bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5795: Leukemic stem cells confer ferroptosis resistance in aggressive blood cancer
Authors: Hassan Nunki , Yi Hangyu , Gaspard-Boulinc Lucie , Wang Jenny 
Published: April 2023

Abstract
Acute myeloid leukemia (AML) is an aggressive blood cancer with limited therapeutic options against leukemic stem cells (LSCs), resulting in poor clinical outcomes for decades. We have demonstrated the clinical importance of aberrant activation of RSPO3/β-catenin pathway in a subset of poor prognosis AML (Cancer Cell, 38:263-278, 2020) and its ability to sustain low levels of reactive oxygen species (ROS), a critical characteristic of human LSCs. This current study has extended our recent finding, and for the first time linked the pathway activation to ferroptosis resistance, a new drug resistance mechanism in cancer therapy. Our single-cell multiomics data in patient-derived xenograft mouse models of relapsed AML showed that the pathway activation in human LSCs led to upregulation of 43 differentially expressed genes associated with iron detoxification (e.g., FTH1) and ROS sensing/detoxification (e.g., PRDX1), two key features of ferroptosis resistance. Consistent with this observation, we found that AML patient specimens with favourable outcomes, which are independent of RSPO3 pathway, were sensitive to RSL3 treatment leading to increased cell death associated with elevated levels of intracellular ROS and iron. In contrast, AML patient specimens with poor clinical outcomes, which critically depend on RSPO3 pathway activation for survival and maintenance of myeloid undifferentiated state, revealed resistance to ferroptosis inducers (e.g., RSL3). Intriguingly, we found that anti-RSPO3 antibody, a clinical-grade drug that inhibits AML LSCs by blocking the interaction of RSPO3 with its receptor, sensitizes human LSCs to RSL3 treatment, leading to reduced cell viability. Overall, this study is the first to demonstrate the role of ferroptosis resistance in human LSCs and provides an opportunity to develop precision combination therapy by concurrently targeting self-renewal and ferroptosis resistance to improve therapeutic outcomes for patients with poor-risk AML.
Citation Format: Nunki Hassan, Hangyu Yi, Lucie Gaspard-Boulinc, Jenny Wang. Leukemic stem cells confer ferroptosis resistance in aggressive blood 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 5795.
Abstract 582: IDO1 inhibition sensitizes metastatic lung tumors to hypoxia/ER stress targeting agent-induced cell death
Authors: Shen Shih-Chun , Dey Souvik , DuHadaway James B. , Prendergast George C. , Muller Alexander J. 
Published: April 2023

Abstract
IDO1 (indoleamine 2,3-dioxygenase), a tryptophan catabolic enzyme, has been demonstrated in our previous studies to support neovascularization by counteracting IFNγ-mediated anti-angiogenesis through IDO1-induced IL6. Physiologically, we observed that the reduced neovascularization associated with IDO1 loss was accompanied by increased intra-tumoral hypoxia within lung metastases of 4T1 breast tumors while eliciting little tumor cell death, lessening the prospects for direct clinical benefit. Several agents have been developed to be selectively cytotoxic under hypoxic/nutrient-deprived conditions, suggesting the potential for therapeutic cooperativity. Inhibiting PERK, a UPR (unfolded protein response) activator, has been shown to promote tumor cell apoptosis under hypoxic conditions both in vitro and in vivo. In Ido1-/- 4T1 tumor-bearing mice, administration of the PERK inhibitor GSK2656157 elicited pronounced metastatic tumor cell death that was elevated significantly over WT controls. Similarly, when WT 4T1 tumor-bearing mice were administered GSK2656157 together with the IDO1 inhibitors Epacadostat, Indoximod or Navoximod, the attenuated neovascularization and elevated regional hypoxia in lung metastases elicited by IDO1 inhibition was accompanied by an increased level of tumor cell death. Co-administration of the hypoxia-activated prodrug Evofosfamide with Epacadostat likewise resulted in elevated metastatic tumor cell death. This contrasts with results obtained with the non-targeted cytotoxic agent Carboplatin that elicited comparable levels of metastatic tumor cell death regardless of Epacadostat co-administration. Altogether, these data establish the potential to benefit treatment in tumor settings where IDO1 inhibition enhances intra-tumoral hypoxia through neovascular regression by facilitating the ability of hypoxia-targeting agents to effectively eliminate tumor cells in a more targeted manner than can be achieved with conventional chemotherapy.
Citation Format: Shih-Chun Shen, Souvik Dey, James B. DuHadaway, George C. Prendergast, Alexander J. Muller. IDO1 inhibition sensitizes metastatic lung tumors to hypoxia/ER stress targeting agent-induced cell death [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 582.
Abstract 5913: Semi-supervised analysis of myeloid and T cell behavior in ex vivo ovarian tumor slices reveals changes in cell motility after treatments
Authors: Laforets Florian , Kotantaki Panoraia , Malacrida Beatrice , Elorbany Samar , Manchanda Ranjit , Donnadieu Emmanuel , Balkwill Frances 
Published: April 2023

Abstract
Cell motility is an important component of anti-tumor responses, allowing immune cells like myeloid and cytotoxic T cells to infiltrate tumors. Using ex vivo human and mouse high-grade serous ovarian cancer (HGSOC) tumor slices combined with time-lapse imaging, we monitored the movement of CD8+ T and myeloid cells in live tumors, in real-time. To analyze the recordings and characterize immune cell movements, we developed a semi-supervised analysis, identifying four types of cell behavior: migrating, long migrating, static and wobbling. Tumor slices were maintained 24h ex vivo, retaining viability and cell movements. We show that ex vivo treatments with LPS altered CD8+ T and myeloid cell behavior. In vivo chemotherapy reduced ex vivo cell movements in human and mouse tumors, and differentially affected CD8+ T and myeloid cells in 60577 and HGS2 murine tumors, respectively chemo-sensitive and chemo-resistant mouse models, suggesting those cell types have different roles in the response to chemotherapy. Ex vivo tumor slices can extend in vivo mouse work to human, providing a stepping stone to translate mouse cancer studies to clinical trials.
Citation Format: Florian Laforets, Panoraia Kotantaki, Beatrice Malacrida, Samar Elorbany, Ranjit Manchanda, Emmanuel Donnadieu, Frances Balkwill. Semi-supervised analysis of myeloid and T cell behavior in ex vivo ovarian tumor slices reveals changes in cell motility after treatments [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 5913.
Abstract 5918: Interrogating host-intratumoral microbial interactions in pancreatic cancer
Authors: Chandra Vidhi , Rajaei Hajar , Baydogan Seyda , Gomez Javier , Ferri-Borgogno Sammy , Maitra Anirban , Riquelme Erick , Sahin Ismet , Burks Jared , Kim Michael , McAllister Florencia 
Published: April 2023

Abstract
Cancer is increasingly becoming a rising cause of mortality worldwide. Microbiota, both within the gut and tumors, has emerged as a significant player influencing tumor growth and responses to therapies. The tumor niche provides a privileged microenvironment for microbial colonization. Recent evidence links microbiota and pancreatic tumorigenesis. Pancreatic ductal adenocarcinoma (PDAC), is an aggressive cancer surrounded by a highly immuno-suppressive tumor microenvironment (TME) which limits efficacy of most available therapies. We have previously reported that rare long-term survival in pancreatic cancer is associated with an intratumoral microbial signature which correlates with enhanced TME immunoactivation, suggestive of microbial mediated immune cell recruitment. A gut-to-tumor microbial crosstalk was also found in a human-to-mouse Fecal Microbiota Transplant (FMT) tumor model. While we have identified the vital role of microbiota in affecting tumor immunity, there is still a gap of knowledge about local microbial interactions within TME. Deeper understanding of the microbial mediated events that are triggered and follow PDAC development, which act to induce and support tumor growth, would provide us with potential novel targets that could be blocked to reverse PDAC immunosuppression and tumor growth. To interrogate the features of the pancreatic tumor microbial niche, we performed spatial co-detection of microbial and host targets to identify the cellular compartment which interacts with microbes inside the TME in clinical samples. We developed novel qualitative and quantitative imaging methodologies for evaluating crosstalk between the host and microbes. We also evaluated the effect of microbial burden on transcriptomic changes in host cells through multiple spatial sequencing approaches. Overall, we dissect the functional role of microbes in orchestrating TME organization and their effect on tumor signaling.
Citation Format: Vidhi Chandra, Hajar Rajaei, Seyda Baydogan, Javier Gomez, Sammy Ferri-Borgogno, Anirban Maitra, Erick Riquelme, Ismet Sahin, Jared Burks, Michael Kim, Florencia McAllister. Interrogating host-intratumoral microbial interactions in pancreatic 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 5918.
Abstract 594: Effects of interstitial pressure on lung cancer cells
Authors: Tokuda Shinsaku , Onoi Keisuke , Yamada Tadaaki , Takayama Koichi 
Published: April 2023

Abstract
Chronic inflammation is a risk factor for various types of cancer. The pressure in the interstitial tissues has been reported to be elevated in chronic inflammation and cancer. However, little is known about the biological effect of pressure from the basal side on epithelia, and a significance of the elevated interstitial fluid pressure in cancer biology is still poorly understood. In this study, we investigated the effect of hydrostatic pressure on cultured lung cancer cells grown on Transwell permeable filters by changing the height of the surfaces of culture medium in the apical and basal sides. A gradient of the hydrostatic pressure from the basal to the apical side induced stratification of epithelia. The elimination of the hydrostatic pressure gradient restored the stratification of epithelia. Interestingly, cavities were found within the stratified epithelia, and the characteristics of apical cell polarity including microvilli and tight junctions were formed in the surfaces the cavities. The cavities with similar aberrant cell polarity were also observed in human lung cancer tissues. The hydrostatic pressure gradient from the basal side also promoted cell proliferation and suppressed apoptosis. On the other hand, the expression levels of phosphorylated ERK and AKT were not significantly affected by the hydrostatic pressure. These results indicate that the pressure from the basal side to the epithelia promotes cell proliferation, suppresses apoptosis and induces aberrant cell polarity, which results in epithelial stratification. The findings in this study suggest that the elevated interstitial fluid pressure in chronic inflammation and cancer tissues facilitates cancer growth and plays a significant role in cancer biology.
Citation Format: Shinsaku Tokuda, Keisuke Onoi, Tadaaki Yamada, Koichi Takayama. Effects of interstitial pressure on lung cancer cells [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 594.
Abstract 5941: Sequencing of targeted- and immune-therapy: delineating time dependent changes in both melanoma cells and the immune microenvironment
Authors: Patel Riyaben , Trigos Anna , Haynes Nicole , Lelliott Emily , McArthur Grant , Sheppard Karen E. 
Published: April 2023

Abstract
Targeted and immune therapies have transformed outcomes for melanoma patients, nevertheless, significant challenges remain to maximize their clinical benefit. BRAF/MEK targeted therapy (TT) is associated with very high initial response rates that are typically short-lived, while in contrast Immune Checkpoint Inhibitors (ICI) provide more durable responses but have lower initial response rates. Hence, it has been proposed that sequencing ICIs with TT would lead to a higher frequency of durable responses. However, there are many unanswered questions regarding the choice of immunotherapy, the best sequencing strategy and the mechanism leading to this synergy. To address these questions, we have optimized a syngeneic mouse melanoma model, YUMMER1.7-PV1 that is sensitive to both TT and ICIs. Importantly, this model recapitulates the known three therapeutic response phases of targeted therapies: initial response, followed by drug tolerance and then resistance. Investigation of the tumor immune microenvironment (TIME) at these three drug-induced phases, demonstrates that the immune suppressive microenvironment present during the acquired resistant phase is primed at the drug tolerance phase. Utilizing this model, we have explored the time-dependent therapy-induced changes in both tumor cells and the TIME during various TT and ICI sequencing strategies. This information will determine the optimal sequencing strategy of targeted therapy and immunotherapy that will deliver better outcomes for melanoma patients.
Citation Format: Riyaben Patel, Anna Trigos, Nicole Haynes, Emily Lelliott, Grant McArthur, Karen E. Sheppard. Sequencing of targeted- and immune-therapy: delineating time dependent changes in both melanoma cells and the immune microenvironment [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 5941.
Abstract 5949: Modulate TAM infiltration at cancer-immune interface by targeting at monocyte migration
Authors: Du Wenxuan , Johnston Adrian , Nair Praful , Zhu Jingyi , Win Khin Sandar , Zhou Bryan , Phillip Jude , Wu Pei-Hsun , Wirtz Denis 
Published: April 2023

Abstract
Extensive infiltration of tumor-associated macrophages (TAMs) into the solid tumor microenvironment (TME), where they promote angiogenesis, initiate metastasis, and tune immunosuppression, has long been proven to correlate with worse patient prognosis. Thus, much significance has been attached on either impeding TAM infiltration or reversing pro-tumoral TAMs back into phagocytic M1 phenotype. Nevertheless, while revealing underlying mechanisms of blocking TAM recruitment, widely adopted in vitro migration assays like Transwell, µ-slides fail to distinguish cell’s random migration from chemotaxis (biased migration) and introduce 3D extracellular matrix environment. Here we present data that monocytes, as major replenishment source of TAMs, massively boost their random migration via paracrine pathway to initiate early-stage infiltration using an advanced 3D multi-compartment organoid model. In addition, before re-educated into TAMs, monocytes in the TME are capable of inducing triple negative breast cancer cells’ hyper-proliferation by activating their MEK/ERK signaling pathway. This work provides evidence that TAM infiltration is driven by monocytes’ random/biased migration separately and identifies a potential combinational immunotherapy targeting at monocytes instead of TAMs.
Citation Format: Wenxuan Du, Adrian Johnston, Praful Nair, Jingyi Zhu, Khin Sandar Win, Bryan Zhou, Jude Phillip, Pei-Hsun Wu, Denis Wirtz. Modulate TAM infiltration at cancer-immune interface by targeting at monocyte migration. [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 5949.
Abstract 5951: The correlation between single nucleotide polymorphism of chemokine receptor and ligand and infiltrating immune cells on tumor microenvironment of gastric cancer
Authors: Yoon Sunjoo , Lee Ju Hyun , Kang Minsu , Oh Hyeon Jeong , Koh Jiwon , Lee Hye Seung , Kang So Hyun , Park Young Suk , Lee Keun-Wook , Kim Jin Won 
Published: April 2023

Abstract
Objective: Chemokines play roles in many normal biological processes, such as hematopoietic cell genesis and leukocyte migration and homing. Chemokines could be responsible for eliciting local accumulation of immune cells within tumor microenvironment. In this study, we examine if genetic variations in chemokine receptor and ligand are associated with infiltrations of immune cells on tumor microenvironment in gastric cancer.
Methods: In 356 gastric cancer patients who received curative surgery followed by adjuvant chemotherapy, total 105 single nucleotide polymorphisms (SNP) in a chemokine ligand and chemokine receptor locus within 16 genes (CXCR4, CXCR2, CXCR1, CX3CR1, CCR8, CCR9, CCR3, CCR2, CCR5, CCRL2, CCR6, CXCR5, CCR6, CXCR6, CCR7, DARC) were genotyped from peripheral blood sample. Total 11 immune markers such as CD3, CD4, CD8, FOXp3, CD68, CD163, L-selectin, i-NOS, ADMA17, Arginase, CD45RO were analyzed for deposition of immune cells according to SNP of chemokine receptor and ligand. Levels of immunohistochemistry staining were quantified by Image Analysis Toolbox and density of immune cells infiltration was calculated.
Results: 32 SNP locus of 8 genes (such as CXCR1, CXCR2, CCR3, CCR2, CCR5, CCRL2, CCR6. CXCR5) were selected using 25% cut-off value of minor allele frequency (MAF). Among 8 genes, CCR5 was the most relevant gene for immune cell infiltration on tumor microenvironment. Intron1-2545G&gt;A (rs1799987) were associated with increased accumulation of CD3+, CD68+ and FOXp3+ cells compared to recessive carriers of the common allele. In CCR5 SNP that contained the common alleles of intron1-2549 G&gt;T (rs2734648) and exon2A-2081 A&gt;G (rs1800023), CD3+, CD4+, CD8+ and FOXp3+ cells were infiltrated more than minor alleles.
Conclusions: The associations between infiltration of immune cells and SNP of chemokine receptor and ligand in gastric cancer were shown. Particularly, CCR5 SNP may be most relevant for correlation with infiltration of immune cells on tumor microenvironment.
Citation Format: Sunjoo Yoon, Ju Hyun Lee, Minsu Kang, Hyeon Jeong Oh, Jiwon Koh, Hye Seung Lee, So Hyun Kang, Young Suk Park, Keun-Wook Lee, Jin Won Kim. The correlation between single nucleotide polymorphism of chemokine receptor and ligand and infiltrating immune cells on tumor microenvironment of gastric 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 5951.
Abstract 5956: Tumor-infiltrating neutrophil progenitors impair homologous DNA repair and promote sensitivity to PARP-inhibition
Authors: Calcinotto Arianna 
Published: April 2023

Abstract
Tumor evolution is one of the major mechanisms responsible for acquiring therapy-resistant and more aggressive cancer clones. Whether the tumor microenvironment through immune-mediated mechanisms might promote the development of more aggressive cancer types is crucial for the identification of additional therapeutical opportunities. Here, we identified a novel subset of tumor-infiltrating neutrophils, defined as tumor-associated neutrophil progenitors (NePs). These NePs are enriched in highly proliferative hormone-dependent breast cancers and impair DNA repair capacity.  Mechanistically, succinate secreted by tumor-associated NePs inhibits homologous recombination, promoting error-prone DNA repair through non-homologous end-joining regulated by PARP-1. Consequently, breast cancer cells acquire  genomic instability, resulting in tumor progression and resistance to endocrine therapies.  Selective inhibition of these pathways induces increased tumor cell kill in vitro  and  in vivo. Intra-tumor NePs score correlates  with copy number alterations in highly proliferative hormone-dependent tumors from breast cancer patients. Treatment with PARP-1 inhibitors counteract the pro-tumorigenic effect of these neutrophils and reverses endocrine resistance.
Citation Format: Arianna Calcinotto. Tumor-infiltrating neutrophil progenitors impair homologous DNA repair and promote sensitivity to PARP-inhibition. [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 5956.
Abstract 5959: Dissecting the stromal drivers of gastroesophageal adenocarcinoma chemoresistance
Authors: Tai Kulsum , Pal Sanjima , Bérubé Julie , Kong Iris , Hoffman Adam , Bailey Swneke , Kirbizakis Aki , Huang Sui , Strasser Michael , Gibbs David , Bertos Nicholas , Sangwan Veena , Ferri Lorenzo 
Published: April 2023

Abstract
Gastroesophageal adenocarcinoma (GEA) is the fastest rising cancer in North America. Over the course of five years, the survival rate is &lt;20%, creating an urgent need for appropriate treatments against GEA. Currently, providing patients with peri-operative systemic docetaxel triplet-based chemotherapy (DCF or FLOT) is the most effective approach to treat GEA. Despite this, for 50% of patients that do present an initial response to therapy, the tumor returns due to pre-existing or newly acquired resistance (i.e., chemoresistance) by the cancer. Researchers have shifted their focus to the tumor microenvironment (TME) as one of the factors influencing chemoresistance in patients. The TME is composed of tumor cells, immune cells and their secreted products, as well as fibroblasts. The components of the TME have been shown to interact with one another to influence tumor growth and progression. Fibroblasts are wound-healing cells that can be transformed into cancer-associated fibroblasts (CAFs) in response to stress and the release of inflammatory products. CAFs are the most abundant cells in the TME, yet their role in the chemoresponse of GEA is still unclear. Previous studies on other cancer types demonstrated that CAF expression is distinct between chemoresistant and chemo-sensitive tumors and certain CAF subpopulations may confer this resistance. This project will investigate the role of CAFs in the chemo-response of GEA using patient-derived organoids (PDOs) and CAFs from &gt;200 GEA patients. A single-cell RNA sequencing atlas developed from &gt;30 GEA DCF- or FLOT-treated patient samples will be used to identify CAF markers and targetable processes. CAF sub-populations will then be elucidated and correlated to tumor response. IF, FACS, and ELISA will be performed for subsequent CAF marker validation and characterization. Ex vivo drug testing with DCF or FLOT will be conducted on PDO-CAF co-cultures to recapitulate their drug response.
Citation Format: Kulsum Tai, Sanjima Pal, Julie Bérubé, Iris Kong, Adam Hoffman, Swneke Bailey, Aki Kirbizakis, Sui Huang, Michael Strasser, David Gibbs, Nicholas Bertos, Veena Sangwan, Lorenzo Ferri. Dissecting the stromal drivers of gastroesophageal adenocarcinoma chemoresistance [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 5959.