tbuckley/cabot-search huggingface dataset:
Abstract B021: Aneuploidy-associated cohesin RAD21 gains promote immune evasion in prostate cancers
Authors: Elise G. DeArment, Ruoxi W. Wang, Kate Lu, Xiaofeng A. Su, Andrew Elliott, Nicholas A. Zorko, Justin H. Hwang, Xiaofeng A. Su
Journal: Cancer Research (2024)

Abstract Aneuploidy, characterized by imbalanced chromosome numbers, is a hallmark of cancer and is strongly correlated with lethal progression in prostate cancer. Our recent work identified that gains of chromosome 8q, the most frequently gained chromosome in aneuploidy prostate cancers, drive cancer progression, partially through the cohesin RAD21 gene located on the chr8q24 region. We demonstrated that increased RAD21 expression accelerates lethal progression and oncogenesis in both prostate cancer and Ewing sarcoma by alleviating oncogenic stress during early-stage oncogenesis in both cell line and organoid models. Therefore, we hypothesize that elevated RAD21 levels could enable cancer cells to evade immune surveillance by mitigating oncogenic stress and DNA damage. In this study, we developed isogenic prostate and breast cancer cell culture models with varying levels of RAD21. Using a natural killer (NK) cell co-culture assay, we observed that cells with elevated RAD21 expression were significantly less susceptible to NK-mediated cytotoxicity and exhibited increased survivorship when co-cultured with NK cells. These findings align with publicly available data showing that tumors with high RAD21 levels have reduced NK cell infiltration in prostate cancer. Our results suggest that increased RAD21 expression, commonly associated with chr8q gains, facilitates immune evasion in cancer cells, thereby promoting early-stage oncogenesis. Understanding the role of RAD21 in immune evasion could reveal novel therapeutic strategies targeting immune surveillance mechanisms in prostate cancer. Citation Format: Elise G. DeArment, Ruoxi W. Wang, Kate Lu, Xiaofeng A. Su, Andrew Elliott, Nicholas A. Zorko, Justin H. Hwang, Xiaofeng A. Su. Aneuploidy-associated cohesin RAD21 gains promote immune evasion in prostate cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B021.
Abstract A036: DDR2 in ovarian tumor CAFs controls ferroptosis and response to Olaparib
Authors: Julien Lesage, Alessandra DiMauro, Katherine C. Fuh, Gregory D. Longmore
Journal: Cancer Research (2024)

Abstract In ovarian cancer, resistance to conventional cancer treatments has stimulated finding alternative targets that induce tumor cell death. Ferroptosis, a lipid peroxide-triggered form of iron-dependent cell death, is one such pathway. Current research has focused primarily on tumor cell-intrinsic mechanisms or how tumor associated immune cells might impact tumor cell ferroptosis. Cancer-associated fibroblasts (CAFs) are other key stromal cells in the tumor microenvironment and play critical roles in cancer progression, metastasis, and chemotherapeutic response. In ovarian cancer, the collagen receptor tyrosine kinase DDR2 is predominantly expressed by tumor stromal CAFs, not immune cell, and high tumor stromal cell expression of DDR2 in ovarian tumors is associated with poor survival and resistance to therapy. Thus, we asked whether DDR2 could impact ferroptosis regulation in CAFs, and if so, how this effect of DDR2 could impact ovarian tumor cell responses to cytocidal therapies. Through various genetic means, we generated multiple DDR2-expressing and DDR2-deficient human ovarian tumor and mouse breast tumor CAFs. We evaluated the response of the various CAFs to ferroptosis inducers (Erastin and RSL3) and inhibitors (Ferrostatin-1 and Deferoxamine). We find that the presence of DDR2 in CAFs protects these cells from induced ferroptosis through regulation of the xCT- GSH-GPX4 antioxidant pathway and cellular iron metabolism. DDR2-dependent regulation of xCT-GSH-GPX4 occurs through non-canonical activation of NRF2 via the Sequestosome-1 (SQSTM1/p62) protein. In iron metabolism, DDR2 affects the labile iron pool (LIP) by regulating ferritinophagy. The actions of DDR2 in CAFs protects these cells against Olaparib therapy, by inhibiting Olaparib-induced ferroptosis. Ovarian tumor CAF culture supernatant was found to protect ovarian tumor cell response to Erastin-induced ferroptosis, in a DDR2- dependent manner. Overall, this study uncovered a novel function of the action of DDR2 in tumor stromal CAFs in controlling iron and the xCT-GSH-GPX4 ferroptosis regulatory axis through non-canonical p62-KEAP1-NRF2 activation. These findings suggest that CAFs, through DDR2-mediated regulation of ferroptosis, could play a role in therapeutic sensitivity/resistance in ovarian cancer. Citation Format: Julien Lesage, Alessandra DiMauro, Katherine C. Fuh, Gregory D. Longmore. DDR2 in ovarian tumor CAFs controls ferroptosis and response to Olaparib [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A036.
Abstract A042: Desmosome mutations in the microenvironment regulate melanoma proliferation
Authors: Mohita Tagore
Journal: Cancer Research (2024)

Abstract Desmosomes are transmembrane protein complexes critical for cell-cell adhesion in epithelial tissues and other cell types. In skin cancers like melanoma, epithelial cells called keratinocytes are the predominant cells in the primary melanoma microenvironment, yet it remains largely unknown whether this cell type is subject to genetic alterations during melanoma development and its role in early melanoma progression. In this study, using an integrative analysis of tumor mutations and protein biophysical interactions, we identify a high frequency of genetic alterations in desmosome-related genes in human cancers, with the highest occurrences in cutaneous melanoma. Notably, over 70% of cutaneous melanoma cases exhibit mutations in desmosome genes and desmosome gene mutations are associated with lowered expression of the desmosome complex in melanoma. Using spatial transcriptomics and immunohistochemistry analyses, we find that the decrease in desmosome gene expression predominantly occurs in keratinocytes within the tumor microenvironment rather than in the melanoma cells themselves. To study the functional significance of this alteration in melanoma development, we used a human melanoma/keratinocyte co-culture system using primary melanoma cell lines. Our studies show that knockdown of desmosome genes in keratinocytes markedly increased proliferation of adjacent melanoma cells in melanoma/keratinocyte co-cultures. Additionally, melanoma cell proliferation is enhanced when exposed to media preconditioned by desmosome-deficient keratinocytes. These observations suggest that the gradual accumulation of mutations in desmosome genes within neighboring keratinocytes may create a conducive environment that primes melanoma cells for neoplastic transformation. This study underscores the critical role of genetic alterations in the tumor microenvironment in melanoma progression and highlights the potential for targeting desmosome-related pathways in therapeutic strategies against melanoma. Citation Format: Mohita Tagore. Desmosome mutations in the microenvironment regulate melanoma proliferation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A042.
Abstract B011: Sensory neurons regulate intracellular and intercellular mitochondrial dynamics in breast cancer cells
Authors: Ankit Tiwari, Yue Wu, Jeremy C. Borniger
Journal: Cancer Research (2024)

Abstract Crosstalk between cancer and the nervous system regulates tumor progression. These interactions occur at both the local (i.e., within the tumor parenchyma) and systemic (e.g., endocrine signaling) levels. More recent work has determined that cancer cells not only interact with their local environment via secreted molecules, but in some cases, via acquiring proteins or organelles from other cells within the tumor microenvironment (TME). Here, we demonstrate that breast cancer cells acquire mitochondria from neurons. Breast cancer cells with higher metastatic potential acquire more mitochondria in NGF dependent manner compared to the cell line with lower metastatic potential. These results suggest that in addition to their known roles in electrochemical and paracrine signaling, tumor-innervating nerves can also enhance cancer cell fitness via transfer of mitochondria. We are now characterizing the mechanisms underlying this transfer, determining the fate of transferred mitochondria in recipient cells, and defining how transferred mitochondria drive cancer development, progression, and metastasis. Further, sensory neurons at the tumor microenvironment dictate the intracellular mitochondria dynamics affecting morphology and function. The change in mitochondria dynamics enhances cancer cell survival and metastasis, we are uncovering how sensory neuron induced mitochondria dynamics drives tumor progression. Citation Format: Ankit Tiwari, Yue Wu, Jeremy C. Borniger. Sensory neurons regulate intracellular and intercellular mitochondrial dynamics in breast cancer cells [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B011.
Abstract B024: Deciphering the neurogenic tumor microenvironment: A novel gene network driving innervation in metastatic melanoma offers prognostic and therapeutic insights
Authors: Anjana Goli, Subhajit Dutta
Journal: Cancer Research (2024)

Abstract Melanoma, a highly aggressive and life-threatening cancer, poses a significant therapeutic challenge, particularly for patients with distant metastasis, who face a 5-year survival rate of only approximately 22.5%. This underscores the urgent need for innovative therapeutic approaches. Emerging evidence suggests that sensory and parasympathetic innervation within the tumor microenvironment (TME) plays a crucial role in driving metastasis and immune evasion, partly through the promotion of M2 macrophages and cancer stem cells. To uncover the mechanisms behind tumor-specific innervation in metastatic melanoma, we employed a systems biology approach integrating bulk RNAseq from diverse melanoma cell lines, TCGA-SKCM data analysis, single-cell RNAseq, and spatial transcriptomics. This comprehensive analysis led us to identify a previously uncharacterized gene regulatory network (GRN) orchestrating tumor innervation. This GRN is driven by axon guidance cues (Netrin, Slit, Semaphorin), their receptors (DCC, Robo, Neuropilin, ITGB1), and transcription factors (RAS, RND1, TFAP2, CAMKII). We further discovered that the pioneer factor FOXC2, known for its association with metastasis, plays a critical role in opening the promoters of innervation-specific genes. Additionally, we identified Ephrin and CXCR4-mediated crosstalk between neurons and tumor cells. Machine learning models validated the accuracy of this GRN in predicting melanoma metastasis, and a neural network-based model confirmed the enrichment of nerve cells near metastatic tumor cells within the TME in TCGA immunohistochemistry data. The functional relevance of this network was further supported by CRISPR-mediated knockout studies, which disrupted tumor-specific signaling pathways. Notably, we also observed the enrichment of genes linked to mRNA processing bodies and neuron-specific membrane-less condensates in metastatic melanoma. These findings highlight the critical role of neuronal infiltration in melanoma metastasis. Currently, therapeutic strategies targeting this aspect of the TME remain limited. Our identified gene set offers potential as a metastatic predictor, and targeting the neural component of the TME represents a promising new therapeutic avenue for melanoma. Citation Format: Anjana Goli, Subhajit Dutta. Deciphering the neurogenic tumor microenvironment: A novel gene network driving innervation in metastatic melanoma offers prognostic and therapeutic insights [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B024.
Abstract B004: Identification of distinct subpopulations of cancer associated fibroblasts in oral squamous cell carcinoma by imaging mass cytometry
Authors: Stian Tornaas, Siren Fromreide, Dimitrios Kleftogiannis, Hans Jørgen Aarstad, Olav K. Vintermyr, Lars Akslen, Harsh Dongre, Daniela Elena Costea
Journal: Cancer Research (2024)

Abstract Background: Although cancer associated fibroblast (CAF) heterogeneity is recognized in oral squamous cell carcinoma (OSCC), the phenotype and role of CAF subpopulations in OSCC is still unknown. Objectives: This study aimed to dissect CAF heterogeneity and spatial location by using imaging mass cytometry on formalin fixed paraffin embedded (FFPE) tissues from primary OSCC. Methods: Imaging mass cytometry (Hyperion technology) was used to identify 24 markers (E-cadherin, EGFR, Ki-67, α-SMA, CD140β, FAP, FSP-1/S100A4, CD90/Thy-1, integrin α-11, collagen-1, tenascin-C, caveolin-1, CD4, CD8a, CD16, CD20, CD68, CD163, FoxP3, granzyme B, CD31, podoplanin, CD146, and YAP-1) in HPV-negative OSCC lesions (n=10). Tissue images were segmented employing the Steinbock framework. Unsupervised clustering of single-cell data was carried out using a bioinformatics pipeline developed in R language. Results: Unsupervised clustering identified several major cell types, with E-cadherin+ cells being the most abundant (30%) and CD146+ being the least abundant cell type (0.62%). Within the immune compartment CD4+ cells were most abundant (11.72%) followed by CD8+ cells (10.6%) and CD68+ cells (10.25%). Cells negative for other major lineage markers and positive for stromal markers were considered as CAFs and they clustered in 6 clusters defined as CAF1 to CAF6. CAF1-3 were high in FAP and CD140β while CAF 4-6 were low expressing FAP and CD140β. CAF1 and 6 expressed high αSMA, while CAF 3 and 5 expressed high collagen-1. CAF6 had high expression of integrin α-11. CAF1 and 3 subtypes were found closer to immune cells whereas CAF2 and 6 were closely located to cancer cells. Conclusions: We identified six distinct subpopulations of CAFs in OSCC by using imaging mass cytometry. Their clinical implications can be further revealed by using this method on larger patient cohorts with FFPE tissues available in diagnostic biobanks. Citation Format: Stian Tornaas, Siren Fromreide, Dimitrios Kleftogiannis, Hans Jørgen Aarstad, Olav K. Vintermyr, Lars Akslen, Harsh Dongre, Daniela Elena Costea. Identification of distinct subpopulations of cancer associated fibroblasts in oral squamous cell carcinoma by imaging mass cytometry [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B004.
Abstract B028: The Role of cDC1 Gene Signatures in gastric cancer prognosis and immune microenvironment modulation
Authors: Song-hee han
Journal: Cancer Research (2024)

Abstract Background and Aim: Gastric cancer (GC) continues to be a major global health burden, with a growing body of evidence highlighting the critical role of conventional type 1 dendritic cells (cDC1s) within the tumor microenvironment. This study aims to elucidate the prognostic significance of cDC1-associated genes—CD141, XCR1, CLEC9A, CADM1, and BTLA—in gastric cancer, as well as to explore the biological mechanisms that underpin their effects on patient outcomes. Materials and Methods: We conducted a comprehensive analysis of RNA- seq data from The Cancer Genome Atlas (TCGA-STAD) and Gene Expression Omnibus (GEO) datasets, focusing on the expression profiles of five cDC1-related genes. Patients were stratified into high and low expression groups based on a defined cDC1 gene signature. To assess the impact of these signatures, we utilized gene set variation analysis (GSVA) to examine relevant oncogenic pathways and performed Kaplan-Meier survival analysis along with Cox proportional hazards modeling to evaluate their prognostic value. Results: Our findings demonstrate that patients exhibiting a high cDC1-related gene signature had significantly worse overall and disease-free survival within the TCGA-STAD cohort. Further analysis revealed marked differences in CD8+ T cell infiltration and cytotoxic activity between the high and low cDC1 signature groups. Additionally, the high cDC1 signature group was strongly associated with upregulated expression of immune checkpoint proteins and the activation of oncogenic pathways, indicating a highly immunosuppressive tumor microenvironment. Conclusions: This study suggests that the cDC1-related gene signature may serve as a potent prognostic biomarker in gastric cancer, offering new insights into the complex interactions between the tumor and immune microenvironment. These results could pave the way for innovative therapeutic strategies that target the immune landscape in gastric cancer, potentially improving patient outcomes. Citation Format: Song-hee han. The Role of cDC1 Gene Signatures in gastric cancer prognosis and immune microenvironment modulation [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B028.
Abstract C005: Tumor vaccines and oncolytic virotherapy: systemic immunity vs. tumor microenvironment
Authors: William Jia
Journal: Cancer Research (2024)

Abstract Tumor vaccines, particularly the innovative mRNA variants, hold immense promise in cancer immunotherapy. Despite their potential, these vaccines encounter formidable challenges in surmounting immune tolerance, the immune-suppressive tumor microenvironment (TME) and more importantly, the resistance developed in cancer cells that are antigen negative. Concurrently, oncolytic virotherapy (OV), a distinct facet of tumor vaccination, significantly alters the TME and releases tumor antigens via lysis to generate a broader spectrum of tumor antigens. This unique property positions OV to induce anti-tumor immunity, as evidenced by prolonged overall survival and abscopal tumor suppression. Recognizing the complementary strengths of mRNA tumor vaccines and OV, we propose a combined approach to address the limitations inherent in each modality. Our study tested this hypothesis by combining a mRNA vaccine targeting HER2 with oncolytic viruses, utilizing a prime-boost strategy on a HER2-expressing CT26 mouse tumor model. Notably, while the mRNA vaccine alone induced specific anti-HER2 systemic immunity, the combination demonstrated a potent immune response against both anti-HER2 and anti-CT26, leading to durable tumor eradication. Our findings highlight that peripheral vaccination has the potential to elicit an immune response in non-immune suppressive environments. However, combining it with virotherapy not only amplifies specific immunity but also induces a broader immune response against a spectrum of tumor antigens. This synergistic combination represents a promising avenue for advancing cancer immunotherapy, offering the potential for improved treatment outcomes and broader applicability of tumor vaccines across diverse cancer types. Citation Format: William Jia. Tumor vaccines and oncolytic virotherapy: systemic immunity vs. tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C005.
Abstract B047: Understanding the role of cancer-associated adipocytes in breast tumor microenvironment to delineate the relationship between obesity and cancer
Authors: Yaechan Song, Hee Ju Na, Han Woong Lee
Journal: Cancer Research (2024)

Abstract Obesity has emerged as a prominent risk factor for the development of malignant tumors. However, the existing literature on the role of adipocytes in the tumor microenvironment (TME) to elucidate the correlation between obesity and cancer remains insufficient. Here, we aim to investigate the formation of cancer-associated adipocytes (CAAs) and their contribution to tumor growth using mouse models harboring dysfunctional adipocytes. Our results reveal that the activation of YAP/TAZ signaling in CAAs induces adipocyte dedifferentiation and the formation of a malignant TME. The additional deletion of YAP/TAZ significantly led to tumor regression by mitigating adipokine secretion such as Lipocalin2 and TNFα. Furthermore, mice fed a high- fat diet exhibit increased YAP/TAZ expression in their adipose tissues. Treatment with the YAP/TAZ inhibitor, verteporfin, suppressed tumor progression, highlighting its efficacy against mice with metabolic dysregulation. These findings provide insights into the key mediators of CAA transformation and their significance in developing a TME. Our study extends to the impact of maladaptive adipocytes as a TME component. We gather multi-omics results including single-nucleus RNA sequencing and spatial transcriptomics (Xenium) to identify the CAA population in the peritumoral region. CAAs are found to modulate the TME via interacting with multiple immune cells, especially macrophages. Xenium result visualizes the proximity between CAAs and macrophages, indicating their cellular interaction. Additionally, our in-vitro co- culture system shows that CAAs recruit macrophages more effectively compared to normal adipocytes. Overall, we strive to understand the importance of adipocyte quality in forming a malignant TME and ultimately introduce therapeutic strategies targeting the tumor microenvironment, especially adipocytes. Citation Format: Yaechan Song, Hee Ju Na, Han Woong Lee. Understanding the role of cancer-associated adipocytes in breast tumor microenvironment to delineate the relationship between obesity and cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B047.