tbuckley/cabot-search huggingface dataset:
Abstract 4390: IGFBP-6 is induced by progesterone to regulate progesterone receptor expression in breast cancer cells
Authors: Francisco Javier Lariz, Pacha Botero, Kevin Houston
Journal: Cancer Research (2024)

Abstract Insulin-like growth factor binding protein-6 (IGFBP-6) is induced by progesterone (P4) in T-47D breast cancer cells. IGFBP-6 regulates insulin-like growth factor 2 (IGF2) by sequestering it to inhibit receptor binding and extend its extracellular half-life. IGF2 binds to insulin-like growth factor 1 receptor or insulin receptor A to promote breast cancer cell proliferation and survival. Progesterone is an ovarian steroid hormone which has complex roles in breast cancer through the actions of progesterone receptor A and B (PR-A and B). Progesterone antagonizes the actions of estradiol (E2), another steroid hormone which promotes proliferation and survival in breast cancer. T-47D cells treated with both P4 and E2 exhibit significantly reduced proliferation compared to treatment with E2 alone. To better understand the role of IGFBP-6 in progesterone signaling, T-47D cells which over-express IGFBP-6 were treated with P4, E2, or both. Overexpressing cells exhibited stronger antagonism compared to controls when co-treated with P4 and E2. RNA-interference was performed to knockdown IGFBP-6 induction in the presence of P4 and E2. Knockdown of IGFBP-6 in the presence of P4 and E2 decreases the antagonistic effects of P4. Expression of both PR-A and PR-B decreases by about 50% when IGFBP-6 is knocked down. These results indicate that IGFBP-6 increases PR expression in response to P4 stimulation. Citation Format: Francisco Javier Lariz, Pacha Botero, Kevin Houston. IGFBP-6 is induced by progesterone to regulate progesterone receptor expression in breast cancer 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 4390.
Abstract 4860: Recommendations for enhancing inclusion and management of esophagus cancer clinical trials: Insights on mortality of esophagus cancer as a second primary malignancy
Authors: Haiyu Zhou, Jinhang Leng, Hongrui Qiu, Qizhi Huang, Jinqiang Zhang
Journal: Cancer Research (2024)

Abstract Background: Esophagus cancer as a second primary malignancy (esophagus-2) is increasingly common, but its prognosis is poorly understood. This study aims to examine the overall, non-cancer related and cancer-specific survival of patients diagnosed with esophagus-2 compared to the first primary esophagus cancer (esophagus-1). Methods: We included primary esophagus cancer patients diagnosed from 1975 to 2020 in the Surveillance, Epidemiology, and End Results program. Esophagus-2 was identified in patients with a previous diagnosis of non-esophageal primary malignancy. Hazard ratios of overall, esophagus cancer-specific and non-cancer related mortality were estimated among patients with esophagus-2 compared to esophagus-1, adjusting for age, sex, tumor stage and other demographic and clinical characteristics. Results: A total of 74521 and 14820 patients were identified as esophagus-1 and esophagus-2. Esophagus-2 patients suffered lower risk of esophagus cancer-specific mortality in initial 5 years but similar risk thereafter, independent of tumor characteristics and treatment. In the first 5 years after diagnosis, patients with esophagus-2 had similar risk of overall mortality with those with esophagus-1 but increased risk thereafter. As for non-cancer related mortality, esophagus-2 patients had higher risk all along. Conclusion: Patients diagnosed with esophagus-2 face a favorable esophagus cancer-specific survival within the early period after diagnosis. However, patients with esophagus-2 are more liable to die of non-cancer cause. A conservative approach to manage esophagus-2 solely based on malignancy history is not supported but effort should be put into surveillance, prevention and management of the comorbidities and complications for the first malignancy. Citation Format: Haiyu Zhou, Jinhang Leng, Hongrui Qiu, Qizhi Huang, Jinqiang Zhang. Recommendations for enhancing inclusion and management of esophagus cancer clinical trials: Insights on mortality of esophagus cancer as a second primary malignancy [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 4860.
Abstract 7204: Therapeutic potential of targeting autophagy to overcome chemoresistance in glioblastoma
Authors: Karrie Mei Yee Kiang, Gilberto Ka Kit Leung
Journal: Cancer Research (2024)

Abstract Glioblastoma (GBM) is the most malignant subtype of brain tumor in adults, characterized by relentless recurrence and an overall survival of approximately 18 months. Temozolomide (TMZ) has been the basis for current standard of care and represents the control-arm in GBM trials. Despite the use of TMZ having shown promising results in improving patient survival, drug resistance and tumor relapse is almost inevitable. Current literature has provided strong evidence on autophagy modulation as an adjuvant therapy to cytotoxic treatments. By using in vitro and in vivo GBM models, combination regimen with TMZ and an autophagy activator significantly enhanced the cytotoxic effect in tumors that were resistant to chemotherapy. Combined treatment readily induced a mortal autophagy flux in chemo-resistant GBM cells resulted from its high intrinsic autophagy. Our findings suggest that treatment resistant tumors are more sensitive to autophagy activation when compared to treatment-naive tumors. As they often exhibit higher basal level of autophagy after long-term chemotherapy, a mortal autophagy flux can be readily achieved. In conclusion, combination therapy of a cytotoxic drug with autophagy modulator is emerging as a novel therapeutic strategy in the adjuvant setting for cancer patients. Citation Format: Karrie Mei Yee Kiang, Gilberto Ka Kit Leung. Therapeutic potential of targeting autophagy to overcome chemoresistance in glioblastoma [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 7204.
Abstract 7561: Standardized conditions for growth of lung cancer tumoroids cultured reproducibly in 3D-cultures
Authors: Karina Malmros, Daniel Carlsén, Hans Brunnström
Journal: Cancer Research (2024)

Abstract Background: Lung cancer is the most common cause of cancer-related death in Sweden with an estimated mortality of 3500 persons in 2021. Late diagnosis and heterogeneity of the disease lead to difficulty in predicting optimal treatment regime for each case. Further development of personalized therapy would be facilitated by reliable and efficient cultivation of cancer cell samples from patients in a clinical setting. A promising method is to grow the cells as 3D structures known as tumoroids, though the choice of extracellular matrix substrate or solid support most suitable for this purpose should be elucidated. Aim: To assess which extracellular matrix substrates or solid supports which enable lung cancer tumoroid generation reproducibly without affecting the status or detection of genetic alterations and protein expression, using lung cancer cell lines. Methods: Eight lung cancer cell lines, where of three adenocarcinoma and five squamous cell carcinomas, were included in this project. Each cell line was characterized with immunohistochemistry (IHC) for commonly expressed antigens in the two lung cancer types. Also, protein detection with Western Blots was performed. Cell lines found not expressing relevant antigens associated with the specific lung cancer variant were discarded. The remaining cell lines were cultivated in BIOFLOAT TC-Platte 96 well plate, Nunclon Sphera flasks, or GrowDex-T hydrogel, later transferred to a Corning Elplasia 6 well plate, and monitored for tumoroid generation. Results: The lung squamous cell carcinomas HCC-95 and HCC-1588 were both positive for CK5 and p40, while H1703 was negative for both markers. The adenocarcinoma H1975 was positive for TTF-1, also, unexpectedly, seen for NCI-H1703, earlier defined as squamous cell carcinoma. The tested cell lines were successfully cultured as tumoroids in the BIOFLOAT TC- 96 well plate, Nunclon Sphera flasks, and GrowDex-T hydrogel. The mutational status of the tumoroids as compared to the original tumors is currently under evaluation. Conclusion: We here show successful 3D culturing of cell lines with alternative substrates. Further fine-tuning of the chosen reproducible system's simplicity and cost is required before culturing tumoroids from lung cancer patients can be launched. Citation Format: Karina Malmros, Daniel Carlsén, Hans Brunnström. Standardized conditions for growth of lung cancer tumoroids cultured reproducibly in 3D-cultures [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 7561.
Abstract 560: IGF1 induces the expression of CYR61 in metastatic prostate cancer
Authors: Greisha L. Ortiz Hernandez, Mya Walker, Leanne Woods-Burnham, Rick A. Kittles, Carlos A. Casiano, Susan Neuhausen
Journal: Cancer Research (2024)

Abstract The cysteine-rich angiogenic inducer 61 (CYR61) is a member of the cellular communication network (CCN) protein family that can be induced by growth factors. CYR61-specific functions are dependent on cellular context. In prostate cancer (PCa), CYR61 contributes to cell growth and survival through its interactions with extracellular ligands, such as integrins avb3 and a6b4, in the extracellular matrix space. Interestingly, CYR61 contains an insulin-like growth factor-binding protein domain suggesting that it may interact with insulin-like growth factor-I (IGF1). High serum levels of IGF1 are directly linked to PCa development and recently have been studied as a predictor of metastatic disease. Given the important roles that IGF1 and CYR61 play in PCa and their potential interaction, it is critical to investigate their molecular interplay. The correlation between PCa aggressiveness and circulating levels of CYR61 and IGF1 is poorly studied. Our goal was to assess the contribution of CYR61-IGF1 interaction to PCa cell proliferation. Their combined role may explain a proportion of aggressive PCa. This study was designed to characterize the role of IGF1-induced expression of CYR61 in metastatic PCa cellular models and to determine if this interaction contributes to aggressive tumor properties (e.g., proliferation, migration, tumorsphere formation). Using immunoblotting, we demonstrated that CYR61 is upregulated in the metastatic cell line PC3. Furthermore, optimized knockdown of CYR61 using siRNA significantly reduced PC3 cell proliferation, viability, and prostasphere formation. To examine the underlying mechanisms associated with IGF1 signaling, we assessed the activation of either the PI3/Akt and MAPK pathways in PC3 cells with CYR61 silencing. CYR61 siRNA-mediated knockdown decreased activation of the PI3/Akt pathway but did not affect the MAPK pathway. In addition, we found that IGF1 induces protein expression of CYR61 in a time-dependent manner, validated by both immunoblotting and confocal microscopy. In conclusion, these data provided evidence that CYR61 expression is induced by IGF1, and its inhibition decreased the capacity of metastatic PCa cells to proliferate, indicating a potential utilization of CYR61 inhibition in the therapy of metastatic PCa. Citation Format: Greisha L. Ortiz Hernandez, Mya Walker, Leanne Woods-Burnham, Rick A. Kittles, Carlos A. Casiano, Susan Neuhausen. IGF1 induces the expression of CYR61 in metastatic prostate 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 560.
Abstract 5681: Identification of dysregulated miRNAs involved in TNBC progression
Authors: Minyoung Lee, Yesol Kim, Dasom Son, Sera Lim, Jong Hoon Park
Journal: Cancer Research (2024)

Abstract Triple negative breast cancer (TNBC) is the most aggressive type of all breast cancer subtypes. Although various studies have been performed to identify prognostic and therapeutic targets for TNBC, the TNBC specific biomarkers have not yet been elucidated. Herein, we identified dysregulated miRNAs in TNBC via analysis of miRNA microarray in breast cancer tissues and found the oncogenic RNA (miR-374a-5p) and tumor suppressive miRNAs (miR-320c, miR-371b-5p). These miRNAs were closely related to overall survival of TNBC patients and status and involved in TNBC progression or drug responsiveness. Collectively, these results suggest that dysregulated miRNAs might serve as potential prognostic marker or therapeutic target for TNBC. Citation Format: Minyoung Lee, Yesol Kim, Dasom Son, Sera Lim, Jong Hoon Park. Identification of dysregulated miRNAs involved in TNBC 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 5681.
Abstract 2580: Targeting chromatin in ovarian cancer stem cells
Authors: Yinu Wang, Jane Frederick, Yaqi Zhang, Elizabeth Thomas Bartom, Greta Bauer, Edward Tanner, Vadim Backman, Daniela Matei
Journal: Cancer Research (2024)

Abstract The dynamic organization of chromatin, governed by epigenetic modifiers, critically regulates cell plasticity and determines cell fate in both normal and malignant stem cells. We hypothesized that chromatin architecture plays a role in regulating transcriptional heterogeneity in ovarian cancer stem cells (OCSCs) to maintain stemness and chemoresistance. PWS microscopy showed that ALDH+ OCSCs derived displayed higher nuclear fractal dimension D signals (P&amp;lt;0.05) than ALDH- non-OCSCs, indicating that chromatin in OCSCs possesses higher packing compared to non-OCSCs. Cut &amp; TAG Sequencing showed that of the 3606-histone repressive H3K27m3 enriched regions (P&amp;lt;0.05, fold change &amp;gt;2), 3208 were detected in OCSCs while 398 peaks were present in non-OCSCs, consistent with findings supporting high D features in OCSCs. The active mark H3K4me3 was enriched at the promoter of stemness-associated genes, including SOX2, ALDH1A3, and FZD7 in OCSCs; and the repressive histone mark H3K27me3 was enriched at the promoter of the epithelial cell marker CDH1 in OCSCs. These results support that the chromatin of OCSCs contains open genomic regions, corresponding to stemness-associated genes and repressed regions associated with genes related to differentiation. RNA sequencing indicated that the coefficient of variance (COV) reflecting transcriptional heterogeneity in OCSCs was higher than in non-OCSCs at baseline. In response to platinum, genes with low baseline expression in OCSCs were most upregulated, supporting increased transcriptional heterogeneity in response to chemotherapy. Inhibitors of epigenetic modifiers (DNMTi, EZH2i, and Dot1Li) induced chromatin re-organization in OCSCs and promoted OCSCs transition toward differentiation, supporting that stemness-associated chromatin structure is targetable. We demonstrated that a Dot1L inhibitor (Dot1Li) targeted OCSCs by decreasing chromatin packing D, resulting in decreased transcriptional heterogeneity. In conclusion, OCSCs harbor highly packed chromatin, contributing to chemoresistance and cell plasticity. Epigenetic modifiers (such as Dot1Li) inhibit stemness by regulating chromatin organization and transcriptional malleability. Citation Format: Yinu Wang, Jane Frederick, Yaqi Zhang, Elizabeth Thomas Bartom, Greta Bauer, Edward Tanner, Vadim Backman, Daniela Matei. Targeting chromatin in ovarian cancer stem 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 2580.
Abstract 755: Fecal microbial dysbiosis is associated with colorectal cancer risk
Authors: Jeongseon Kim, Madhawa Gunathilake, Hyun Yang Yeo, Jae Hwan Oh, Byung Chang Kim, Nayoung Han, Bun Kim, Hyojin Pyun, Mi Young Lim, Young-Do Nam, Hee Jin Chang
Journal: Cancer Research (2024)

Abstract Although there is evidence of an association between the fecal microbiota and colorectal cancer (CRC) risk in epidemiologic studies, there is a lack of data from large-scale population-based studies. To address this gap, we assessed the dysbiosis of the fecal microbiome in a large-scale study in Korea. We recruited 287 CRC patients from the Center for Colorectal Cancer, National Cancer Center Hospital, Korea to perform 16S rRNA gene sequencing of fecal samples. A total of 287 age- and sex-matched healthy participants were selected from 890 cohort of healthy Koreans that are publicly available (PRJEB33905). The microbial dysbiosis index (MDI) was calculated based on the differentially abundant species. The association between MDI and CRC risk was observed using conditional logistic regression. Alpha-diversity indices were not significantly different between CRC cases and controls. The first three principal coordinates derived by a principal coordinate analysis (PCoA) based on weighted UniFrac distance explained 41.24% of the overall microbial diversity, with a significant divergence of the microbial composition between CRC patients and controls (PERMANOVA p=0.001). Three enterotypes were found based on CRC patients’ microbial composition. Those who were in the third tertile of the MDI showed a significantly increased risk of CRC in the total population (OR: 6.59, 95% CI: 3.83-11.33, p-trend&amp;lt;0.001) compared to those in the lowest tertile. Similar results were found for men (OR: 6.58, 95% CI: 3.17-13.63, p-trend&amp;lt;0.001) and women (OR: 6.69, 95% CI: 2.91-15.37, p-trend&amp;lt;0.001). Dysbiosis in the fecal microbiota may be associated with an increased risk of CRC. Due to the potentially modifiable nature of the gut microbiota, our findings may have implications for CRC prevention among Koreans. Key words: Fecal microbiome, 16S rRNA gene sequencing, Microbial dysbiosis, Colorectal cancer Citation Format: Jeongseon Kim, Madhawa Gunathilake, Hyun Yang Yeo, Jae Hwan Oh, Byung Chang Kim, Nayoung Han, Bun Kim, Hyojin Pyun, Mi Young Lim, Young-Do Nam, Hee Jin Chang. Fecal microbial dysbiosis is associated with colorectal cancer risk [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 755.
Abstract 886: Integrated deep learning model for predicting DNA methylation and tumor types from histopathology in central nervous system tumors
Authors: Eldad David Shulman, Danh-Tai Hoang, Rust Turakulov, Zied Abdullaev, Omkar Singh, Emma M. Campagnolo, Eric A. Stone, MacLean P. Nasrallah, Eytan Ruppin, Kenneth Aldape
Journal: Cancer Research (2024)

Abstract Precision in diagnosis of diverse central nervous system (CNS) tumor types is crucial for optimal patient treatment. DNA methylation profiles, which capture the methylation status of thousands of individual CpG sites, are data-driven means to enhance diagnostic accuracy, but this technique is expensive, time-consuming, and not yet routinely available. To address this, we developed DEPLOY, a deep-learning model that predicts 10 major categories of CNS tumors from histopathology. DEPLOY integrates three distinct components: the first classifies CNS tumors directly from histopathology slide images (‘direct model’); the second initially generates predictions for DNA methylation beta values, which are subsequently used for tumor classification (‘indirect model’); and the third classifies tumor types directly from routinely available patient demographics. First, we find that DEPLOY accurately predicted beta values from histopathology images, suggesting that application of inferred methylation data is a promising approach for deep learning histopathology-based classifiers. Using a 10-class model trained on an internal dataset, we apply this model on two independent external test datasets of 1,522 and 348 cases, achieving top-1 accuracies of 96% and 94%, respectively on samples which are predicted with high confidence. Taken together, DEPLOY could assist pathologists in diagnosing CNS tumors, in an equitable very low-cost manner, within a clinically relevant short time frame. Citation Format: Eldad David Shulman, Danh-Tai Hoang, Rust Turakulov, Zied Abdullaev, Omkar Singh, Emma M. Campagnolo, Eric A. Stone, MacLean P. Nasrallah, Eytan Ruppin, Kenneth Aldape. Integrated deep learning model for predicting DNA methylation and tumor types from histopathology in central nervous system tumors [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 886.
Abstract 5694: Elucidating areca nut-induced miRNA-mRNA regulatory networks in head and neck cancer pathogenesis
Authors: Hung-Han Huang, Guo-Rung You, Kai-Hsin Lin, Yin-Ju Chen, Ann-Joy Cheng
Journal: Cancer Research (2024)

Abstract Areca nut has been considered a high-risk carcinogen for head and neck cancer (HNC) in Southeast Asia, while its molecular effects, especially on the miRNA regulatory roles, remain elusive. This study characterized miRNA-mRNA networks associated with areca nut-related HNC. We integratively analyzed the areca nut-induced mRNA profile and TCGA-HNSC gene set. A total of 2575 genes were identified, with 1971 upregulated and 604 downregulated in cancers. The KEGG pathway analysis revealed that these genes were enriched in the cellular functions related to motility and stress response. Experimental studies confirmed that arecoline promoted cell migration, invasion, and chemo-radioresistance. We further cross-analyzed the miRNAs induced by areca nut and dysregulated in TCGA-HNSC data and defined 71 molecules affected, with 35 upregulation and 36 downregulation. Using the multimiR tool to map potential mRNA-miRNA interactions, we uncovered that these miRNAs were connected to 2173 genes. These molecules participated in several oncogenic mechanisms, such as ErbB and PI3K-Akt signaling, cell adhesion, and DNA damage response. We endeavored to establish miRNA-mRNA interaction networks with the functions of cellular motility and stress response via the Cytoscape analytical method. Our data revealed nexus comprising 41 miRNAs with 83 mRNAs, and 38 miRNAs with 66 mRNAs, respectively, co-regulate these two malignant functions. A key miRNA, miR-410-3p, downregulated in HNC and decreased following areca nut treatment, was studied. Ectopic expression of miR-410-3p attenuated areca nut-induced cell invasion and exerted modulatory effects on its target oncogenes, CRK. Thus, our study delineates a comprehensive view of the miRNA-mRNA interplay altered by areca nut, illustrating a sophisticated mechanism of carcinogenesis and suggesting new avenues for diagnostic and therapeutic strategies in HNC. Citation Format: Hung-Han Huang, Guo-Rung You, Kai-Hsin Lin, Yin-Ju Chen, Ann-Joy Cheng. Elucidating areca nut-induced miRNA-mRNA regulatory networks in head and neck cancer pathogenesis [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 5694.