coupled with the potent cytotoxic agent monomethyl auristatin E (MMAE), it demonstrated exceptional efficacy in eliminating cancer cells expressing HER2, FGFR, or both receptors. Our current investigation focused on quantifying the interaction between HER2 and FGFR1 receptors on the cell surface upon treatment with these bispecific molecules. Leveraging fully quantified spectral imaging FRET (FSI-FRET), a technique utilizing spectrally resolved two-photon microscopy. We directly monitor the association of HER2 and FGFR1 in the plasma membrane. Our findings revealed that the bispecific AfHER2-lFGF2 molecule forces interaction between HER2 and FGFR1 on the cell surface. Furthermore, we analyzed the activation of the HER2-FGFR1 complex and subsequent downstream signaling pathways using western blotting. In summary, our research uncovers the ability of the AfHER2-lFGF2 bispecific protein to foster direct interaction between HER2 and FGFR receptors on the cell membrane. By employing state-of-the-art techniques like FSI-FRET, we elucidated the mechanisms governing this interaction and, by western blotting, downstream signaling pathways. These insights emphasize the potential of AfHER2-lFGF2 as a promising therapeutic agent for targeting HER2, FGFRs, and HER2/FGFRs-positive cancers. This approach paves the way for targeted therapies in addressing the prevalent global health challenge of breast cancer. Citation Format: Mateusz Adam Krzyscik, Kalina Hristova. HER2-FGFR1 interaction induced by bispecific molecules: A novel strategy for treating 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 1917.