bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3899: CHST11 mediated SEMA7A expression contributes to TKI resistant in lung cancer
Authors: Li Chien-Hsiu Chris , Chan Ming-Hsien , Chang Yu-Chan , Hsiao Michael 
Published: April 2023

Abstract
An extracellular matrix has been demonstrated to be one of the substances that promote tumor cells to become driven by external stimuli to change their biology or malignancy. The main component of extracellular matrix, chondroitin sulfate, has been confirmed as a factor in the progression of tumors. Nevertheless, a great deal remains unknown regarding the precise mechanisms that drive Chondroitin sulfate production and how these details are communicated to cancer cells. According to our previous studies, the main enzyme responsible for Chondroitin sulfate synthesis, carbohydrate sulfotransferase 11 (CHST11), plays a crucial role in lung cancer cell metastatic spread. Nevertheless, the relationship between CHST11 expression and regulatory mechanism in response to lung cancer treatment is unclear, especially for tyrosine kinase inhibitor (TKI). A clinical correlation analysis was used in this study to identify molecules which were highly correlated with the overexpression of CHST11 and identified GPI-anchored protein semaphorin 7A (SEMA7A) as a candidate. According to the TCGA database, expression of upregulated SEMA7A is correlated with poor prognosis and cellular malignancy in lung cancer patients. A SEMA7A-based gene correlation analysis finds that the affected gene ontology is highly similar to CHST11, particularly integrin signaling, which may contribute to Gefitinib resistance. A GSEA analysis reveals a significant effect of CHST11 overexpression on mitotic spindle processes, some of which molecules are clinically relevant to CHST11 or SEMA7A. These molecules have been reported to be involved in TKI resistance events such as MARCKS, MYO1E, and PDLIM5. Based on the TCGA database, these molecules and integrins also display significant clinical relevance in lung cancer patients. A CHST11-mediated increase in SEMA7A in the mitotic spindle process of cells may serve as one of the possible means of reducing TKI-induced mitotic cell death, and thereby promoting the ability of lung cancer cells to become resistant to TKIs. Hence, targeting the CHST11-SEMA7A axis may offer a therapeutic strategy option that could be used to target drug resistance in lung cancers. [Keywords: CHST11, SEMA7A, Integrin, Drug resistant, Lung cancer] (Reference: https://pubmed.ncbi.nlm.nih.gov/35985204/; https://pubmed.ncbi.nlm.nih.gov/36181245/)
Citation Format: Chien-Hsiu Chris Li, Ming-Hsien Chan, Yu-Chan Chang, Michael Hsiao. CHST11 mediated SEMA7A expression contributes to TKI resistant in lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3899.
Abstract 3903: Role of the miR-301a/Fra-2/GLIPR1 axis in lung cancer cisplatin resistance
Authors: Lovat Francesca , Vinciguerra Gian Luca Rampioni , Capece Marina , Distefano Rosario , Nigita Giovanni , Vecchione Andrea , Croce Carlo M. 
Published: April 2023

Abstract
Lung cancer is the leading cause of cancer-related mortality in both men and women worldwide. Despite the administration of platinum compounds represents the main treatment, the majority of tumors remains intrinsically resistant. In lung cancer, miR-301a exerts a main role by modulating the activity of transcription factors like NF-kB and Stat3. Here, we dissected the contribution of miR-301a in the regulation of its new identified target Fos-related antigen-2 (Fra-2), a transcription factor that belongs to the Fos/AP-1 family. By microarray analysis, we discovered that Fra-2 overexpression increased glioma pathogenesis-related protein 1 (GLIPR1) levels, a mediator of cisplatin resistance in lung cancer. Its mechanism of regulation is still unclear. We demonstrated that GLIPR1 is also a miR-301a target. In vitro, modulation of miR-301a reduced Fra-2 and GLIPR1 levels; conversely, Fra-2 overexpression significantly increased GLIPR1 and miR-301a. Then, by chromatin immunoprecipitation assay, we confirmed that Fra-2 interacts with the promoter regions of both GLIPR1 and MIR301A genes, supporting that miR-301a/Fra-2/GLIPR1 axis could be autoregulated by feedback loop in which Fra-2 promotes the transcription of MIR301A gene. Investigating the effect of this new axis on the response to cisplatin, we observed that both Fra-2/GLIPR1 overexpression and miR-301a silencing induced cisplatin resistance in lung cancer cells. By contrast, silencing of GLIPR1 and combined administration of low doses of Fos/AP-1 inhibitor restored the cisplatin sensitivity in Fra-2 overexpressing cells. In the lung adenocarcinoma samples from the TCGA dataset, miR-301a overexpression inversely correlated with Fra-2 and GLIPR1 expression. Consistently, the overexpression of miR-301a identified a fraction of tumors with low expression of Fra-2 and GLIPR1 in an internal cohort of lung cancer samples. Altogether, our findings identify the miR-301a/Fra-2/GLIPR1 axis that contributes to cisplatin resistance in lung cancer cells and could serve as biomarker to stratify patients who may benefit from cisplatin administration, alone or in combination with Fos/AP-1 inhibitors.
Citation Format: Francesca Lovat, Gian Luca Rampioni Vinciguerra, Marina Capece, Rosario Distefano, Giovanni Nigita, Andrea Vecchione, Carlo M. Croce. Role of the miR-301a/Fra-2/GLIPR1 axis in lung cancer cisplatin resistance. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3903.
Abstract 3905: Epigenetic primming reveals the central role of epigenetic state in the anti-tumor activity of vitamin D in pancreatic ductal adenocarcinoma
Authors: He Bo , Stoffel Lauren , He Clifford Jiajun , Li Albert Mao , Jiang Haowen , Cho Kumsun , Flowers Brittany M. , Ferreira Sofia , Attardi Laura D. , Ye Jiangbin 
Published: April 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, which is largely due to the intrinsic resistance to a broad spectrum of therapies. Vitamin D (VD) has been extensively studied as a potential preventive or therapeutic agent for PDAC treatment. Although accumulating evidence supports that VD has beneficial effects on PDAC treatment, controversies still exist. The major reason for this inconsistency is that VD resistance widely occurs in PDAC. However, the underlying mechanism by which the VD resistance occurs remains largely unknown. Here, we report that epigenetic primming by glyceryl triacetate (GTA) and 5-azacytidine (5-Aza) overcomes VD resistance in PDAC. Mechanistically, increasing global H3K27 acetylation with GTA and reducing global DNA methylation with 5-Aza not only elevate the VDR expression but also reprogram the VD responsive genes. Consistently, combination treatment with VD analogue calcipotriol (CPT) and epigenetic primming overcomes the VD resistance to inhibit cell proliferation and migration through activating genes involved in negative regulation of cell proliferation and cell migration, while CPT treatment alone has the opposite effects. Intriguingly, further studies in mouse PDAC cells suggest that VDR expression does not always corelate with VD responsiveness. Using the gain and loss of function experiments, we demonstrate that VDR is necessary but not sufficient to trigger the anti-tumor activity of VD, highlighting that epigenetic state is the key determinant of VD responsiveness in PDAC. Collectively, these data reveal a previously undefined mechanism for VD resistance in PDAC and has the potential to guide VD clinical trials in the future.
Citation Format: Bo He, Lauren Stoffel, Clifford Jiajun He, Albert Mao Li, Haowen Jiang, Kumsun Cho, Brittany M. Flowers, Sofia Ferreira, Laura D. Attardi, Jiangbin Ye. Epigenetic primming reveals the central role of epigenetic state in the anti-tumor activity of vitamin D in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3905.
Abstract 3936: ALK fusion oncogene driven SERPINB4 expression enhances tumor survival in NSCLC
Authors: Chuang Tzu-Po , Lai Wei-Yun , Gabre Jonatan L. , Lind Dan E. , Umapathy Ganesh , Bokhari Abdulmalik A. , Bergman Bengt , Kristenson Linnea , Thorén Fredrik B. , Le Anh , Doebele Robert , Eynden Jimmy V. , Palmer Ruth H. , Hallberg Bengt 
Published: April 2023

Abstract
Anaplastic lymphoma kinase (ALK) fusion variants in non-small-cell-lung cancer (NSCLC) consist of numerous dimerising fusion partners, with the most common being EML4. Clinical data suggests that the degree of treatment benefit in response to ALK tyrosine kinase inhibitors (TKIs) differs among the variant present in the patient tumor. Therefore, a better understanding the oncogenic signaling networks driven by different ALK-fusion variants is important. Here, we developed highly controlled doxycycline-inducible cell models bearing four different ALK fusion proteins, namely EML4-ALK-V1, EML4-ALK-V3, KIF5B-ALK, and TFG-ALK, in the context of non-tumorigenic NL20 human bronchial epithelial cells. These were complimented by patient-derived NSCLC cell lines harboring either EML4-ALK-V1 or EML4-ALK-V3 fusions. RNA-seq and phosphoproteomics analysis were employed to identify dysregulated genes and hyper/hypo-phosphorylated proteins associated with ALK fusion expression. Among ALK fusion induced responses, we noted a robust inflammatory signature that included up-regulation of the Serpin B4 serine protease inhibitor in both NL20-inducible cell models and ALK-positive NSCLC patient-derived cell lines. We show that STAT3 is a major transcriptional regulator of SERPINB4 downstream of ALK fusions, along with NF-kB and AP1. The upregulation of SERPINB4 promotes survival of ALK fusion expressing cells and inhibits natural killer (NK) cell-mediated cytotoxicity. In conclusion, our study reveals a novel ALK downstream survival axis that regulates Serpin B4 expression and identifies a molecular target that has potential for therapeutic impact targeting the immune response together with ALK TKIs in NSCLC.
Citation Format: Tzu-Po Chuang, Wei-Yun Lai, Jonatan L. Gabre, Dan E. Lind, Ganesh Umapathy, Abdulmalik A. Bokhari, Bengt Bergman, Linnea Kristenson, Fredrik B. Thorén, Anh Le, Robert Doebele, Jimmy V. Eynden, Ruth H. Palmer, Bengt Hallberg. ALK fusion oncogene driven SERPINB4 expression enhances tumor survival in NSCLC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3936.
Abstract 3994: Differential regulation of hormone receptors and Ki67 in luminal breast carcinomas and tumor-adjacent mammary glands by mifepristone treatment
Authors: Saldain Leo , Vanzulli Silvia , Vazquez Paula Martinez , Burruchaga Javier , Spengler Eunice , Lanari Claudia , Rojas Paola 
Published: April 2023

Abstract
Since antiprogestins inhibit the growth of preclinical mammary tumor models expressing higher levels of progesterone receptor (PR) isoform A (PRA) than isoform B (PRB), we designed a window-of-opportunity trial (MIPRA; NCT02651844) to study the benefits of mifepristone (MFP) in luminal breast carcinomas from postmenopausal patients selected by their PR+ expression (&gt;50%) and their PR isoform ratio (PRA/PRB&gt;1.5; PRA-H). A decrease in the cell proliferation marker Ki67 was registered after treatment in 14 out of the 20 tumors evaluated. This inhibition was associated with a decrease in PR, estrogen receptor (ER) and pSer118ER evaluated by immunohistochemistry while no changes in pSer167ER expression were observed (PMID: 36269797). In selected tissues from these samples we observed that the staining intensity in trapped glands within the MFP-treated tumors did not follow a similar trend as that of tumor cells. Thus, the aim of this study was to evaluate the expression of hormone receptors and Ki67 in non-neoplastic human mammary glands (nnMG) adjacent to the PRA-H tumor tissue of postmenopausal patients, treated (n=8) or not (n=9) with MFP. No differences in PR, ER and pSer118ER expression were observed between MFP-treated nnMG and those from untreated patients. Notably, contrarily to what occurred in tumors, there was a significant decrease of pSer167ER expression (p=0.008) in the MFP-treated nnMG compared to the untreated glands, suggesting a selective modulation in the AKT-mediated activation of ER. Regarding the proliferative state of the nnMGs, there was a slight but significant increase (p=0.02) in Ki67 expression in MFP-treated vs. non-treated nnMG. Data regarding the effect of antiprogestins in normal mammary glands is limited and points, in premenopausal women, to a decrease in the Ki67 index after treatment. The basal quiescent status of nnMG in postmenopausal women may explain this slight stimulatory effect. In conclusion, our results show that MFP exerts a specific regulatory effect in PRA-H tumors that is not observed in the nnMG, probably due to the fact that nnMG have presumably equimolar levels of PRA and PRB. In addition, to counteract the possible stimulatory effect that MFP may induce on nnMG, the combination of MFP and tamoxifen treatment is suggested.
Citation Format: Leo Saldain, Silvia Vanzulli, Paula Martinez Vazquez, Javier Burruchaga, Eunice Spengler, Claudia Lanari, Paola Rojas. Differential regulation of hormone receptors and Ki67 in luminal breast carcinomas and tumor-adjacent mammary glands by mifepristone treatment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3994.
Abstract 4071: Identification of myeloma-specific T cell receptors by functional single cell interaction analyses
Authors: Wagner Tim R. , Boğa Eren , Schmidt Patrick , Osen Wolfram , Platten Michael , Goldschmidt Hartmut , Raab Marc S. , Friedrich Mirco J. , Eichmüller Stefan B. 
Published: April 2023

Abstract
Innovative immunotherapy approaches such as adoptive transfer of chimeric antigen receptor (CAR) T cells or tumor infiltrating lymphocytes (TILs) have shown great success in the treatment of solid tumors and hematological malignancies. Although treatment of multiple myeloma with CAR T cells can induce deep responses, relapses frequently occur due to antigen escape and limited CAR T cell persistence. TCR-engineered T cells may mediate sustained antitumor effects upon recognition of intracellular targets, thereby significantly increasing the range of relevant target antigens. In our project, we propose to identify T cell receptors (TCRs) specifically targeting autologous myeloma cells. Tumor-reactive T cells were identified using the Berkeley Lights Lightning platform, allowing simultaneous functional analysis of up to 1500 individual T cell/target cell interactions per run. Reactive T cells have been identified upon detection of secreted chemokines (IFNγ, TNFα, IL-2) and by measurement of CD137 surface expression. Tumor-reactive T cells showing various cytokine secretion patterns and CD137 expression profiles could be detected in each myeloma patient (7 to 26 of approx.1200 cells tested per patient). Individual tumor reactive T cells have been isolated for TCR sequencing. Recovered TCR genes will be cloned and overexpressed in autologous T cells for functional validation and analysis of tumor derived neoepitope specificity. In summary, we present a pipeline allowing identification of myeloma-recognizing T cells and recovery of bona fide tumor-reactive TCRs eligible for patient-individualized T cell therapy.
Citation Format: Tim R. Wagner, Eren Boğa, Patrick Schmidt, Wolfram Osen, Michael Platten, Hartmut Goldschmidt, Marc S. Raab, Mirco J. Friedrich, Stefan B. Eichmüller. Identification of myeloma-specific T cell receptors by functional single cell interaction analyses. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4071.
Abstract 4089: PanCAR-specific antibody-cytokine fusion proteins
Authors: Keane John T. , Posey Avery D. 
Published: April 2023

Abstract
CAR-T cells are a potent immunotherapy that redirect T cell specificity towards cell surface tumor-associated antigens. While this therapy has been effective in hematological malignancies, therapies against solid tumors not achieved the same efficacy due to a multitude of additional challenges, including a lack of tumor specific antigens and an immunosuppressive tumor microenvironment. One strategy to increase T cell potency is to use fourth generation CAR-T cells that also secrete an immunostimulatory factor, such as a cytokine. We have created CAR-T cells targeting Tn-MUC1 utilizing a scFv from the 5E5 antibody that also secrete interleukin-12 (IL-12), interleukin-18 (IL-18), and interleukin-23 (IL-23). These cytokine-secreting CAR-T cells have shown an increase in efficacy against multiple epithelial based tumors in impedance-based killing assays. In a xenograft model of human breast cancer, CAR-T cells secreting IL-12 and IL-23 were able to significantly delay tumor growth compared to non-transduced T cells, CAR-T cells alone, and CAR-T cells secreting IL-18. While these cells showed good efficacy in vivo, clinical translation is difficult due to concerns over cytokine storm due to the constitutive secretion of cytokines. To overcome this, we created a fusion protein utilizing an antibody specific to an invariant region found in majority of CAR molecules, including those utilized commercially available therapies and under pre-clinical development, fused to the three immunostimulatory cytokines. In impedance-based killing assays, antibody-cytokine fusions stimulated non-cytokine secreting CAR-T cells to completely clear the tumor at an E:T ratio in which the CAR-T cells incubated with only the antibody alone were unable to control the tumor growth. Interestingly, combination therapy of CAR-T cells and antibody-cytokine fusions outperformed CAR-T cells constitutively secreting the same cytokines in in vitro assays. This work highlights the use of a single reagent capable of increasing the efficacy of the majority of CAR-T cell therapies and may be an important contribution towards treating solid tumor malignancies with CAR-T cell therapies.
Citation Format: John T. Keane, Avery D. Posey. PanCAR-specific antibody-cytokine fusion proteins. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4089.
Abstract 4141: Effects of exercise on tumorigenesis, immune system, and the gut microbiome in a bladder carcinogen mouse model
Authors: LaMorte Joseph P. , Tian Brittany , Ginwala Rashida , Bukavina Laura , Abbosh Philip 
Published: April 2023

Abstract
Recent studies have begun to demonstrate the therapeutic capacity of physical exercise on cancer treatment outcomes. While this research suggests exercise may improve health in cancer patients, the specific mechanisms by which exercise influences tumor progression remain largely unknown. We hypothesized that exercise alters the gut microbiome and promotes immune cell activation in relevant immune sites. Therefore, we utilized BBN (N-butyl-N-(4-hydroxybutyl)-nitrosamine), a carcinogen that mimics human muscle invasive bladder cancer conditions, and voluntary exercise wheels to determine the effect of exercise on bladder carcinogenesis, gut microbiome, and the immune system. Ultrasound imaging revealed that the average tumor volume of female exercising mice was 11.9% of the total bladder volume at time of sacrifice, while the tumor volume of their non-exercising counterparts was 56.4%, a difference determined to be significant using a two-tailed t-test with p-value of 0.05. A similar trend was seen in male mice, though the difference between groups was not significant. Immune cell analysis did not show significant variation in cytotoxic T cell, helper T cell, macrophage, or dendritic cell populations between exercising and non-exercising mice in spleen, colon, or bladder tissues as measured by FACS. Standardization of the amount exercised, as evaluated by expression of myosin and actin levels in the tibialis anterior muscle, and sequencing of the gut microbiome are in progress and could better indicate the mechanism of exercise-induced tumor suppression.
Citation Format: Joseph P. LaMorte, Brittany Tian, Rashida Ginwala, Laura Bukavina, Philip Abbosh. Effects of exercise on tumorigenesis, immune system, and the gut microbiome in a bladder carcinogen mouse model. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4141.