tbuckley/cabot-search huggingface dataset:
Abstract LB207: C5ar1 is a novel biomarker and potential therapeutic target in advanced cutaneous squamous cell carcinoma
Authors: Lauri Heiskanen, Liisa Nissinen, Elina Siljamäki, Jaakko Knuutila, Teijo Pellinen, Markku Kallajoki, Jyrki Heino, Pilvi Riihilä, Veli-Matti Kähäri
Journal: Cancer Research (2024)

Abstract Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer and the metastatic disease is associated with poor prognosis. At present, there are no established molecular markers to predict the metastasis risk and prognosis of patients with primary cSCC. Recently, the role of specific complement components in the progression of cSCC has been shown. Here, we have examined the role of complement C5a receptor C5aR1 in the progression and metastasis of cSCC. The results show that the expression of C5aR1 is increased in cSCC cells in 3D spheroid coculture model in the presence of fibroblasts and that treatment with recombinant C5a increases invasion of cSCC cells in this model. Staining for C5aR1 was detected on the surface of tumor cells in the invasive edge of human cSCC xenograft tumors in vivo. Staining of metastatic and non-metastatic primary human cSCCs, premalignant epidermal lesions and normal skin for C5aR1 with multiplexed fluorescence and chromogenic immunohistochemistry revealed stronger expression of C5aR1 on surface of cSCC tumor cells compared to epidermal cells in cSCC in situ, actinic keratosis and normal skin. Increased expression of C5aR1 on tumor cell surface was associated with the metastasis risk of primary cSCCs and independently predicted poor disease-specific survival of patients with primary cSCC. These results reveal the role of C5aR1 in cSCC progression and identify C5aR1 as a novel biomarker for metastasis risk and poor prognosis of patients with cSCC. The results also suggest C5aR1 as a novel therapeutic target for treatment of locally advanced and metastatic cSCC. Citation Format: Lauri Heiskanen, Liisa Nissinen, Elina Siljamäki, Jaakko Knuutila, Teijo Pellinen, Markku Kallajoki, Jyrki Heino, Pilvi Riihilä, Veli-Matti Kähäri. C5ar1 is a novel biomarker and potential therapeutic target in advanced cutaneous squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB207.
Abstract SY41-01: Selection of targeted neoantigens for personalized cancer vaccines
Authors: Derin Keskin
Journal: Cancer Research (2024)

Abstract Neoantigen targeting personalized cancer vaccines (PCV) have the potential to revolutionize cancer treatment. These personalized vaccines rely on accurate epitope prediction and selection. We previously reported phase I trials of neoantigen targeting PCV in melanoma and glioblastoma multiforme (GBM). Recently we concluded a trial in renal cell carcinoma (RCC) where the neoantigen targeting PCV was immunogenic in all patients, targeted cancer drivers, and demonstrated in vitro reactivity to primary patient tumors. The neoantigen selection pipeline at DFCI supporting clinical trials utilizes immunopeptidome-trained epitope prediction algorithms to design synthetic long peptides as vaccine antigens containing predicted HLA Class I neoantigens. We also prioritize highly expressed neoantigens and neoantigens originating from cancer drivers as vaccine epitopes. For future iterations of this pipeline, we aspire to include novel classes of neoantigens originating from endogenous human retroviruses (ERV), fusion epitopes, novel or unannotated open reading frames (nuORFs), and immunopeptidome-identified neoantigens. The neoantigen selection pipeline is currently supporting multiple cancer vaccine trials at DFCI targeting melanoma, GBM, RCC, ovarian cancer, and chronic lymphocytic leukemia (CLL). Citation Format: Derin Keskin. Selection of targeted neoantigens for personalized cancer vaccines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr SY41-01.
Abstract LB189: Elucidating a mechanistic link between progranulin and lysosomal function in SW13 cells: Implications for inflammation and lipid metabolism
Authors: Kathryn J. Leyva, Andrew Z. Yang, Pegah Biparva, Chika Okonya, Chandana K. Uppalapati, Alisha M. Harrison, Agnes S. Pascual, Elizabeth E. Hull
Journal: Cancer Research (2024)

Abstract The SW13 human adrenocortical carcinoma line is a uniquely powerful model in which to probe the relationship between progranulin processing and cellular activity as it exists in two epigenetically distinct subtypes. The SW13- subtype has an epithelial morphology and is highly proliferative, while the SW13+ subtype has a mesenchymal-like phenotype and a higher metastatic potential. These two subtypes both express progranulin and interconvert by epigenetic mechanisms, as treatment of SW13- cells with histone deacetylase inhibitors (HDACi) adopt a SW13+ phenotype. Progranulin is composed of 7½ highly conserved granulin repeats which are subject to proteolytic processing and may serve as a prognostic biomarker in cancer as progranulin units regulate varied cellular activities including proliferation, migration, inflammation, and lysosomal function. Thus, biological activity of progranulin is dependent on the cellular proteases expressed. Indicative of differential processing, treatment of SW13- cells with exogenous progranulin results in an increase in growth rate, while no effect on SW13+ cell growth was observed. As the SW13+ subtype expresses a higher amount of progranulin than the SW13- subtype, these data are consistent with an inability of SW13+ to process endogenous progranulin to mitogenic granulin unit(s). Immunoblotting with granulin-specific antibodies indicates that progranulin may be processed differently in each subtype. In this work, we focused on lysosomes as a potential site for differential processing of progranulin for two reasons. First, lysosomal proteases have been shown to process progranulin and progranulin itself plays a role in lysosome maturation. Second, differences in lysosomal pH between the two subtypes have been detected using two pH-sensitive dyes which localize to the lysosome. Interestingly, proteomic analysis of lysosomes isolated from each subtype confirms lysosomal dysfunction and suggests upregulation of inflammatory proteins in SW13+ cells. Both proteomics and lipidomics suggest alterations in lipid metabolism. Ongoing experiments will address whether restoration of lysosomal function impacts progranulin production and/or processing in SW13 subtypes. Citation Format: Kathryn J. Leyva, Andrew Z. Yang, Pegah Biparva, Chika Okonya, Chandana K. Uppalapati, Alisha M. Harrison, Agnes S. Pascual, Elizabeth E. Hull. Elucidating a mechanistic link between progranulin and lysosomal function in SW13 cells: Implications for inflammation and lipid metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB189.
Abstract SY41-02: Experimental methods for high throughput discovery and validation of tumor antigens
Authors: James R. Heath
Journal: Cancer Research (2024)

Abstract The discovery and validation of tumor associated T-cell antigens, which can include neoantigens, viral antigens, cancer testis antigens, and others, is fundamental to the design of both cancer vaccines and engineered cell cancer immunotherapies. However, identifying tumor specific antigens that are highly presented within tumors, and identifying and validating T cell receptors (TCRs) that are specific to those antigens, remains a non-trivial exercise. Even identifying and validating a single antigen-specific T cell clonotype for advancement into a clinic trial remains a daunting task. In this talk, I will discuss a number of new experimental and computational tools that are designed to accelerate this process. The experimental toolsets include reagents and strategies that allow for the capture and analysis of T cells specific to hundreds to thousands of tumor-associated Class I and Class II antigens simultaneously, with as many as 100 patient bloods analyzed in a single experiment. Single cell analysis of the resulting data yields a deep characterization of the captured T cells, including T cell receptor α/β genes, antigen-MHC specificity, T cell phenotype, and donor identification. This type of analysis, in turn, provides large data bases that can fuel new computational strategies that can be harnessed (at a still early stage) to predict which TCRα/β genes associate with which putative antigen-MHCs, or to extract the biochemical and biophysical characteristics of TCR-antigen pairings that influence T cell phenotype. Thus, this presentation will span both new experimental and new computational toolsets. Citation Format: James R. Heath. Experimental methods for high throughput discovery and validation of tumor antigens [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr SY41-02.
Abstract LB209: YBX1 is a negative regulator of post-transcriptional program associated to EMT, invasion and metastasis in cSCC
Authors: Stefano Sol, Fabiana Boncimino, Kristina Todorova, Anna Mandinova
Journal: Cancer Research (2024)

Abstract Y-box binding protein 1 (YB-1), which is encoded by YBX1 gene, is a multifunctional cold-shock protein that binds both DNA and RNA to orchestrate transcription as well as RNA processing and translation. Recently, we demonstrated that YBX1 is a post-transcriptional effector required for the maintenance of epidermal homeostasis. Although it was well known that YBX1 plays prominent pro-oncogenic roles in malignant transformation and cell invasion in a wide variety of cancers, the role of YBX1 in cutaneous squamous cell carcinoma (cSCC) is poorly understood. Here, we report that YBX1 protein level is higher in cSCC tumor compared with non-neoplastic skin, but it goes down in metastatic states. According to this finding, YBX1-KD cSCC primary cell lines show an increase of cell migration and invasion in vitro assay and in a context that mimics the natural three-dimensional environment of tumor with organotypic skin equivalent cultures. Furthermore, we found that YBX1-KD promotes an epithelial-to-mesenchymal transition and leads to the detection of more metastases in vivo after tail vein injection of YBX1-KD cSCC cells when compared with the injection of control cells. YBX1 is predominantly found in the cytoplasm of SCC cells. Therefore, we focused on the role of YBX1 as a post-transcriptional regulatorand performed an eCLIP-seq (crosslinking immunoprecipitation sequencing) to identify its direct RNA targets. We found that YBX1 binds novel pro-invasive RNA regulons associated to cell-cell and cell-matrix adhesions. Through the interpolation of the analysis of RNA-seq and SILAC, we found that YBX1 KD up-modulates at post-transcriptional level several targets, involved into invasion and metastasis. Our study reveals that, in human cutaneous squamous cell carcinoma, loss of function of YBX1 promotes migration, invasiveness and metastasis, through the induction of an epithelial-to-mesenchymal transition regulated at post-transcriptional level. Citation Format: Stefano Sol, Fabiana Boncimino, Kristina Todorova, Anna Mandinova. YBX1 is a negative regulator of post-transcriptional program associated to EMT, invasion and metastasis in cSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB209.
Abstract SY39-03: Illuminating the tumor immune GPCRome: Novel immunotherapy targets
Authors: J. Silvio Gutkind
Journal: Cancer Research (2024)

Abstract Immune checkpoint blockade (ICB) targeting PD-1 and CTLA-4 has revolutionized cancer treatment. However, many cancers do not respond to ICB, prompting the search for additional strategies to achieve durable cancer remission. In this regard, G-protein-coupled receptors (GPCRs) represent the largest family of cell surface receptors involved in signal transduction and are the target of &amp;gt;30% of all approved drugs. GPCRs are the most pharmacologically favorable targets due to their druggability and direct relevance to many key physiological processes and a myriad of human diseases. However, GPCRs have been largely underexploited in oncology, and specifically understudied in cancer immunotherapy. GPCRs are primarily coupled to 4 distinct families of G proteins α subunit (Gαi, Gαs, Gαq, and Gα12), which dictate the signaling events controlled by each GPCR. Recently, we cross-integrated large single-cell RNA-sequencing datasets from CD8+ T cells covering 19 distinct cancer types and identified an enrichment of Gαs-coupled GPCRs on exhausted CD8+ T cells. These include GPCRs activated by inflammatory mediators, protons, neurotransmitters, and metabolites that accumulate in the tumor microenvironment, thereby promoting T cell dysfunction. We also developed transgenic mice expressing a chemogenetic CD8-restricted Gαs-GPCR and showed that a Gαs-PKA signaling axis promotes CD8+ T cell exhaustion and immunotherapy failure. These studies revealed that tumor cells may avoid immune elimination by stimulating Gαs-GPCRs on infiltrating CD8 T cells, thereby exposing novel druggable immune checkpoints that can be exploited therapeutically. We have recently extended these studies and mapped the expression patterns of all human GPCRs in nearly a million-tumor infiltrating immune cells. The emerging tumor-immune GPCR atlas may provide a valuable resource to explore the role of GPCRs in cancer immunology. Ultimately, our study may reveal new and exciting GPCR therapeutic targets to enhance the response to ICB, and help identify potential co-medications that may limit the success of ICB therapies. Citation Format: J. Silvio Gutkind. Illuminating the tumor immune GPCRome: Novel immunotherapy targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr SY39-03.
Covalent Coupling Assisted Hydrophilic Perovskite Spheres for Ratiometric Fluorescent Visual Multichannel Immunoassay (Adv. Healthcare Mater. 9/2024)
Authors: Yaqin Han, Jia An, Mengdi Yuan, Junan Fang, Jiajing Zhang, Lanju Liang, Yufei Liu
Journal: Advanced Healthcare Materials (2024)
Abstract LB203: CRISPR anchor screens to identify co-vulnerabilities and drug combinations in DepMap
Authors: Jenny Serra-Vinardell, Zoe Posner, Alison Cameron, Yuqi Chen, Negin Karisani, Barbara De Kegel, Joshua M. Dempster, Andrew J. Aguirre, Francisca Vazquez
Journal: Cancer Research (2024)

Abstract The Cancer Dependency Map (DepMap) aims to systematically map the landscape of cancer vulnerabilities by profiling a wide range of cancer cell lines that collectively represent the heterogeneity of human cancer. An increasing number of targets and biomarkers emerging from this effort are in drug development or clinical trials. However, it is clear that drug resistance is a significant challenge and that drug combinations will be required. CRISPR anchor screens involve introducing an "anchor" which can be either a drug or genetic perturbation, alongside the sgRNA library. This approach provides a way to investigate resistance mechanisms, potential drug combinations, or co-vulnerabilities. As a proof of concept, here we describe CRISPR anchor screens with MRTX1133 as the anchor, which is a potent and selective KRASG12D inhibitor currently in clinical trials. We performed genome-scale loss-of-function CRISPR-Cas12a screens in the presence of MRTX1133 in pancreatic and lung cancer cell lines that harbor the KRASG12D. The goal of these screens was to identify cancer dependencies that are either present or enhanced in the presence of MRTX1133. We find multiple such MRTX1133-induced dependencies that are either common across all cell lines screened or unique to one or a few. This shows that the response to MRTX1133 can vary depending on the context, highlighting the importance of finding biomarkers to predict the response. Identifying the biomarkers of these context-specific dependencies would provide strategies to select patient populations that would respond to the drug combinations. This study not only provides valuable insights into enhancing the efficacy of KRAS-targeted therapies but also serves as a pioneering effort in incorporating innovative CRISPR screen modalities into the DepMap. Citation Format: Jenny Serra-Vinardell, Zoe Posner, Alison Cameron, Yuqi Chen, Negin Karisani, Barbara De Kegel, Joshua M. Dempster, Andrew J. Aguirre, Francisca Vazquez. CRISPR anchor screens to identify co-vulnerabilities and drug combinations in DepMap [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB203.
Abstract LB308: Transcriptional profiling uncovers a unified program underlying the human metastatic and adjacent microenvironments
Authors: Etan R. Aber, Cristina F. Contreras, Mohd Omar Sikder, Kathy P. Li, Greta E. Forbes, Vishaka Gopalan, Sridhar Hannenhalli, Rosandra N. Kaplan
Journal: Cancer Research (2024)

Abstract Metastasis is the primary cause of death in patients with solid tumors, yet the treatment-refractory metastatic microenvironment is poorly characterized. To gain a comprehensive understanding of microenvironmental regulation of human metastasis, we performed single-cell RNA sequencing covering endothelial, stromal, myeloid, lymphoid, and malignant cells from 28 lung and liver samples of the metastatic microenvironment and metastasis-free adjacent microenvironment from patients with metastatic adrenocortical carcinoma compared to healthy donors for a total of 275,903 cells. We discovered that the adjacent microenvironment in patients with metastatic cancer is significantly different from healthy tissue without cancer: The adjacent microenvironment has many immunosuppressive and pro-tumorigenic features similar to primary tumor and metastatic tissue. As adjacent tissues are potential sites for subsequent metastasis, the shared changes between the adjacent and metastatic microenvironments suggest that these elements of the treatment-refractory metastatic microenvironment may dictate metastasis. Importantly, these pathologic features of the adjacent and metastatic microenvironments associate with poor outcomes for patients and may be targetable. Lastly, we identify a mechanism by which tumor cells may be remotely driving and coordinating these changes in both the metastatic and adjacent microenvironments. Taken together, our study identifies shared and microenvironment-specific changes underlying a global program of metastasis. Citation Format: Etan R. Aber, Cristina F. Contreras, Mohd Omar Sikder, Kathy P. Li, Greta E. Forbes, Vishaka Gopalan, Sridhar Hannenhalli, Rosandra N. Kaplan. Transcriptional profiling uncovers a unified program underlying the human metastatic and adjacent microenvironments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB308.
Abstract LB169: Using a global reporter on transcript abundance to identify a selective inhibitor of Nrf2 signaling in KEAP1-mutant non small cell lung cancer
Authors: Timothy J. Read, Leah Damon, Reo Yoo, Carter Grochala, Cole Liechty, Christy Rhine, Jenna Rimel, David Simpson, Riley Lundblad, Casey Pham, Richard Steel, Joey Azofeifa
Journal: Cancer Research (2024)

Abstract Loss-of-function mutations in Kelch-like ECH-associated protein 1 (KEAP1) are common in non-small cell lung cancer (NSLC) and result in particularly poor prognosis. Such mutations activate the transcription factor Nrf2, leading to aberrant expression of chemoprotective genes and rendering cells resistant to chemotherapy. We used our chemo-transcriptomic platform, termed GRETA, for Global Reporter on Transcript Abundance, to identify compounds that inhibit Nrf2 transcription factor activity in KEAP1-mutant NSCLC cell lines. After defining the transcriptomic signature imparted by constitutive activation of Nrf2 in a KEAP1 KO NCI-H1975 cell line, we generated over 10,000 transcriptomes to identify compounds that dampen the Nrf2-overactive transcriptional signature. One such compound, ARP-4316, displays selectivity for KEAP1-mutant cell lines, reduces nuclear Nrf2 protein levels, and reduces Nrf2 transcriptional activity in an ARE reporter assay. Furthermore, ARP-4316 synergizes with 5-fluorouracil in two KEAP1-mutant cell models, A549 and NCI-H2122, suggesting that ARP-4316 may sensitize KEAP1 mutant cell lines to chemotherapy by inhibiting Nrf2 transcriptional activity. Efforts to identify the cellular target and mechanism of action of ARP-4316 are underway. Citation Format: Timothy J. Read, Leah Damon, Reo Yoo, Carter Grochala, Cole Liechty, Christy Rhine, Jenna Rimel, David Simpson, Riley Lundblad, Casey Pham, Richard Steel, Joey Azofeifa. Using a global reporter on transcript abundance to identify a selective inhibitor of Nrf2 signaling in KEAP1-mutant non small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB169.