tbuckley/cabot-search huggingface dataset:
Abstract 3758: Evaluation of breast cancer-derived extracellular vesicles as diagnostic indicator for HER2 status
Authors: Sol Moon, Min Woo Kim, Young Kim, Suji Lee, Hyojung Lee, Joon Ye Kim, Seung Il Kim, Jee Ye Kim
Journal: Cancer Research (2024)

Abstract HER2-low is a new distinct type of breast cancer that is characterized by low levels of the HER2 protein. As treatment paradigms for HER2-low breast cancer are rapidly evolving with the approval of antibody-drug conjugates, identification of HER2-low breast cancer with more sensitive and reproducible HER2 assays is needed. We aimed to investigate the utility of liquid biopsy in isolating tumor-derived extracellular vesicles (TDEs) for diagnosis of HER2 status. We adopted an affinity-based approach to isolate TDEs and performed CNV analysis of the ERBB2/neu genes using the tumor DNA present in TDEs (etDNA). HER2 status of etDNA had been determined by droplet digital PCR using HER2/EIF2C ratio, a highly accurate method to quantify DNA copy number. In our study, we utilized a variety of breast cancer cell lines categorized as HER2-low (MDA-MB-231, MCF7, ZR-75-1) and HER2-high (MDA-MB-453, BT-474, SK-BR-3) to confirm HER2 expression in extracellular vesicles (EVs) by flow cytometry. This analysis successfully demonstrated that EVs effectively reflect the HER2 status of the tumor cells, evidenced by a strong Pearson correlation coefficient (r=0.987, p&amp;lt;0.001). Further clinical validation was conducted with plasma samples from 22 breast cancer patients. In the clinical study, we observed a significant correlation between the CNV of tumor DNA present in TDEs and the HER2 status of primary tumors (p&amp;lt;0.01). Additionally, the Receiver Operating Characteristic (ROC) analysis yielded an impressive area under the curve (AUC) value of 0.838 (p&amp;lt;0.01), demonstrating a high level of accuracy in differentiating between high and low HER2 groups, with a sensitivity of 55.6% and a specificity of 100%. In summary, we show potential diagnostic tools for real-time, less invasive determination of HER2 status in primary tumors, providing continuous monitoring methods for HER2 status. Although further validation in larger cohorts and prospective studies is needed, our study indicates that TDE analysis could contribute to the assays for identification of the HER2 status in breast cancer patients. Citation Format: Sol Moon, Min Woo Kim, Young Kim, Suji Lee, Hyojung Lee, Joon Ye Kim, Seung Il Kim, Jee Ye Kim. Evaluation of breast cancer-derived extracellular vesicles as diagnostic indicator for HER2 status [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 3758.
Abstract 5436: A therapeutically targetable dysadherin/YAP axis promotes cancer stem features and tumor aggressiveness in hepatocellular carcinoma
Authors: So-El Jeon, Tae-Young Jang, Choong-Jae Lee, Hyeon-Ji Yun, Yeong-Hoon Cho, Da-Ye Lim, Jeong-Seok Nam
Journal: Cancer Research (2024)

Abstract Hepatocellular carcinoma (HCC) remains one of the most challenging tumors to treat. Cancer stem-like cells (CSCs) are believed to be important in HCC development, immune evasion, and treatment resistance. Dysadherin is a cell membrane glycoprotein linked to cancer progression by endowing HCC with CSC features. However, the underlying mechanism of increasing CSC characteristics in refractory advanced HCC is not entirely understood. A comprehensive bioinformatics study revealed that dysadherin-expressing HCC cells were associated with cancer stemness and the YAP signaling activation. Dysadherin knockdown or overexpression in liver cancer cell lines attenuated or increased cancer stemness and aggressiveness via YAP signaling, respectively. Correspondingly, dysadherin deficiency lowered cancer stemness and aggressiveness in the HCC mouse model by blocking the YAP pathway. Mechanistically, dysadherin promoted YAP nuclear localization, which activated stem cell transcription factors such as OCT4, KLF4, and MYC. Of note, our comprehensive gain and loss of function studies in CSCs demonstrated that targeting the dysadherin/YAP axis could boost sorafenib’s therapeutic effect and suppress PD-L1 expression, which helps tumor cells escape from immune surveillance. Thus, our results highlight that the dysadherin/YAP axis drives the aggressive phenotype of HCC, providing a potential therapeutic strategy for HCC. Citation Format: So-El Jeon, Tae-Young Jang, Choong-Jae Lee, Hyeon-Ji Yun, Yeong-Hoon Cho, Da-Ye Lim, Jeong-Seok Nam. A therapeutically targetable dysadherin/YAP axis promotes cancer stem features and tumor aggressiveness 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 5436.
Abstract 5261: Immunologic signatures of peripheral blood cells in patients with advanced pancreatic cancer under lenvatinib-pembrolizumab maintenance therapy
Authors: Vincent Chung, Ferdynand Kos, Edwin Manual, Shannon Dempsey, Don J. Diamond
Journal: Cancer Research (2024)

Abstract Background: The treatment of pancreatic cancer is limited by chemotherapy toxicities which impacts quality of life. This is a phase 2 clinical trial of lenvatinib and pembrolizumab as maintenance therapy in patients with advanced pancreatic cancer. We observed preclinical activity of this combination in pancreatic mouse models. We hypothesize that this combination may address unmet needs to minimize toxicities associated with standard treatments, stimulate anti-tumor T cell immunity, and improve the progression free and overall survival. Exploratory studies aim to characterize immune-related systemic changes in peripheral blood over the course of therapy and to identify global changes in expression of tumor-related genes in needle biopsy samples of liver metastatic lesions. Methods: Multiplex gene expression analysis of unsorted peripheral blood mononuclear cells (PBMC) was performed using PanCancer Immune Profiling Panel on NanoString nCounter platform. PBMC samples from pre- through week 32 of treatment were assessed for differential expression of 730 immune profiling genes defining T cell functions and associated immune categories. Results: PBMC immune profiling from 4/5 patients show a distinctive pattern of increased activation of T cells during the first 9 weeks of treatment followed by a sharp inhibition starting at weeks 9-12 after 3-4 cycles of treatment (CD3E, CD247, LCK, TBX1, TCF7, STAT4, IL2RG). Subsequent upregulation of macrophage-derived scavenger, inflammatory, and immunosuppressive gene expression patterns continued for the remainder of treatment (CD14, MSR1, MARCO, CD68, TGFB1, IL10RA). The median PFS of first 10 patients was 21.5 (9-32) weeks. Conclusions: Immunotherapy resistance may be related to rapidly developing terminal differentiation and unresponsiveness of T cells in parallel with upregulation of macrophage-derived inflammatory and immunosuppressive processes. Studies are on-going to prevent inhibition of the T-cells. Citation Format: Vincent Chung, Ferdynand Kos, Edwin Manual, Shannon Dempsey, Don J. Diamond. Immunologic signatures of peripheral blood cells in patients with advanced pancreatic cancer under lenvatinib-pembrolizumab maintenance 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 5261.
Abstract 218: Deciphering tumoroid-CAF interactions through a spatially segregated coculture model
Authors: Sung Min Kim, Yoo Ri Ko, Hye Seon Park, Se Jin Jang
Journal: Cancer Research (2024)

Abstract In the context of lung cancers, cancer-associated fibroblast (CAF) plays a pivotal role as a key component of the tumor microenvironment (TME), affecting tumor growth, invasion, metastasis, immune modulation, and drug resistance. Despite the recognized impact of CAFs, the precise interaction between the CAF and tumor cell remains elusive. Previous studies have reported that CAFs stimulate tumor cell growth both in vitro and in vivo. However, our tumoroid models reveal an intriguing phenomenon where CAFs inhibit tumoroids growth within Matrigel. This led us to hypothesize that paracrine signaling might be the primary mode of interaction between CAFs and tumor cells. To unravel the intricacies of this interaction, we developed an innovative coculture method. Using hydrophobic barrier, we segregated the coculture of nine sets of CAFs and tumoroids within a single well, preventing CAFs from infiltrating the tumoroid culture area. This setup enabled interaction solely through paracrine signaling. Surprisingly, cocultured tumoroids exhibited no significant differences compared to individually cultured tumoroids. Conversely, cocultured CAFs displayed a remarkable increase in growth compared to their individually cultured counterparts. This suggests that tumoroids influence CAF growth, while CAFs do not significantly impact tumoroid growth. Furthermore, in three coculture sets, tumor cells within the Matrigel migrated towards the CAF culture area, indicating that CAFs induce tumor cell metastasis. Immunofluorescence staining confirmed this metastatic phenomenon. To identify the paracrine factors influencing CAFs and tumoroids, we employed RNA-sequencing, single-cell RNA-sequencing, and proteomic analysis of culture soup. Proteomic analysis revealed a substantial increase in proteins and signaling pathways related to the extracellular matrix in cocultures compared to single cultures. Our findings suggest that tumor cells recruit CAFs, promoting CAF growth to establish and fortify their TME, ultimately leading to drug resistance, metastasis, and immune modulation Citation Format: Sung Min Kim, Yoo Ri Ko, Hye Seon Park, Se Jin Jang. Deciphering tumoroid-CAF interactions through a spatially segregated coculture model [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 218.
Abstract 2922: Sensory innervation as a novel driver of ovarian cancer progression
Authors: Matthew Knarr, Katherine Cummins, Dusan Racordon, Hunter Reavis, Timothy Lippert, Ryan Hausler, Priyanka Rawat, Suyeon Ryu, Jamie Moon, Dave Hoon, Roger Greenberg, Paola Vermeer, Ronny Drapkin
Journal: Cancer Research (2024)

Abstract One of the main challenges currently faced in ovarian cancer treatment is that the primary platinum/taxane therapy used to treat patients does not meaningfully extend survival. The overall survival for ovarian cancer patients with advanced disease is less than 30% with most patients recurring within 5 years of initial therapy. Once resistant disease develops there are few second line therapy options, which inevitably leads to disease progression. Thus, there is a critical need to identify new therapies that can overcome ovarian cancer chemoresistance and produce meaningful increases in patient survival. In recent years, new efforts have focused on targeting the tumor microenvironment (TME), the complex mixture of non-cancer cells that surround and support the cancer cells within the tumor. Different strategies have evolved to target the TME, such as immune checkpoint inhibitors or angiogenesis inhibitors. However, these TME targeting therapies have limited effect when used to treat ovarian cancer patients. Most ovarian tumors have a microenvironment that is highly immunosuppressive and do not respond or are resistant to angiogenesis inhibitors. Thus, new TME targeting therapies must be developed that can induce a therapeutic effect in ovarian tumors and can be used to treat most ovarian cancer patients. A novel TME component ripe for therapeutic targeting are the nerve fibers that infiltrate tumors in a process termed tumor innervation. Recent studies in several cancers have shown that tumor innervation can promote tumor growth/metastasis. However, in ovarian cancer the role of innervation in promoting cancer progression remains undefined. Here we show that Transient Receptor Potential cation channel subfamily V member 1 (TRPV1)+ sensory innervation plays a significant role in driving ovarian cancer growth and metastasis. Analysis of patient samples shows that sensory nerve fiber innervation is much higher in ovarian tumors vs benign reproductive tissue. In addition, ablation of TRPV1 sensory nerve fibers in vivo causes reduced tumor burden and prolongs survival in a syngeneic mouse model of ovarian cancer metastasis. Taken together, our results establish TRPV1+ sensory innervation as a novel driver of ovarian cancer growth/metastasis and a potential therapeutic target for ovarian cancer treatment. Citation Format: Matthew Knarr, Katherine Cummins, Dusan Racordon, Hunter Reavis, Timothy Lippert, Ryan Hausler, Priyanka Rawat, Suyeon Ryu, Jamie Moon, Dave Hoon, Roger Greenberg, Paola Vermeer, Ronny Drapkin. Sensory innervation as a novel driver of ovarian cancer 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 2922.
Abstract 5350: Decr2 regulates tumor cell ferroptosis and immunotherapy efficacy
Authors: Shuyin Li, Jason Shapiro, Hardik Shah, Emily F. Higgs, Lishi Xie, Yuanyuan Zha, Jonathan Trujillo, Alexandra Cabanov, Tyler A. Jones, Blake Flood, Ken Hatogai, Justin Kline, Thomas F. Gajewski
Journal: Cancer Research (2024)

Abstract Checkpoint blockade therapies have transformed the landscape of cancer care. Durable clinical responses have been observed in a subset of patients. However, many patients do not respond, and understanding the mechanisms that determine tumor resistant to checkpoint blockade drugs could potentially benefit more patients. Ferroptosis is a relatively newly described form of regulated cell death distinct from apoptosis and necroptosis. Recently, T cell-promoted tumor ferroptosis was shown to be an anti-tumor mechanism and targeting this pathway could be a potential therapeutic approach. To identify genes critical to immunotherapy resistance, B16.SIY cells were transduced with a genome-scale gRNA lentivirus to generate loss of function mutants. In vitro-primed CD8+ T cells isolated from 2C/Rag2-/- TCR transgenic mice specific for the SIY antigen were co-cultured with transduced B16.SIY tumor cells. Resistant mutants were identified by deep sequencing of survival clones. The gene encoding Decr2, a peroxisomal 2,4-dienoyl-CoA reductase, was identified. Decr2 mutants were relatively resistant to CD8+ T cell killing in vitro. Consistent with this resistance to CD8+ T cell killing, Decr2 knock-down tumors showed minimal response to anti-PD-L1 therapy in vivo. Tumor microenvironment analysis in Decr2 knockdown B16.SIY tumors showed failed antigen specific CD8+ T cells’ expansion and less IFN-γ production after anti-PD-L1 treatment. Knock-down of Decr2 resulted in diminished ferroptosis, triggered either by pharmacologic inducers or antigen-specific CD8+ T cells. Mechanistic studies revealed that Decr2 knockdown resulted in diminished induction of polyunsaturated ether phospholipids (PUFA-ePLs), which is due to reduced polyunsaturated ether phospholipids synthesis rate . Analysis of melanoma tumors from human patients revealed that up-regulation of Decr2 was associated with anti-PD-1 efficacy. Our results proved Decr2 knock down suppressed tumor ferroptosis and confer tumors resistance to anti-PD-L1 therapy by reducing the polyunsaturated ether phospholipids (PUFA-ePLs) synthesis. Citation Format: Shuyin Li, Jason Shapiro, Hardik Shah, Emily F. Higgs, Lishi Xie, Yuanyuan Zha, Jonathan Trujillo, Alexandra Cabanov, Tyler A. Jones, Blake Flood, Ken Hatogai, Justin Kline, Thomas F. Gajewski. Decr2 regulates tumor cell ferroptosis and immunotherapy efficacy [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 5350.
Abstract 1109: LINC01770 stabilizes TEAD1 expression to mediates nasopharyngeal cancer radiation resistance rendering tumor cells vulnerable to ferroptosis
Authors: Qingqing Xu, Ciming Sun, Suixian Zhang, Xuan Li, Lei Chen, Ming Chen
Journal: Cancer Research (2024)

Abstract Background: Long noncoding RNAs (lncRNAs) regulate various essential biological processes, including cell proliferation, differentiation, apoptosis, migration, and invasion. However, in nasopharyngeal carcinoma (NPC), the clinical significance and mechanisms of lncRNAs in malignant progression are unknown. Methods: LINC01770 expression was determined using quantitative real-time reverse transcription PCR, and its prognostic value was evaluated using Kaplan-Meier survival analysis. RNA sequencing and bioinformatic analysis were used to determine the potential function of LINC01770, and its biological effects were investigated using in vitro and in vivo experiments. Mass spectrometry-coupled RNA pull-down assays and western blotting identified LINC01770 interacting proteins, followed by confirmation using RNA immunoprecipitation (RIP) assays. Ferroptosis and lipid peroxidation were detected using flow cytometry. Results: LINC01770 was overexpressed in NPC tissues according to microarray screening. Patients with NPC showing high LINC01770 expression experienced shorter survival and worse prognosis. In vitro and in vivo experiments suggested that knockdown of LINC01770 expression significantly inhibited the proliferation, migration, and invasion of NPC cells. Sequencing and functional complementation experiments showed that LINC01770 regulates the proliferation and metastasis of NPC through TEA domain transcription factor 1 (TEAD1). Meanwhile, RIP and PCR experiments suggested that LINC01770 and TEAD1 were common targets of microRNAs miR-615-5p and miR-1293. Overexpression of LINC01770 promoted ferroptosis in vitro and in vivo through the TEAD1/Acyl-CoA synthetase long chain family member 4 (ACSL4)/transferrin receptor (TFRC) pathway. Conclusions: LINC01770 is a prognostic biomarker for NPC and participates in the regulation of TEAD1 signaling pathway through competitive binding to miRNA-615-5p and miRNA-1293, resulting in NPC metastasis and progression. Radiation resistant cells are in a delicate balance between lipid peroxidation and increased vulnerability to ferroptosis, suggesting that ferroptosis could be used to kill NPC cells and reverse their radiotherapy resistance during the malignant progression of NPC caused by high expression of LINC01770. Thus, inducing ferroptosis could be used to treat recurrent and refractory NPC. Citation Format: Qingqing Xu, Ciming Sun, Suixian Zhang, Xuan Li, Lei Chen, Ming Chen. LINC01770 stabilizes TEAD1 expression to mediates nasopharyngeal cancer radiation resistance rendering tumor cells vulnerable to ferroptosis [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 1109.
Abstract 681: Rewiring collagen architecture using a highly potent bi-thiazole inhibitor of LOX mediates chemosensitization in triple-negative breast cancer
Authors: Metin Cetin, Ozge Saatci, Abdol-Hossein Rezaeian, Chintada N. Rao, Chad Beneker, Harrison Taylor, Breanna Pederson, Ioulia Chatzistamou, Brian Buckley, Susan Lessner, Peggi Angel, Campbell McInnes, Ozgur Sahin
Journal: Cancer Research (2024)

Abstract Lysyl oxidase (LOX) is the founding member of the LOX family proteins and mediates the conversion of lysine residues in collagen I and elastin precursors into highly reactive aldehydes, leading to crosslinking of extracellular matrix (ECM). LOX is upregulated in aggressive tumors with high stiffness, and its higher expression correlates with metastasis, therapy resistance, and worse clinical outcome; however, relatively LOX-specific, orally bioavailable inhibitors are still lacking. Here we discovered bi-thiazole derivatives as potent LOX inhibitors by combining a robust screening platform for drug-like molecules, cell- and recombinant protein-based assays. Structure-activity relationship analysis further identified a potent and relatively LOX-specific lead compound (LXG6403) that reduces collagen content and crosslinking, and fibronectin assembly, leading to increased chemoresponse in triple-negative breast cancer (TNBC) cell lines and PDX organoids in 3D collagen. LXG6403 shows favorable pharmacokinetic properties, reduces collagen content and crosslinking, as demonstrated by the state-of-the-art MALDI-MSI and MP-SHG analyses, respectively. This leads to better drug penetration, inhibition of FAK signaling, and induction of ROS generation/DNA damage, leading to G1 arrest and apoptosis in chemoresistant TNBC PDXs. Overall, our novel, potent, tolerable bi-thiazole LOX inhibitor enhances chemoresponse in TNBC, the deadliest breast cancer subtype. Citation Format: Metin Cetin, Ozge Saatci, Abdol-Hossein Rezaeian, Chintada N. Rao, Chad Beneker, Harrison Taylor, Breanna Pederson, Ioulia Chatzistamou, Brian Buckley, Susan Lessner, Peggi Angel, Campbell McInnes, Ozgur Sahin. Rewiring collagen architecture using a highly potent bi-thiazole inhibitor of LOX mediates chemosensitization in 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 681.