bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A042: Desmosome mutations in the microenvironment regulate melanoma proliferation
Authors: Tagore Mohita 
Published: November 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 B004: Identification of distinct subpopulations of cancer associated fibroblasts in oral squamous cell carcinoma by imaging mass cytometry
Authors: Tornaas Stian , Fromreide Siren , Kleftogiannis Dimitrios , Aarstad Hans Jørgen , Vintermyr Olav K. , Akslen Lars , Dongre Harsh , Costea Daniela Elena 
Published: November 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 B024: Deciphering the neurogenic tumor microenvironment: A novel gene network driving innervation in metastatic melanoma offers prognostic and therapeutic insights
Authors: Goli Anjana , Dutta Subhajit 
Published: November 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 B031: Lean adipocyte-derived lipid decreases metastatic potential of breast cancer cells
Authors: Jackson Abigail E. , Hilgendorf Keren I 
Published: November 2024

Abstract
Obesity rates are increasing globally, making it of critical importance to study obesity-linked diseases. Breast cancer is the most common cancer in women, and obesity is associated with both increased incidence and metastatic progression of breast cancer. Metastasis formation depends on a cancer cell leaving the primary site, migrating through the bloodstream, and establishing new growth in a distant site. Both metastasizing cell-intrinsic and metastatic site-dependent factors can help to regulate the effectiveness of this process; however, it is unknown whether obesity-linked metastasis depends on changes to the metastasizing cell and/or changes to the distant metastatic site. This study aims to characterize how the lean versus obese tumor microenvironment impacts breast cancer metastasis and identify adipocyte-derived molecules that modulate the metastatic potential of breast cancer cells. We and others have shown that obesity leads to increased metastasis formation in mouse models of orthotopic breast cancer. However, my preliminary data show that an obese metastatic site is not sufficient to increase metastasis formation in an intravenous injection model of metastasis, emphasizing the importance of the primary tumor microenvironment in programming breast cancer cells for metastasis. Cancer cell stemness helps to mediate metastasis formation and can be assessed in vitro with the mammosphere assay. Importantly, my data demonstrate that a secreted lipid from lean, but not obese, adipocytes potently inhibits the ability of breast cancer cells to form mammospheres. Furthermore, this inhibition induces a G1/S cell cycle arrest. Together, these data suggest that lean adipocytes in the breast cancer tumor microenvironment act in a paracrine manner to decrease the metastatic potential of breast cancer cells. My work demonstrates the role of adipocytes in the regulation of metastasis in breast cancer and provides important insight into the role of the tumor microenvironment in mediating metastasis in lean versus obese conditions.
Citation Format: Abigail E. Jackson, Keren I Hilgendorf. Lean adipocyte-derived lipid decreases metastatic potential of 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 B031.
Abstract B035: Reciprocal macrophage - T cell interactions regulate anti-tumor immunity
Authors: Sudhakaran Meenakshi , Lombardi Sofia , Ayma Sophie , Krummel Matthew F. , Kersten Kelly 
Published: November 2024

Abstract
Cancer immunotherapy (including immune checkpoint blockade (ICB)) has shown great promise in the treatment of some solid cancers, but responses in breast cancer patients are limited. While breast cancer is generally considered poorly immunogenic, the abundance of CD8+ T cells correlates with clinical response. CD8+ T cells are critical mediators of anti-tumor immunity and the main target for ICB. However, the onset of terminal functional T cell exhaustion poses a major challenge. Although T cell exhaustion has been linked to persistent antigen exposure, it remains unclear how the immune composition of the breast tumor microenvironment (TME) contributes to this dysfunctional T cell state. Breast cancers are heavily infiltrated with tumor-associated macrophages (TAMs) and their abundance correlates with T cell exhaustion and poor prognosis. Previously, we discovered a spatiotemporal co-dependency between exhausted T cells (TEX) and TAMs in mouse models of melanoma and breast cancer. We showed that TEX actively recruit monocytes to the TME and shape their differentiation trajectory into TAMs. Reciprocally, these TAMs ‘capture’ T cells in long-lived synaptic interactions that contribute to functional T cell exhaustion. Our current work is focused on studying the TEX-derived chemokines that regulate these TAM – T cell interactions in the breast TME with the ultimate goal to alleviate immune evasion and improve responsiveness of breast cancer to immunotherapy.
Citation Format: Meenakshi Sudhakaran, Sofia Lombardi, Sophie Ayma, Matthew F. Krummel, Kelly Kersten. Reciprocal macrophage - T cell interactions regulate anti-tumor immunity [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 B035.
Abstract B042: The impact of opioids on the pancreatic tumor immune microenvironment
Authors: Maraszek Kathryn , Feigin Michael 
Published: November 2024

Abstract
Pancreatic cancer is a highly lethal malignancy with a 5-year survival rate of 12.8%. Due to the high prevalence of cancer-related pain, 75% of pancreatic cancer patients are prescribed opioids. Opioids, which signal through the G protein-coupled receptor (GPCR) mu-opioid receptor (MOR), have peripheral effects outside of their analgesic function. Importantly, several studies have correlated opioids with worsened survival of patients receiving immunotherapy. However, the mechanism behind this is unknown. Immunotherapy is largely ineffective in pancreatic cancer, due in part to the tumor microenvironment (TME) characterized by dense, desmoplastic stroma, with cancer-associated fibroblasts (CAFs) comprising up to 90% of the tumor volume. CAFs play a large role in immunosuppression and therapy resistance, such as through promoting infiltration of immunosuppressive cells, resulting in reduced presence of antitumor immune cells and impaired immunotherapy efficacy. While the role of CAFs in promoting immunosuppression in the tumor microenvironment is well characterized, the effect of opioids on this phenomenon is unknown. We now provide evidence that MOR directly regulates CAF function. Specifically, knockdown of MOR in CAFs reduces gene expression of alpha-smooth muscle actin (aSMA) and leukemia inhibitory factor. MOR knockdown in CAFs also decreases protein expression of aSMA and type 1a collagen. We hypothesize that opioids promote MOR-dependent CAF activation and secretion of pro-inflammatory cytokines, resulting in a more immunosuppressive TME, and thus impaired immunotherapy response. The long-term goal of this work is to determine the role of opioids on CAFs in the pancreatic TME, as well as the role of MOR in promoting immunosuppression and the resulting value of MOR as a target to improve immunotherapy efficacy. This research is clinically significant because it could uncover a novel mechanism driving immunosuppression caused by a medication commonly prescribed to almost all pancreatic cancer patients.
Citation Format: Kathryn Maraszek, Michael Feigin. The impact of opioids on the pancreatic tumor immune 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 B042.
Abstract C031: Targeting colorectal cancer-associated fibroblasts with all-trans retinoic acid to reprogram the tumor microenvironment
Authors: Choi Brandon , Zhou Yuyuan , Kim Seungil , Mumenthaler Shannon M. 
Published: November 2024

Abstract
Cancer-associated fibroblasts (CAFs) are a prominent component of the tumor microenvironment (TME) and are known for their role in supporting tumor growth and progression through interactions with cancer cells and other stromal elements. Liver metastatic CAFs (lmCAFs), in particular, play an important role in establishing the secondary niche that facilitates tumor metastasis. Reprogramming the stroma, particularly targeting the pro-tumorigenic functions of lmCAFs, has emerged as a promising therapeutic intervention to disrupt the supportive environment tumors rely on for progression. An initial drug screen of FDA-approved oncology therapies was conducted on patient-derived colorectal cancer (CRC) CAFs and tumor organoids (PDTOs) to identify compounds that may be re-purposed as stroma targeting agents. All-trans retinoic acid (ATRA) was shown to specifically inhibit the proliferation of CAFs without affecting CRC-PDTOs. ATRA is an active metabolite of Vitamin A that exerts its canonical biological effects by binding to nuclear retinoic acid receptors (RAR). The differential RAR expression in multiple CAFs and PDTOs was confirmed with bulk RNA sequencing, with higher expression found in the CAF lines. Subsequent analysis included the qPCR assessment of glycolysis enzyme levels, CAF activation markers, and ATRA signaling in lmCAFs following treatment with ATRA for 5 days. Protein expression of key components of the TGF-b signaling pathway, including SMAD 2/3, Akt, and b-catenin, were also analyzed. Treatment of lmCAFs with ATRA induced expression of RARb and ALDH1A1, biomarkers associated with ATRA signaling pathways. In one patient-derived CAF line, ATRA treatment exhibited a decrease in CAF activation markers (e.g. aSMA) and glycolytic enzymes (e.g. lactate dehydrogenase). On the other hand, another CAF line showed increased fibroblast activation and a shift away from metabolic dependency on glycolysis upon ATRA treatment. Additionally, ATRA targeted TGF-b signaling through the pSMAD 2/3 and Akt pathways, highlighting the multifaceted impact on CAF function and heterogeneity. ATRA effectively reprograms some CAFs by inhibiting their proliferation and altering key signaling pathways, thereby disrupting the pro-tumorigenic environment of the TME. The results of this study suggest that ATRA holds potential as a therapeutic strategy to target and reprogram the CAFs within the permissive stromal components essential for tumor progression.
Citation Format: Brandon Choi, Yuyuan Zhou, Seungil Kim, Shannon M. Mumenthaler. Targeting colorectal cancer-associated fibroblasts with all-trans retinoic acid to reprogram the 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 C031.
Abstract C033: Identifying and targeting prostate cancer therapy resistance mechanisms driven by the tumor microenvironment
Authors: Heng Chu Tony Lok , Bankhead Armand , Coleman Ilsa , Frank Sander , Nelson Peter S. , Arman Tarana 
Published: November 2024

Abstract
Background: Prostate cancer is a prevalent malignancy in men, with treatment resistance posing a significant challenge to successful cure. Acquired Resistance to Therapy (ART) arises from two main components: (1) Tumor Microenvironment (TME) and (2) mutations or epigenetic changes at gene level within the tumor cells themselves. While most cancer therapies target the intrinsic biology of cancer cells, growing evidence indicates that these treatments can also harm the stromal cells within TME, potentially driving ART. The biology of ART may vary based on the types of treatments, cell types, and organ locations. Thus, this study aims to dissect ART components driven by TME-mediated cellular processes in a comprehensive manner. Hypothesis: We propose that cancer therapies induce stress responses in non-cancerous cells within the TME. These stress responses involve the secretion of cytokines, mediators, and growth factors, which we term Stress Response Secretory Programs (SRSPs). We further hypothesize that targeting SRSPs could overcome ART that helps to improve treatment specificity and efficacy. Materials and Methods: We employed comprehensive single-cell profiling of common metastatic sites included liver, prostate, lung, bone, lymph node and spleen in preclinical models to identify secreted proteins and dysregulated pathways caused by genotoxic therapies. In vitro, we evaluated treatment resistance in murine prostate epithelial cell lines (Myc-CAP) by exposing them to conditioned media (CM) from irradiated murine fibroblasts (F4M2), using cell growth assays. Results: Single-cell RNA sequencing of organ samples revealed significant expressions of SRSPs and increased inflammatory responses in liver and prostate fibroblasts as well as other stromal cells treated with carboplatin. In vitro, CM from irradiated F4M2 cells enhanced cell proliferation and survival of Myc-CAP cells in response to docetaxel treatment. Conclusion: Our findings highlight the crucial role of SRSPs in mediating ART through interactions within the TME, which alter tumor cell phenotypes. Targeting these SRSPs holds potential for overcoming treatment resistance and improving therapeutic outcomes, underscoring the need to consider TME complexity in cancer treatment strategies.
Citation Format: Tony Lok Heng Chu, Armand Bankhead, Ilsa Coleman, Sander Frank, Peter S. Nelson, Tarana Arman. Identifying and targeting prostate cancer therapy resistance mechanisms driven by the 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 C033.