tbuckley/cabot-search huggingface dataset:
Abstract 179: Identification of a novel crosstalk between MDSC and NKregs in immunotherapy resistant triple negative breast cancer
Authors: Megha Das, Samantha Henry, Shailesh Singh, Camila Dos Santos, Rumela Chakrabarti
Journal: Cancer Research (2024)

Abstract Triple-negative breast cancer (TNBC) is one of the most aggressive forms of breast cancer and lacks standard treatment options. Although immunotherapy shows some response in these patients along with chemotherapy, heterogeneity of tumor cells and immune cells results in significant low response to immunotherapy treatment. Based on single cell sequencing which enables identity of heterogenous population at single cell level and functional studies involving preclinical mouse models, our laboratory recently identified distinct CD56brightSOCS3highCD11b−CD27− immature NK cells subpopulations, with diminished cytotoxic granzyme signatures that promote TNBC tumor progression. However, the precise characterization and functionality of these rogue tumor promoting NK cells remains unclear in clinical samples. Here, we aimed to illustrate mechanistic insight of these novel immature NK subpopulation in context of immunotherapy resistant TNBC patient samples. The scRNA seq analysis of TNBC patient samples identified four specific subclusters of NK cells in TNBC. We further found that NK2 and NK3 subclusters are CD56dim Granzymehigh cytotoxic NK cells and the other two subclusters (NK0 and NK1) are CD56bright immature NKs. Interestingly, the NK0 and NK1 subcluster specifically exhibit distinctive characteristics and functions. Notably, CD56bright immature NK1 cells, identified as tissue-resident NK cells, were engaged in direct communication with myeloid-derived suppressor cells (MDSCs). The CD56bright NK0 possesses moderate to low SOCS3 expression and moderate to high granzyme expression with elevated early NK activation markers and inhibitory receptor expressions, suggesting its regulatory property (NKregs). scRNA seq and flow cytometry analysis showed higher NKregs and immunosuppressive MDSC population, specifically with high monocytic-MDSCs (mMDSCs) in non-responder TNBC (to adjuvant combinational treatment of chemo and immunotherapy) patient samples rather than responder patients’ tissue. Based on in silico analysis, we further found a potential crosstalk between these mMDSC &amp; NKreg within the tumors of non-responsiveness of TNBC patients. Overall, our studies show a connection of MDSCs and NKregs in TNBC patients, who do not respond to immunotherapy, highlighting a possible mechanism for immunotherapy resistance, which could be targeted in near future for better treatment options in TNBC. Citation Format: Megha Das, Samantha Henry, Shailesh Singh, Camila Dos Santos, Rumela Chakrabarti. Identification of a novel crosstalk between MDSC and NKregs in immunotherapy resistant triple negative 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 179.
Abstract 1635: Inhibition of FANCA Suppresses Breast Cancer Development by Regulating Cell Cycle Progression
Authors: Liang Luo, Wenjun Liu, Fenghua Yuan, Fang Li, Anna Palovcak, Daniel Calkins, Karoline Briegel Briegel, Yan Li, Christian Mason, Zhao-Jun Liu, Sylvia Daunert, Yanbin Zhang
Journal: Cancer Research (2024)

Abstract FANCA is one of the 22 known Fanconi anemia (FA) pathway genes that are involved in interstrand crosslink (ICL) repair. We have also shown that and FANCA plays a role in double strand break repair by promoting strand annealing and exchange. In this report, we describe that FANCA expression in breast cancer is significantly elevated within TCGA databases and in patient tumors-derived sections on both transcription and translation levels and this elevation is associated with poor outcomes of the breast cancer patients. Importantly, we have found that overexpressing FANCA in breast cancer cell line MDA-MB-231 promotes tumor growth both in vitro and in vivo. We have also demonstrated that FANCA inactivation by knocking out or knocking down inhibits growth of MDA-MB-231 in vitro and in vivo by causing cell cycle arrest at G1 phase resulting from hypophosphorylation of Rb protein. Our RNA-seq data has indicated that E2F targets are also downregulated in FANCA knockout (KO) cells compared to the wildtype (WT) MDA-MB-231 cells, which is consistent with the G1/S cell cycle arrest and Rb hypophosphorylation. Intriguingly, heterozygous FANCA KO in a breast cancer mouse model MMTV-PyMT model has shown reduction of breast tumor formation and volume. Our goal is to elucidate the role of FANCA in breast cancer development and to evaluate the potential of FANCA as a target for breast cancer treatment. Citation Format: Liang Luo, Wenjun Liu, Fenghua Yuan, Fang Li, Anna Palovcak, Daniel Calkins, Karoline Briegel Briegel, Yan Li, Christian Mason, Zhao-Jun Liu, Sylvia Daunert, Yanbin Zhang. Inhibition of FANCA Suppresses Breast Cancer Development by Regulating Cell Cycle Progression [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 1635.
Abstract 1785: The role of <i>BRCA1</i> on metabolic pathways in an <i>in vivo</i> system
Authors: Stacey L. Hembruff, Alexander Dekonenko, John Thyfault, Mihaela Sardiu, Michael Washburn, Roy A. Jensen, Lisa M. Harlan-Williams
Journal: Cancer Research (2024)

Abstract The role of BRCA1 in cellular metabolism is not well characterized and what we do understand has been mostly demonstrated in vitro. Our studies aim to fully characterize the role of BRCA1 in metabolic pathways in a whole-body system. In vivo studies using C57BL/6 wild-type and transgenic humanized BRCA1 mice demonstrate the effect of human BRCA1 on the whole-body metabolic phenotype and start to elucidate the mechanism by which this occurs. We used Promethion metabolic chambers and glucose tolerance tests to measure a number of metabolic outputs of male and female mice that had either normal mouse Brca1 gene expression (wild-type/WT mice) or a knock-out mouse Brca1/knock-in human BRCA1 (humanized/HU mice). Humanized BRCA1 mice are more lean, hyperactive and demonstrate a sexual dimorphism in glucose tolerance when compared to wild-type mice on the same genetic background. To begin to elucidate the mechanisms behind the observed metabolic phenotype, we used a metabolic tissue, female mouse skeletal muscle, to perform mass spectrometry, SuperArray, and Western blot analysis. Proteomic samples were sent to the IDeA National Resource for Quantitative Proteomics at the University of Arkansas Medical Sciences for processing and analysis. Proteomic and genomic analysis showed changes in a number of metabolic pathways that may be implicated in the observed whole body metabolic phenotype. We can conclude that changing the expression levels of BRCA1 in an in vivo model altered the overall metabolic profile of C57BL/6 mice. This is the first in vivo evidence demonstrating the effects of BRCA1 expression in whole body metabolism. Citation Format: Stacey L. Hembruff, Alexander Dekonenko, John Thyfault, Mihaela Sardiu, Michael Washburn, Roy A. Jensen, Lisa M. Harlan-Williams. The role of BRCA1 on metabolic pathways in an in vivo system [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 1785.
Abstract 632: AKT supports cancer cell survival through modulation of cholesterol homeostasis
Authors: Igor Vivanco, Khine N. Myint, Sean Wallace, Glorianne Lazaro, Eleftherios Kostaras, Nikolaos Palaskas
Journal: Cancer Research (2024)

Abstract AKT is a critical effector kinase downstream of PI3K activation. It has been shown to regulate a variety of cellular processes important for homeostasis, many of which are altered during oncogenesis. Not surprisingly, AKT is constitutively activated in a large number of human cancers, and has consequently been pursued as a therapeutic target for many years. Some of these functions are directly involved in establishing one or more hallmarks of cancer including sustained proliferative signaling, resisting cell death, and reprogrammed cellular metabolism. Although AKT inhibitors have demonstrated clinical benefit (most recently in a phase III trial) in combination with other therapies, single agent activity has been limited to a few cases with relatively infrequent activating AKT1 mutations. We have previously proposed that the clear disconnect between the high frequency of AKT activation in cancer and the lack of broad clinical activity of AKT inhibitors is due, at least in part, to the inability of existing compounds to block non-catalytic functions. We have found that while allosteric AKT inhibitors are partial suppressors of these functions, ATP-competitive inhibitors fail to suppress these functions to any significant extent. We now provide evidence that one important non-catalytic function of AKT that impinges on its oncogenic function is the regulation of cholesterol metabolism. We show that AKT represses the activation of LXRβ, thereby maintaining a level of intracellular cholesterol that is compatible with cancer cell viability, and that this repression does not require catalytic activity. Consistently, we find that allosteric AKT inhibitors induce LXRβ activation, and that genetic or pharmacological suppression of LXRβ function limit the growth inhibiting effects of these drugs. Our findings suggest that through a kinase-independent activity, AKT may play a significant role in the regulation of cholesterol homeostasis, and that the therapeutic potential of AKT inhibitors could be broaden by optimizing their ability to interfere with these functions. Citation Format: Igor Vivanco, Khine N. Myint, Sean Wallace, Glorianne Lazaro, Eleftherios Kostaras, Nikolaos Palaskas. AKT supports cancer cell survival through modulation of cholesterol homeostasis [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 632.
Abstract 5626: Essential role of Slug during the evolution of drug-tolerance in lung adenocarcinoma
Authors: Jenny Ostendorp, Hannah Lea Tumbrink, Pascal Hunold, Michaela Hoehne, Philipp Jurmeister, Anastasia Dekker, Felix Heisel, Johannes Brägelmann, Frederick Klauschen, Robert Haensel-Hertsch, Martin L. Sos
Journal: Cancer Research (2024)

Abstract A major obstacle in the efficacy of targeted therapies of oncogene-driven tumors are drug-tolerant persister cells (DTPs) that build the basis for the outgrowth of drug-resistant clones and ultimately limit patient survival. During treatment, DTPs enter a reversible senescent state to survive therapy while cell death is induced in non-DTPs. Here, using RNA-Seq and proteomic analyses, we identified drug-induced TGFβ2 secretion in DTPs derived from different oncogene-driven lung cancer cell lines. As expected, TGFβ2 induces epithelial-to-mesenchymal transition (EMT) that over time promotes the ability of cells to survive targeted therapy. Using CRISPR/Cas9-mediated loss-of-function and reconstitution experiments we show that downstream of TGFβ2, expression of the transcription factor SNAI2 (SLUG) is essential for the outgrowth of DTPs during targeted treatment. Unsupervised RNA-Seq data analyses in combination with Cut&amp;Tag profiling revealed that EMT signaling is in part a SLUG regulated process but that is also independent of direct SLUG binding at the transcription start sites (TSS) of EMT signature genes. In contrast, we observed high occupancy of SLUG at TSS of genes involved in the regulation of cell cycle, being repressed in DTPs and at TSS of genes that regulate sphingolipid metabolism and MAPK signaling, being induced in DTPs. In line with our previous findings, a motif-based analysis of the Cut&amp;Tag data (TOBIAS) furthermore uncovered a tight connection between DTP outgrowth and inflammatory signaling induced through IRF7, IRF4 or STAT1 activation. In vivo, EGFR-mutant SLUG deficient cells showed a significantly prolonged tumor onset and a higher response rate to osimertinib treatment. Overall, we uncover a major role of TGFβ2/SLUG-mediated EMT signaling that may be induced indirectly through SLUG-dependent reprogramming of cell cycle directed and metabolic processes in drug tolerant cells. These insights may offer unique therapeutic opportunities to limit the outgrowth of drug resistant tumors in cancer patients. Citation Format: Jenny Ostendorp, Hannah Lea Tumbrink, Pascal Hunold, Michaela Hoehne, Philipp Jurmeister, Anastasia Dekker, Felix Heisel, Johannes Brägelmann, Frederick Klauschen, Robert Haensel-Hertsch, Martin L. Sos. Essential role of Slug during the evolution of drug-tolerance in lung 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 5626.
Abstract 3095: A high-throughput phenotypic screen to identify small molecule inhibitors of Werner helicase
Authors: Christine A. Moomau, Yipin Lu, Xiaobin Zhang, Xiang Zhai, Lina Gu, Qing Sheng, Fang Li, Yaoyu Chen
Journal: Cancer Research (2024)

Abstract Werner helicase (WRN) is a RecQ DNA helicase involved in genome maintenance and DNA damage repair. It has recently been shown to be essential to cancer cells with high microsatellite instability (MSI-H). In MSI-H cancer cells, WRN depletion was shown to induce DNA damage and disrupt mitoses, resulting in a distinct phenotype of enlarged and fragmented nuclei. Here, we present a high-throughput phenotypic screen to identify compounds that selectively induce enlarged nuclei in MSI-H cancer cells. In HCT116, an MSI-H colorectal cancer cell line, approximately 40% of cells exhibited enlarged nuclei when WRN was depleted using siRNA. In contrast, fewer than 10% of control cells displayed this phenotype. In HT29, a microsatellite stable (MSS) cancer cell line, no such difference in nuclear morphology was observed, suggesting that the phenotype is specific to MSI-H cells. We used high content imaging to screen our in-house diversity library of approximately 175,000 compounds in 384-well format. 4,260 compounds induced enlarged nuclei in HCT116 cells, a 2.4% hit rate. After re-screening hits in HCT116 along with two additional MSI-H cancer cell lines, SW48 and SNU-407, and counter-screening in HT29 cells, 144 hits were confirmed to specifically enlarge nuclei in MSI-H but not MSS cells. Using the ADP-Glo Kinase Assay, two of these compounds were confirmed to inhibit WRN ATPase activity, suggesting WRN inhibition as a potential mechanism for their specific effects in MSI-H cells. This screen will also identify compounds which selectively kill MSI-H cells through mechanisms beyond direct inhibition of WRN, including interaction with WRN complex members or other members of DNA damage repair pathways. Validation studies including the assessment of cell viability and DNA damage in a panel of MSI-H and MSS cell lines will be performed. Our study proposes a phenotypic screening strategy for identifying small molecules with the potential to target WRN and uncover additional novel mechanisms for treating MSI-H cancers. Citation Format: Christine A. Moomau, Yipin Lu, Xiaobin Zhang, Xiang Zhai, Lina Gu, Qing Sheng, Fang Li, Yaoyu Chen. A high-throughput phenotypic screen to identify small molecule inhibitors of Werner helicase [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 3095.
Abstract 4139: Prolyl 4-hydroxylase subunit alpha 1 acts as a novel target for lung adenocarcinoma brain metastasis
Authors: Yan He, Zhenyu Luo, Yucheng Dong, Rui Wan, Xue Zhang, Hua Bai, Jie Wang
Journal: Cancer Research (2024)

Abstract Lung cancer is the most lethal cancer worldwide, with a high incidence of distant metastasis. Many lung adenocarcinoma (LUAD) patients experience brain metastasis during the disease process with unfavorable prognosis. Our previous study has discovered that P4HA1 was exclusively upregulated in brain metastatic cells. Through the analysis of single-cell RNA sequencing of LUAD samples, we found that the expression of P4HA1 in brain metastatic tumor cells is higher than that in primary tumor cells. This finding was further confirmed by immunohistochemical staining. Significantly, a strong presence of P4HA1 in primary tumors is associated with a reduced duration of disease-free survival in individuals with LUAD. Overexpression of P4HA1 in A549 and PC9 cell lines significantly increased the incidence of brain metastasis in BALB/c nude mice, whereas knockdown of P4HA1 in high brain metastatic cells significantly decreased the incidence of brain metastasis and reduced the tumor foci in brain with improved survival. Utilization of DHB, a P4HA1 inhibitor, exerts both therapeutic and preventive effects in relieving brain metastases in nude mice. Furthermore, remarkable inhibition of tumor growth by DHB was observed in patient derived xenograft (PDX) models. RNA sequencing analysis demonstrated that the reduction of P4HA1 expression had a substantial impact on cell adhesion and extracellular matrix (ECM)-receptors interactions. Western blotting analysis verified that the decrease in P4HA1 expression led to a drop in the expression of adhesion molecules ICAM1, VCAM1, NCAM1, as well as integrin molecules ITGA2 and ITGA3. Furthermore, when endothelial cells were co-cultured with conditioned medium from tumor cells, it was observed that the expression of the tight junction molecule ZO1 was reduced after co-culturing with conditioned medium from P4HA1 knockdown A549 cells. The results from the in vitro blood-brain barrier (BBB) model and in vivo biofluorescence imaging indicate that P4HA1 promoted brain metastasis of LUAD via modulating the ability of tumor cells to cross the blood-brain barrier. In conclusion, our study reveals that overexpression of P4HA1 promotes metastatic spread to the brain, and targeting P4HA1 could be a promising therapeutic strategy for the treatment of lung adenocarcinoma brain metastasis. Citation Format: Yan He, Zhenyu Luo, Yucheng Dong, Rui Wan, Xue Zhang, Hua Bai, Jie Wang. Prolyl 4-hydroxylase subunit alpha 1 acts as a novel target for lung adenocarcinoma brain metastasis [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 4139.
Abstract 4138: Evaluation of breast triple-negative 4T1-derived tumor metastatic development in gender-different mouse
Authors: Chunhong Shao, Melanie He, Luke Tsung-Huang Tsai
Journal: Cancer Research (2024)

Abstract Background and Objective: Breast cancer in men is a rare and less-studied case, with therapeutic strategies predominantly relying on clinical treatment protocols established for women. To support the clinical treatment concept, Dr. Martin-Martinez's lab observed no differences in the time of orthotopic breast mammary fat pad tumor development, necrosis, or color change of tumor tissue between male and female mice. However, the clinical treatment readout, especially tumor metastasis, is different in men and women, and current models for breast cancer are inadequate due to the absence of metastases. It is necessary to evaluate the development of breast cancer 4T1-derived tumor metastasis in male and female mice. Method and Result: 4T1-Luc breast cancer cells were implanted in male and female Balb/c mice via various routes, including inguinal fat pad injection, tail vein injection, caudal artery injection, portal vein injection, and Intratibial Injection. Illuminance images showed no significant differences in tumor metastatic development between genders for inguinal fat pad, tail vein, and intratibial injections. However, following caudal artery injection, early-stage metastasis differed; male mice developed femoral head metastasis, while female mice developed lung metastasis. In the late stage, male mice displayed lung and femoral bone metastasis, while female mice primarily showed lung metastasis with barely bone metastasis. Conclusion: While both male and female mice showed similar primary breast tumor development, mouse gender affected tumor metastasis differently, particularly when tumor cells went through the caudal artery. Male mice presented earlier femoral head metastasis and less lung metastasis than female mice. Based on this work, sex hormones would affect both hormone-related and nonhormone-related tumor metastasis. To elucidate whether this phenomenon is caused by estrogen or androgen or to test if a drug has any beneficial effects, HD Biosciences provides established tumor metastatic cell-delivering platforms and over 1000 cancer cell lines for target validation and drug efficacy study. Citation Format: Chunhong Shao, Melanie He, Luke Tsung-Huang Tsai. Evaluation of breast triple-negative 4T1-derived tumor metastatic development in gender-different mouse [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 4138.
Abstract 4754: Targeted inhibition of the HNF1A/SHH axis by triptolide overcomes paclitaxel resistance in non-small cell lung cancer
Authors: Peichao Li, ngbing Li, Lingxiao Yang, Lei Liu, Xiaogang Zhao
Journal: Cancer Research (2024)

Abstract Paclitaxel resistance is commonly associated with a poor prognosis in non-small cell lung cancer (NSCLC) patients, and there are no promising pharmacological treatments for paclitaxel resistance. Here, we constructed human NSCLC-derived paclitaxel-resistant cell lines as an effective tool to explore the mechanisms of chemoresistance. We discovered that triptolide, a monomer compound extracted from Tripterygium wilfordii Hook F, was able to reverse paclitaxel resistance by reducing ABCB1 expression in vivo and in vitro. Through high-throughput sequencing, we found that the SHH-initiated Hedgehog signaling pathway played an important role in this process. More importantly, triptolide could directly target HNF1A, a transcription factor of SHH, and inhibited HNF1A/SHH expression, ensuing in attenuation of Hedgehog signaling. Clinically, we found a positive correlation between HNF1A and SHH expression in both NSCLC tumor tissue microarrays and cancer network databases. These findings illuminated a novel molecular mechanism through which triptolide effectively targets and inhibits HNF1A, thereby impeding the activation of the Hedgehog signaling pathway and reducing the expression of ABCB1. This finding indicated the potential clinical application of triptolide and provided promising prospects in targeting the HNF1A/SHH pathway as a therapeutic strategy for NSCLC patients with paclitaxel resistance. Citation Format: Peichao Li, ngbing Li, Lingxiao Yang, Lei Liu, Xiaogang Zhao. Targeted inhibition of the HNF1A/SHH axis by triptolide overcomes paclitaxel resistance 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 4754.