bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4282: Crosstalk between the immune system and the extracellular matrix in the context of melanoma and aging
Authors: Harper Elizabeth I. , Chhabra Yash , Carey Alexis , Rocha Murilo Ramos , Hüser Laura , Wang Vania , Dixit Agrani , Weeraratna Ashani 
Published: March 2024

Abstract
Aging is an independent prognostic factor for the diagnosis of melanoma. The extracellular matrix of the skin has well-documented changes with age, such as the loss of HAPLN1, which can lead to differential metastasis in aged individuals. The aged microenvironment can contribute to the phenotype switch, where aged individuals have smaller primary tumors but more metastases, i.e., going instead of growing. The extracellular matrix (ECM) has been shown to modulate the immune response either through direct binding of ECM proteins or through mechanotransduction, but it is unclear how aging affects this crosstalk. Our hypothesis is that the ECM can modulate immune response to melanoma and affect response to immune checkpoint blockade (ICB) therapy. Melanoma cells cultured on cell derived matrices (CDMs) from young and aged human fibroblasts show differential levels of expression of PD-L1, a ligand that binds to PD-1 on T cells to induce T cell exhaustion. Antibodies targeting PD-1/PD-L1 are one of the main ICB treatments available to melanoma. We are also investigating T cell motility on young and aged CDMs, as well as correlating T cell infiltration in murine tumors with ECM signatures as identified by second harmonic generation microscopy. Therefore, we have compiled evidence that aging affects the crosstalk between the extracellular matrix and the immune system, providing a new horizon for therapeutic improvement of response in older patients.
Citation Format: Elizabeth I. Harper, Yash Chhabra, Alexis Carey, Murilo Ramos Rocha, Laura Hüser, Vania Wang, Agrani Dixit, Ashani Weeraratna. Crosstalk between the immune system and the extracellular matrix in the context of melanoma and aging [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 4282.
Abstract 430: Precision diet and lipid modulating agents to induce lipid oxidation in breast cancer
Authors: Yavari Mahsa , Torpey Jordan , Sabatier Marie , Carmona Alanis , Szylo Krystina , Flores Midori , Palma Mario , Fraser Cameron , Liang Yanshan , Hui Sheng Tony , Zeleznik Oana , Eliassen Heather , Ubellacker Jessalyn 
Published: March 2024

Abstract
Metastasis is the primary cause of breast cancer-related mortality, and understanding the intricate relationship between the tumor microenvironment, lipid metabolism, and metastasis is crucial for preventing cancer progression. Previous work from our group demonstrated that high exogenous levels of oleic acid, a monounsaturated fatty acid (MUFA), in the lymph node environment protects melanoma cells from ferroptosis. Ferroptosis is an iron-dependent form of cell death induced by accumulation of lipid peroxides, which are commonly formed from polyunsaturated fatty acids (PUFAs), but not MUFAs. Here, we hypothesized that increasing dietary PUFAs would alter the exogeneous lipid content of the lymph node environment, thus rendering breast cancer cells more sensitive to ferroptosis. To test this, we determined the in vitro sensitivity of 4T1 triple negative breast cancer cells to ferroptosis when treated with various PUFAs and MUFAs. We also assessed the impact of various PUFA and MUFA fatty acid-enriched diets on breast cancer metastasis and ferroptosis resistance in the lymph nodes in vivo. In concordance with previously published work, our results demonstrated that pharmacological induction of ferroptosis in vitro increased lipid oxidation and was mitigated by fatty acid treatments with higher MUFA compared to PUFA content. In vivo, cancer cells in lymph nodes of mice on palm oil diets had lower lipid oxidation compared to cancer cells from tumors in the mammary fat pad. These findings support the hypothesis that dietary lipids can alter ferroptosis response and the extent of lipid oxidation in breast cancer cells within lymph nodes. Our research has the potential to further reveal mechanistic connections between dietary lipids, the lymphatic microenvironment, and breast cancer progression.
Citation Format: Mahsa Yavari, Jordan Torpey, Marie Sabatier, Alanis Carmona, Krystina Szylo, Midori Flores, Mario Palma, Cameron Fraser, Yanshan Liang, Sheng Tony Hui, Oana Zeleznik, Heather Eliassen, Jessalyn Ubellacker. Precision diet and lipid modulating agents to induce lipid oxidation in 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 430.
Abstract 4308: Same-section spatial multiomic analyses using MICS technology for investigating the dynamics of the tumor microenvironment
Authors: Park Dongju , Neil Emily , Hennessey Rebecca C. , DiBuono Michael , Lafayette Hanna , Lloyd Erica , Lo Hsinyi , Femel Julia , Makrigiorgos Alex , Lu Shaina , Lee John , Soliman Sameh , Mangiardi Dominic , Praveen Paurush , Staubach Fabian , Hindman Ryan , Rothmann Thomas , Santos Telma , Borbe Stefan , Meyer Hansueli , Wantenaar Tanya , Wang Jinling , Müller Werner , Pinard Robert , Bosio Andreas 
Published: March 2024

Abstract
The recent increase in image-based, spatially-resolved technologies enables researchers to profile the tumor microenvironment (TME) by capturing gene expression profiles within tissue sections. However, a significant limitation of these technologies is the lack of ability to resolve protein and RNA information in the same section, as well as conveniently analyze multimodal data sets. Here, we report a spatial RNA detection method, RNAsky, using Miltenyi Biotec’s MACSima™ Platform as an automated, multiomic approach. Our method integrates spatial proteomics and transcriptomics data to provide in-depth profiling with single-cell resolution on the same tissue section. We demonstrate these capabilities by characterizing key immune-oncology markers across normal and diseased tissues using our specialized MACS® iQ View analysis software. MACS iQ View provides fast segmentation and intuitive gating and clustering strategies to simultaneously assess protein and RNA data. We investigated the impact of clustering using protein, RNA, or the combination of both to evaluate the contribution of different information modalities on TME spatial dynamics. This cutting-edge approach will enable the identification of valuable parameters and new cell types, furthering the discovery and development of predictive and prognostic biomarkers.
Citation Format: Dongju Park, Emily Neil, Rebecca C. Hennessey, Michael DiBuono, Hanna Lafayette, Erica Lloyd, Hsinyi Lo, Julia Femel, Alex Makrigiorgos, Shaina Lu, John Lee, Sameh Soliman, Dominic Mangiardi, Paurush Praveen, Fabian Staubach, Ryan Hindman, Thomas Rothmann, Telma Santos, Stefan Borbe, Hansueli Meyer, Tanya Wantenaar, Jinling Wang, Werner Müller, Robert Pinard, Andreas Bosio. Same-section spatial multiomic analyses using MICS technology for investigating the dynamics of the tumor microenvironment [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 4308.
Abstract 4318: CD24 enhances cisplatin resistance in ovarian cancer by suppressing autophagy
Authors: Chen Yuh-Ling , Hong Tse-Ming , Wen Yu-Yi 
Published: March 2024

Abstract
Ovarian cancer is one of the most common gynecological cancers with the highest mortality rate. Most patients are diagnosed with advanced disease and will relapse due to chemoresistance. CD24, a highly glycosylated GPI-anchored membrane protein. Recent studies have shown that CD24 expression is significantly up-regulated in ovarian cancer and is associated with chemotherapy resistance, and CD24 also plays an inhibitory role in tumor immunity by binding to Siglec-10 on macrophages. However, the molecular mechanisms of how CD24 affects chemotherapy resistance in ovarian cancer remain unclear. In this study, we used shRNAs to knockdown CD24 and explore the impact and mechanism of CD24 on the chemotherapy resistance of ovarian cancer cells. The results showed that knockdown of CD24 in ovarian cancer cells SKOV3 and TOV21G significantly reduced cell proliferation and arrested the cell cycle in S phase. Knockdown of CD24 also significantly increased the sensitivity of ovarian cancer cells to cisplatin but had no effect on paclitaxol treatment. Further experiments showed that knockdown of CD24 increased cisplatin sensitivity by promoting autophagy-induced cell death. In addition, Gene Set Enrichment Analysis (GSEA) was used to analyze the correlation between the expression of CD24 and its biological functions in the TCGA ovarian cancer dataset. The results showed that CD24 is mostly correlated to cell proliferation and autophagy-related pathways in ovarian cancers. Further mouse xenograft tumor transplantation experiments also confirmed that knockdown of CD24 reduced tumor size and increased sensitivity to cisplatin treatment by increasing cell autophagy. Taken together, these results indicate that CD24 regulates cell growth and chemoresistance in ovarian cancer cells and that inhibition of CD24 may be helpful in the treatment of ovarian cancer.
Citation Format: Yuh-Ling Chen, Tse-Ming Hong, Yu-Yi Wen. CD24 enhances cisplatin resistance in ovarian cancer by suppressing autophagy [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 4318.
Abstract 4321: The oncogenic DMTF1β splice variant promotes autophagy-dependent cancer cell motility
Authors: Tschan Mario P. , Xu Jun , Bill Anna M. 
Published: March 2024

Abstract
The oncogenic isoform DMTF1β, which is generated by alternative splicing of the DMTF1 tumor suppressor gene is associated with increased cell proliferation and tumorigenesis. Despite these correlative findings little is known about the DMTF1β mechanism of action. In order to decipher the oncogenic DMTF1β signaling pathway, we performed RNA sequencing of DMTF1β depleted prostate cancer cells and analyzed the DMTF1β-specific protein interactome in these cells. Interestingly, autophagy-related pathways belonged to the most downregulated networks in DMTF1β knockdown cells. Moreover, we found that predominantly DMTF1β, but not a protein lacking the β-specific domain interacts with the key autophagy ULK1-ATG13 protein complex. These interactions were confirmed by co-immunoprecipitation and proximity ligation assays. Importantly, DMTF1β binding to ULK1 stabilized this key autophagy protein. Accordingly, knocking down DMTF1β significantly lowered autophagic flux in breast and prostate cancer cells as assessed by LC3-dependent and independent autophagy assays. Since published data show an important role for autophagy in migration and invasion of cancer cells, we next investigated whether DMTF1β is regulating these cellular processes. Indeed, DMTF1β depleted breast and prostate cancer cells displayed significantly decreased wound closure, trans-well invasion and metastatic foci formation in a zebra fish xenograft model. Importantly, pharmacological inhibition of ULK1 kinase activity or knocking down ULK1 reversed DMTF1β-mediated cancer cell migration. In agreement, decreased cell motility in DMTF1β knockdown cancer cells could be rescued by ectopic expression of the VPS34 complex member Beclin-1. In summary, we identified a novel DMTF1β-ULK1 signaling pathway that activates aberrant cancer cell migration most probably by increasing basal cell autophagy. Targeting autophagy using ULK1 inhibitors may represent a promising strategy to lower metastatic activity of tumor cells.
Citation Format: Mario P. Tschan, Jun Xu, Anna M. Bill. The oncogenic DMTF1β splice variant promotes autophagy-dependent cancer cell motility [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 4321.
Abstract 4324: IL6ST increases sorafenib-resistance in hepatocellular carcinoma by regulating BECN1-mediated mitophagic cell death
Authors: Ma Hwan , Roh Yoon-Seok 
Published: March 2024

Abstract
Introduction: Sorafenib resistance is often seen in patients with late-stage hepatocellular carcinoma (HCC) and it is a serious concern for the treatment of these patients. Lethal mitophagy plays an important role in anti-tumorigenic mechanisms by inducing mitochondrial dysfunction and mitophagic cell death. Sorafenib resistance is associated with the activation of IL6ST signaling, inhibiting mitochondrial quality. However, how lethal mitophagy regulates sorafenib resistance through IL6ST and mitochondrial dysfunction in HCC is not fully understood.
Experimental procedures: Hepatocyte-specific TAK1 deleted (TAK1ΔHep) and TAK1/IL6STΔHep were used for in vivo study. Histology, immunoblots, qPCR, microscopy, FACS, and seahorse bioanalyzer were used for analyzing liver and tumor tissues and Hep3B cells.
Results: We identified that sorafenib suppressed IL6ST signaling and that IL6ST signaling was activated in sorafenib-resistant HCC. The number and maximum size of spontaneous HCC in 9-month-old TAK1ΔHep mice were decreased when hepatocyte IL6ST was additionally deleted. Expression of pro-carcinogenic H-19, c-SRC, and MDM2 was increased in 1-month-old TAK1/IL6STΔHep mice compared to TAK1ΔHep mice. An additional IL6ST deletion induced decreases in mitochondrial membrane potential and glycolysis, suggesting that IL6ST protects against mitochondrial dysfunction. Interestingly, IL6ST deletion increases PRKN and BECN1 interaction and translocation to normal mitochondria and subsequent degradation, hereafter referred to as lethal mitophagy. Furthermore, inhibition of BECN1 restores IL6ST deletion-induced lethal mitophagy in HCC, suggesting that IL6ST-mediated lethal mitophagy is dependent on BECN1. Mechanistically, IL6ST inhibited BECN1-lethal mitophagy through STAT3(S705) phosphorylation independently of mTORC1 activation. Notably, enhanced BECN1 through a combination of sorafenib and inhibition of IL6ST increased mitophagic cell death, reducing sorafenib resistance and tumor growth. In addition, enhanced lethal mitophagy through inhibition of GP130 effectively killed sorafenib-resistant HCCs by silencing sorafenib resistance. We further defined the relationship between IL6ST, BECN1, and PRKN expression and sorafenib resistance in terms of HCC patients, RNA sequencing datasets.
Conclusion:  These results provide the importance of IL6ST in the development of sorafenib resistance and could be an innovative treatment strategy for sorafenib-resistant patients by regulating the IL6ST/STAT3/BECN1 axis-regulated lethal mitophagy.
Citation Format: Hwan Ma, Yoon-Seok Roh. IL6ST increases sorafenib-resistance in hepatocellular carcinoma by regulating BECN1-mediated mitophagic cell death [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 4324.
Abstract 4341: Non canonical mitochondrial hotspot mutations in cancer
Authors: Boscenco Sonia , Tait-Mulder Jaqueline , Kim Minsoo , Tang Cerise , Zucker Mark , Park Tricia , Wei Wei , Chinnery Patrick F. , Gammage Payam A. , Reznik Ed 
Published: March 2024

Abstract
The vast majority of recurrent somatic mutations arising in tumors affect protein-coding genes in the nuclear genome. Here, through population-scale analysis of 15,619 whole tumor genomes, we report the discovery of highly recurrent mutations affecting both the small (12S, MT - RNR1) and large (16S, MT - RNR2) RNA subunits of the mitoribosome. In total, we identified 70 recurrent, hotspot mutations affecting either subunit of the mitoribosome. Compared to non-hotspot positions, rRNA hotspots preferentially affect positions participating in Watson-Crick base pairing, and tend to arise at positions under strong purifying selection in the germline. Consistent with their putative selection, hotspot rRNA alleles arose at higher heteroplasmy than silent mutations under neutral selection. Transcriptional and metabolomic profiling of the m.1227G&gt;A MT - RNR1 hotspot revealed a heteroplasmic dosage-dependent shift in energy generation towards glycolysis. Mutations disrupting the mitoribosome therefore represent a novel class of functional mutations under positive selection in cancer genomes.
Citation Format: Sonia Boscenco, Jaqueline Tait-Mulder, Minsoo Kim, Cerise Tang, Mark Zucker, Tricia Park, Wei Wei, Patrick F. Chinnery, Payam A. Gammage, Ed Reznik. Non canonical mitochondrial hotspot mutations in 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 4341.
Abstract 436: Extracellular glutathione catabolism as an alternative cyst(e)ine source in cancer
Authors: Hecht Fabio , Zocchi Marco , Tuttle Emily , Asantewaa Gloria , Scales TashJaé , Alimohammadi Fatemeh , Ward Nathan , DeNicola Gina , Harris Isaac 
Published: March 2024

Abstract
Glutathione (GSH) is the most abundant antioxidant in the human body and plays essential roles in physiology and disease. Unchecked oxidative stress is involved in tumor initiation and progression. Paradoxically, clinical and laboratory data show that ROS-scavenging molecules such as glutathione not only fail to impede tumor growth but, in many cases, accelerate it. Still, preliminary data from our lab show that genetically ablating tumors’ ability to synthesize GSH does not affect their growth. This finding suggests that the favorable influence of glutathione on tumor growth may arise from external sources. Yet, the mechanism cancer cells employ to take advantage of extracellular glutathione in this context is unknown. Here, we show that γ-glutamyl-transpeptidase 1 (GGT1), an enzyme that localizes on the outer side of the cell’s membrane, can break down extracellular GSH, yielding glutamate and the dipeptide cysteinylglycine. Cysteinylglycine can be further metabolized, generating cysteine and glycine to the cells. We found that the addition of exogenous GSH, as well as cysteinylglycine, can mitigate cell death, proliferation arrest, and oxidative stress caused by cystine depletion. The overexpression of human GGT1 in cancer cells significantly reduces the amount of glutathione needed to rescue cell fitness. Accordingly, pharmacologic inhibition of GGT1 activity prevented GSH's ability to rescue cell proliferation. Moreover, an unbiased pharmacological screening revealed that GGT1-mediated cysteine acquisition renders cancer cells resistant to inhibitors of cystine uptake and utilization, supporting the role of GGT1 as a source of cyst(e)ine. Our findings reveal that cancer cells can access cysteine, a vital yet scarce amino acid, through GGT1's ability to break down glutathione, which is present in remarkably high concentrations within the tumor microenvironment. Although the downstream proteins involved in the transport and utilization of GSH breakdown products are yet to be identified, we anticipate this pathway has the potential to uncover novel therapeutic avenues for cancer treatment by targeting alternative pathways of nutrient acquisition that are potentially implicated in cancer progression and therapy resistance.
Citation Format: Fabio Hecht, Marco Zocchi, Emily Tuttle, Gloria Asantewaa, TashJaé Scales, Fatemeh Alimohammadi, Nathan Ward, Gina DeNicola, Isaac Harris. Extracellular glutathione catabolism as an alternative cyst(e)ine source in 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 436.
Abstract 4386: Androgen hormone signaling regulates the association between the hippo pathway component YAP1 and RNA binding protein NPM1
Authors: Dwead Abdulrahman M. , Al-Mathkour Marwah M. , Cinar Bekir 
Published: March 2024

Abstract
Prostate cancer represents a major health concern for men in the United States and globally, disproportionately affecting men of African descent. Despite recent advances, the precise etiology and molecular mechanisms underpinning fatal prostate cancer in humans remain inadequately understood. RNA binding proteins (RBPs) regulate various aspects of RNA biology, and when their regulation is disrupted, they can lead to human diseases, including cancer. However, the comprehensive alterations in RBP-mRNA interactions in prostate cancer have not been explored. In this study, we investigated the dynamics of RBPs and their interactions with polyadenylated mRNA in the castration-sensitive LNCaP and castration-resistant C4-2 prostate cancer cell lines. Using an enhanced RNA interactome capture assay in combination with mass spectrometry, we discovered that LNCaP and C4-2 cells showed distinct RBP-mRNA interaction patterns in steady-state growth conditions and in response to androgen treatment. Additionally, we investigated the interplay between the oncogene Yes-associated protein 1 (YAP1) and the RNA-binding protein nucleophosmin (NPM1). We identified NPM1 as a component of the YAP1 protein complex through mass spectrometry-based proteomics. Our proximity ligation assay demonstrated that androgen signaling could regulate the interaction between YAP1 and NPM1. Also, our GST-pulldown revealed that NPM1 binds to the proline-rich domain of YAP1 in LNCaP cells, while the WW/SH3 domain of YAP1 mediates the interaction with NPM1 in C4-2 cells. Genetic and pharmacological inhibition of NPM1 activity reduced prostate cancer cell growth in culture by modulating cell cycle progression. Furthermore, our computational and immunological analysis of prostate tumor tissues indicated that the upregulation of NPM1 might be associated with the clinical advancement of human prostate cancer. These findings underscore the critical role of the molecular functional connection between YAP1 and RBPs and the global changes in RBP and RNA interaction patterns, in the progression and recurrence of prostate cancer.
Citation Format: Abdulrahman M. Dwead, Marwah M. Al-Mathkour, Bekir Cinar. Androgen hormone signaling regulates the association between the hippo pathway component YAP1 and RNA binding protein NPM1 [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 4386.