tbuckley/cabot-search huggingface dataset:
Abstract 5426: SMC2 orchestrates non-small cell lung cancer proliferation, invasion, and metastasis by modulating the ERK/AKT/NF-κB pathways
Authors: Yan He, Zhenyu Luo, Yiyao Wang, Shan Xiong, Rui Wan, Xue Zhang, Hua Bai, Jie Wang
Journal: Cancer Research (2024)

Abstract Chromatin instability has been associated with the expression of structural maintenance of chromosomes (SMC) family members and is a common feature in many tumors. SMC family members have been associated with poor outcomes in several cancer types. However, little is known about their functions and mechanisms in promoting cancer progression, particularly in non-small cell lung cancer (NSCLC). Here, we evaluated the expression of SMC family members in the tumor microenvironment of NSCLC specimens using single-cell RNA sequencing analyses. After a survival analysis, it was found that the sole factor associated with a poor prognosis for NSCLC was member SMC2 expression. Immunohistochemistry was used with data from the Human Protein Atlas, the Cancer Genome Atlas, and the Gene Expression Omnibus databases to confirm the overexpression of SMC2 in NSCLC. We demonstrated that SMC2 regulates not only the fluctuations in the critical states of tumor cells, which are defined by different transcriptome and metabolic properties but also coordinates the immunological components and cell-to-cell communications of the immune milieu, potentially through the pleiotrophin and the Galectin pathways. In vitro and in vivo evidence support the pro-metastatic role of SMC2 in NSCLC. Subsequent investigations showed that SMC2 increases NSCLC progression and metastasis via modulating the ERK/AKT/NF-κB pathway and the epithelial-mesenchymal transition process. Our research clarifies the role and potential mechanisms of SMC2 in NSCLC, providing new treatment options and valuable insights for the management of NSCLC. Citation Format: Yan He, Zhenyu Luo, Yiyao Wang, Shan Xiong, Rui Wan, Xue Zhang, Hua Bai, Jie Wang. SMC2 orchestrates non-small cell lung cancer proliferation, invasion, and metastasis by modulating the ERK/AKT/NF-κB pathways [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 5426.
Abstract 6972: Programmed death-ligand 1 (PD-L1) upregulates c-MET phosphorylation via protein tyrosine phosphatase and contributes to the development of <i>MET</i> amplification in epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer
Authors: Derek De-Rui Huang, Chia-Chi Hsu, Wei-Hsun Hsu, Bin-Chi Liao, James Chih-Hsin Yang
Journal: Cancer Research (2024)

Abstract High expression of programmed death-ligand 1(PD-L1) is associated with poor survival outcomes in epidermal growth factor receptor (EGFR) mutation non-small cell lung cancer (NSCLC) patients receiving EGFR tyrosine kinase inhibitors (EGFR-TKIs). In this study we aimed to determine how increased PD-L1 affects the signal transduction of EGFR-mutant NSCLC cells. We first established PD-L1 overexpression EGFR mutant NSCLC cells, and discovered that PD-L1 overexpression cells had upregulated c-MET phosphorylation compared with parental cells using receptor tyrosine kinase array study. Subsequently, we demonstrated that knocking out PD-L1 (CD 274) in EGFR mutant NSCLC cells resulted in down-regulation of c-MET phosphorylation. Since protein tyrosine phosphatases (PTP) are known key regulators for c-MET phosphorylation and dephosphorylation, the activity of PTP was assessed. In PD-L1 overexpression EGFR mutant NSCLC cells, the PTP activity was decreased, whereas in PD-L1 knock-out cells, the PTP activity was increased. Additionally, the downregulation of c-MET phosphorylation in PD-L1 knock-out cells could be restored by adding PTP inhibitor (Na3VO4). The gene expression analysis showed that PTP expression was down-regulated in PD-L1 overexpression cells, indicating that PD-L1 upregulates c-MET phosphorylation by reducing PTP expression. We further established xenograft animal models using NSCLC cells with strong baseline c-MET phosphorylation to determine the effect of c-MET phosphorylation on osimertinib (a 3rd-generation EGFR-TKI) treatment. We found that tumor cells with strong c-MET phosphorylation were prone to develop MET amplification as acquired resistance under osimertinib, which could be overcome with combination of osimertinib and tepotinib, a c-MET inhibitor. Taken together, our results expand our understanding of PD-L1’s role beyond an immune checkpoint in EGFR mutant NSCLC. PD-L1-regulated MET alterations could be a crucial mechanism leading to poor treatment outcome of EGFR-TKIs in PD-L1 overexpression EGFR mutant NSCLC. Citation Format: Derek De-Rui Huang, Chia-Chi Hsu, Wei-Hsun Hsu, Bin-Chi Liao, James Chih-Hsin Yang. Programmed death-ligand 1 (PD-L1) upregulates c-MET phosphorylation via protein tyrosine phosphatase and contributes to the development of MET amplification in epidermal growth factor receptor (EGFR) mutant 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 6972.
Abstract 1612: Timing ecDNA acquisition across cancer
Authors: Andrew R. Lynch, Peter Van Loo
Journal: Cancer Research (2024)

Abstract Extrachromosomal DNA (ecDNA) are acentric, circular DNA fragments which form after DNA double strand breaks. They segregate randomly during mitosis, promoting high-level amplifications of positively selected oncogenes such as EGFR and MYC. The prevalence of ecDNA across several cancer types, such as glioblastoma and sarcoma, has made promising therapeutic targets. However, while DNA damage is a hallmark of nearly all cancers, the formation of ecDNA is not, and the determinants for ecDNA acquisition are unclear. Furthermore, whether the timing of tumors’ acquisition of ecDNA (i.e., early or late clonal or sub-clonal) affects patient survival and drug resistance is unclear. Here, we leverage orthoganol information from ecDNA amplicons, such as mutation allele frequency and sequence synteny, to develop computational methods for elucidating the evolutionary history of ecDNA. Applying these to several cancer subtypes in TCGA, we find that most ecDNAs arise early in tumor evolution. We expect these results will help identify determinants of ecDNA acquisition and its temporal influence on patient survival. Citation Format: Andrew R. Lynch, Peter Van Loo. Timing ecDNA acquisition across 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 1612.
Abstract 2864: Transcriptional repressor REST controls autophagy in Sonic Hedgehog medulloblastoma through the VHL-HIF1α axis
Authors: Ashutosh Singh, Donghang Cheng, Jyothishmathi Swaminathan, Yan Zheng, Nancy Gordon, Vidya Gopalakrishnan
Journal: Cancer Research (2024)

Abstract Introduction: Medulloblastoma (MB) is the most common malignant brain tumor in children. It is categorized into four molecular subgroups, each with unique genetic and epigenetic alterations, molecular signatures, and differences in clinical features and treatment responses. Targeted therapy for MB has failed in the clinic, prompting new studies of mechanisms involved in MB tumorigenesis and progression. Experimental Procedure: The transcriptomic information of the MB patients was obtained from the publicly available RNAseq datasets and was analyzed for differential expression and clustering analysis. Patient-derived orthotopic xenografts of medulloblastoma tumors with high- and low-REST expression were histologically and biochemically studied for autophagy markers. Furthermore, the SHH-MB cell lines were studied to get a mechanistic understanding of the REST-driven autophagy in this MB subgroup. Summary: Our data showed that autophagy, a process responsible for cellular recycling, and genes associated with this pathway exhibit distinctive expression patterns in human MB subgroups. Specifically, we demonstrate that autophagy is induced in one of the MB subgroups (Sonic Hedgehog-SHH) in response to elevated expression of the RE1-silencing transcription factor (REST), a transcriptional repressor and a canonical regulator of neuronal differentiation genes. REST is also a driver of SHH-MB metastasis. Pharmacological inhibition of autophagy decreases MB cell growth, suggesting it is a pro-survival pathway in REST-driven SHH MBs. In mechanistic studies, we found REST-dependent autophagy induction to involve upregulation of the hypoxia-inducible factor 1-alpha (HIF1α) due to REST-mediated silencing of the von Hippel-Lindau (VHL) gene. The VHL gene product promotes HIF1α ubiquitination and proteasomal degradation, and its loss in SHH-MBs with elevated REST expression drives HIF1α stabilization and nuclear localization to activate target autophagy-related genes. Conclusion: Our work is the first to link VHL to MB pathology. VHL loss of function in cancers has been mainly attributed to mutational events. Here, we report a novel mechanism of VHL loss, namely its epigenetic silencing by REST. Our findings provide the foundation for future pre-clinical investigations to examine the feasibility of autophagy blockade as a therapeutic strategy for REST-driven SHH MBs. Citation Format: Ashutosh Singh, Donghang Cheng, Jyothishmathi Swaminathan, Yan Zheng, Nancy Gordon, Vidya Gopalakrishnan. Transcriptional repressor REST controls autophagy in Sonic Hedgehog medulloblastoma through the VHL-HIF1α axis [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 2864.
Abstract 3903: Discovery of ULBP6 as a novel immuno-oncology target using pleiotropic signals from 23andMe’s genetic and health survey database
Authors: Susanne Tilk, Pierre Fontanillas, Wei-Jen Chung, Clifford Hom, Shi Shi, Anh Diep, Kim Gerrick, Mauro Poggio, Pranidhi Sood
Journal: Cancer Research (2024)

Abstract 23andMe has assembled one of the largest platforms for human genetics research that combines genotypes from 14 million individuals, 80% of which are consented to participate in research, with billions of phenotypic data points collected from health survey data. Using these large scale genetic and phenotypic datasets, we have developed a unique target discovery platform that has identified hundreds of pleiotropic genetic variants with opposing directionality of effects in cancer and immune diseases. These immune-oncology (I/O) genetic associations point to already clinically validated immune checkpoint receptors (e.g., CTLA4) and those currently in clinical trials (e.g., CD200R1). This suggests that these I/O genetic associations could be linked to genes that are broadly utilized by tumor cells to evade the immune system and could be used to identify novel therapeutic targets involved in regulating anti-tumor immune response. Here, we utilized expression quantitative trait loci (eQTLs) and annotation of coding single nucleotide polymorphisms (SNPs) to link one of these signals to a causal gene, and identified ULBP6, a stress-induced ligand for the activating immunoreceptor NKG2D found on NK and T cells. ULBP6 is known to be shed from the cell surface of tumor cells to block its interaction with NKG2D to evade immune surveillance. Expression profiling of ULBP ligands in various tumor types using MSD, IHC, bulk and single-cell RNA-seq revealed tumor-intrinsic up-regulation of ULBP6 in squamous cancer subtypes. Collectively, these data suggest that ULBP6 is a promising therapeutic target, and that can potentially enhance anti-tumor immunity. Citation Format: Susanne Tilk, Pierre Fontanillas, Wei-Jen Chung, Clifford Hom, Shi Shi, Anh Diep, Kim Gerrick, Mauro Poggio, Pranidhi Sood. Discovery of ULBP6 as a novel immuno-oncology target using pleiotropic signals from 23andMe’s genetic and health survey database [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 3903.
Abstract 2878: Hyperthermia increases the efficacy of aminolevulinic acid-mediated photodynamic therapy in human osteosarcoma cells
Authors: Paige J. Baugher
Journal: Cancer Research (2024)

Abstract Osteosarcoma is a malignant osteoid tumor that arises from mesenchymal cells exhibiting osteoblastic differentiation. Common treatments for this neoplasm include limb-salvage surgery and/or amputation of the affected limb, either of which can substantially decrease quality of life. Therefore, other, less invasive treatments should be explored. Photodynamic therapy (PDT) represents a more targeted, less invasive treatment possibility for osteosarcoma. Previous data from my laboratory demonstrated that aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) can be used to induce significant cell death in human osteosarcoma MG-63 cells in vitro. However, delivering high doses of drugs to deep osteosarcoma tumors could prove difficult, so we aim to explore the use of combination therapies to increase the efficacy of ALA-PDT in human osteosarcoma cells. Previous studies have shown that hyperthermia (increased temperature) can induce cell death in cancer cells. Furthermore, data suggest that combining PDT with hyperthermia can induce cell death in cancer cells synergistically by activating differential death-inducing pathways. However, hyperthermia in combination with ALA-PDT has not been explored in human osteosarcoma. Therefore, we aim to investigate the possibility that hyperthermia in combination with ALA-PDT can increase cell death in human osteosarcoma cells compared to ALA-PDT alone. Data from our lab show that compared to normal body temperature (37°C), cell death in MG-63 human osteosarcoma cells was not significantly increased by mild hyperthermia alone (40°C and 43°C respectively), while moderate hyperthermic temperatures alone (46°C and 49°C) did significantly increase cell death. We also found that at moderately hyperthermic temperatures, ALA-PDT does not increase cell death any further compared to moderate hyperthermia alone. Furthermore, we found that at the mildly hyperthermic temperature of 40°C, cell death was not significantly increased any further by ALA-PDT compared to ALA-PDT alone. However, our data do show that at a temperature of 43°C, hyperthermia plus ALA-PDT increased cell death compared to ALA-PDT alone. Therefore, our data suggest that inducing mild hyperthermia could increase the efficacy of ALA-PDT in human osteosarcoma cells. Citation Format: Paige J. Baugher. Hyperthermia increases the efficacy of aminolevulinic acid-mediated photodynamic therapy in human osteosarcoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2878.
Abstract 1611: DNA methylation co-operates with genomic alterations during non-small cell lung cancer evolution
Authors: Francisco Gimeno-Valiente, Carla Castignani, Elizabeth Cadieux L. Cadieux, Nana E. Mensah, Olga Chervova, Mariam Jamal-Hanjani, Nicholas McGranahan, Stephan Beck, Jonas Demeulemeester, Miljana Tanic, Charles Swanton, Peter Van Loo, Nnennya Kanu
Journal: Cancer Research (2024)

Abstract Aberrant DNA methylation patterns have been described in nearly all human cancers, yet their interplay with genomic alterations during tumor evolution is poorly understood. To explore this crosstalk, we performed reduced representation bisulfite sequencing on 217 tumor regions from 59 patients from the TRACERx study, all with matched adjacent normal tissue, to deconvolve tumor methylation rates. We combined two new metrics for integrative evolutionary analysis with DNA and RNA sequencing data. I-TMD (intra-tumoral methylation distance) quantifies intra-tumor DNA methylation heterogeneity. MR/MN classifies genes based on the rate of hypermethylation at regulatory (MR) versus non-regulatory (MN) CpGs, to identify driver genes exhibiting recurrent functional hypermethylation. We observed early DNA methylation of VIPR2 and ZNF714 co-occurring with driver mutations in CDKN2A and STK11, respectively. Finally, we found DNA methylation-linked dosage compensation of essential genes co-amplified with neighboring oncogenes. Our identification of hypermethylated driver genes under positive selection may open new avenues for therapeutic stratification of patients with non-small cell lung cancer. Citation Format: Francisco Gimeno-Valiente, Carla Castignani, Elizabeth Cadieux L. Cadieux, Nana E. Mensah, Olga Chervova, Mariam Jamal-Hanjani, Nicholas McGranahan, Stephan Beck, Jonas Demeulemeester, Miljana Tanic, Charles Swanton, Peter Van Loo, Nnennya Kanu. DNA methylation co-operates with genomic alterations during non-small cell lung cancer evolution [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 1611.
Abstract 3407: Physical activity and post-menopausal breast cancer in the Multiethnic Cohort Study
Authors: Jasmeet K. Gill, Gertraud Maskarinec, Song-Yi Park, Lynne Wilkens, Loic Le Marchand
Journal: Cancer Research (2024)

Abstract Much research has been conducted on the relationship between physical activity and breast cancer, with meta-analyses showing 10 – 21% reduction in breast cancer risk for postmenopausal women with high compared to low level of physical activity. However, few studies have explored this relationship in non-Caucasian women. We analyzed data from 74,177 post-menopausal African American, Caucasian, Japanese American, Latina, and Native Hawaiian women in the Multiethnic Cohort in Hawaii and California. Data on physical activity (hours and metabolic equivalents (METs)) was based on a self-administered questionnaire at baseline (1993–1996). Multivariate Cox proportional hazards models provided estimates of hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for risk factors. We observed no associations between breast cancer risk and hours of moderate/vigorous activity per week (HR=1.01, 95% CI: 0.91-1.10, Ptrend=0.71), MET-hours of moderate/vigorous activity per week (HR=1.03, 95% CI: 0.94-1.13, Ptrend=0.92), and total METs-measured as average MET level per day multiplied by 7 (HR=0.94, 95% CI: 0.86-1.03, Ptrend=0.37) when comparing the highest quartile to the lowest. When examining the data across race/ethnicity, we observed a reduction in risk of breast cancer for total METs (HR=0.75, 95% CI: 0.61-0.94, Ptrend=0.05) among Latina women. Analysis across strata of BMI showed no differences across subgroups. In this study, we did not observe any consistent protective association between physical activity and breast cancer risk. Citation Format: Jasmeet K. Gill, Gertraud Maskarinec, Song-Yi Park, Lynne Wilkens, Loic Le Marchand. Physical activity and post-menopausal breast cancer in the Multiethnic Cohort Study [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 3407.
Abstract 3833: Primary cutaneous diffuse large B-cell lymphoma-leg type and clinicopathologic determinants of survival: Analysis of a pooled database
Authors: Philip A. Haddad, Millicent Amankwah
Journal: Cancer Research (2024)

Abstract Background: Primary Cutaneous Diffuse Large B-cell Lymphoma-Leg Type (PCDLBCL-LT) is a rare but non-indolent subtype of B-cell lymphoma. While most PCDLBCL-LT starts over the lower extremities, some cases may present at other cutaneous sites. The determinants of survival outcomes in this disease are not very well defined. Therefore, we conducted this pooled database analysis to identify the prognostic factors, clinicopathological characteristics, and therapeutic strategies that influence survival in this disease. Methods: To study the demographic characteristics, molecular and immunohistochemical signatures, therapeutic interventions, survival, and prognostic factors, we compiled a pooled database of 122 cases that fit the diagnostic criteria for PCDLBCL-LT. Kaplan-Meier survival curves were constructed. Cox proportional hazards model and Log-rank tests were used to assess the influence of demographic and clinicopathologic factors on overall survival (OS) and disease-free survival (DFS). Results: A total of 122 patients with confirmed PCDLBCL-LT were identified. The median age was 76. There was a male preponderance with M:F of 2.4. Seventy-three percent involved the extremities. The median duration of symptoms before diagnosis was 3.5 months. Involvement of lymph nodes, bone marrow, bone, and CNS occurred in 11%, 3%, 4%, and 3%, respectively. Constitutional symptoms were reported in 5%. The median OS and DFS of the whole group were 39 and 32 months, respectively. Patients younger than 70 had better median DFS (NR vs. 24 months, p=0.02) with a non-significant better median OS. Lymphadenopathy (45 vs. 18 months, p=0.006) and stage T3 compared to T1/T2 (16 vs 41 months, p=0.006) were associated with worse OS. Sex, constitutional symptoms, IHC phenotype, extra-lymphatic/extra-cutaneous organ involvement, and histologic cutaneous patterns did not impact OS. Compared to no treatment, chemotherapy, XRT+/-surgery, and stem cell transplant had numerically better OS without reaching statistical significance (5 vs. 39 vs. 41 vs. NR months, p=0.15). Patients who attained CR as their best response also had a superior median OS compared to responses less than CR and none (61 vs. 23 vs. 11 months, p&amp;lt;0.0001). Conclusion: This study presents updated clinicopathologic data from a large, pooled cohort of patients with PCDLBCL-LT. It identifies age, lymph node involvement, T stage, type of therapy, and quality of response to treatment as critical determinants of OS. Citation Format: Philip A. Haddad, Millicent Amankwah. Primary cutaneous diffuse large B-cell lymphoma-leg type and clinicopathologic determinants of survival: Analysis of a pooled database [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 3833.