bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA020: Increased mitochondrial DNA mutation burden with age limits lung cancer
Authors: White Eileen 
Published: January 2023

Abstract
Mitochondrial DNA (mtDNA) mutations accumulate with age and are found in some cancers. However, the relationship between cancer and mtDNA mutations, and the pathogenicity of those mutations, is not known. To address this question, we created a new mouse model of non-small cell lung cancer (NSCLC) with an increased mtDNA mutation burden. This model was generated by breeding the NSCLC mice model carrying floxed alleles of p53 and KrasG12D, with the mtDNA mutator mouse bearing a germline polymerase gamma mutation that disables proofreading function (POLGD257A) that is responsible for the accumulation of mtDNA mutations over time. The mutator mice with NSCLC had reduced tumor burden and prolonged survival after tumor induction in comparison to POLG wild type mice with NSCLC. Both tumor and normal tissue from mutator mice had elevated mtDNA mutation burden in comparison to wild type mice. The prolonged survival of POLGD257A mice with NSCLC was even more pronounced in older animals where mtDNA mutation burden was further increased. The same was true for a mouse model with a single pathogenic mtDNA mutation found in mitochondrial disease, indicating that it is not the number of mutations, but rather the disabling of mitochondrial function by mutation that causes reduced tumor growth. This suggested that elevated mtDNA mutation with age may suppress NSCLC. To address the mechanism by which accumulation of mtDNA mutations suppress tumor growth we examined metabolism and immune functions. We found that mtDNA mutations caused tumor cell metabolic dysfunction including increased glycolysis and decreased respiration with dependency of glycose and serine and glycine as carbon sources in vitro. Moreover, mtDNA mutations caused tumor dependence on serine and glycine in vivo. Thus, elevated mtDNA mutation burden with age may increase probability of suppression of mitochondrial function, resulting in specific metabolic dependencies in NSCLC. Thus, tumors with mtDNA mutation accumulation may be susceptible to therapeutic dietary restriction of serine and glycine.
Citation Format: Eileen White. Increased mitochondrial DNA mutation burden with age limits lung cancer [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA020.
Abstract IA023: Age against the machine: How the aging microenvironment drives tumor progression
Authors: Weeraratna Ashani 
Published: January 2023

Abstract
Patients 65 and older account for 69% of all new cancer diagnoses. Melanoma is a deadly disease, with chances of survival for patients with stage IV disease totaling only 27%. Age-related changes- both secreted and biophysical- drive metastasis, immune cell recruitment, and changes in the vasculature. Age-related changes also impact the ability of tumor cells to respond to targeted therapy, and new data from our lab indicate this may be sex specific. Our recent studies also show that age-related changes in the lung microenvironment facilitate a permissive niche for efficient outgrowth of disseminated dormant tumor cells, in contrast to the aged skin, where age-related changes suppress melanoma growth but drive dissemination. We now show that age-induced changes in distal metastatic microenvironments promote efficient reactivation of dormant melanoma cells in the lung due to changes in Wnt signaling pathways. Overall, our studies argue for placing mechanistic studies of cancer biology into the context of aging.
Citation Format: Ashani Weeraratna. Age against the machine: How the aging microenvironment drives tumor progression [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr IA023.
Abstract PR002: Cytokines surge in the blood years prior to a cancer diagnosis in elderly individuals
Authors: Chen Guangbo , Zheng Hong , Rosenberg-Hasson Yael , Araya Saron , Padilla Cindy , Sarin Kavita , Dekker Cornelia L. , Grant Philip , Maecker Holden T. , Furman David , Shen-Orr Shai , Khatri Purvesh , Davis Mark M. 
Published: January 2023

Abstract
How the human immune system reacts prior to a cancer diagnosis is largely unknown. Here we analyze a longitudinal cohort of 133 healthy individuals (18 to over 90 years old), 28 of whom developed cancers over nine years. We find the global abundance of a broad spectrum of cytokines (26 out of 32 assayed) surges 2-3 years before cancer diagnosis but not with other conditions (such as inflammatory or cardiovascular diseases). These cytokine surges precede cancer diagnosis only in those 80 years or older, suggesting age-specific inflammatory effects. Meanwhile, in early-stage (but not late-stage) tissues across 10 cancer types, aging elevates cytokine transcriptional activity, which coincides with an age-dependent expansion of the inflammatory macrophage population. We further find that macrophage is a major producer of cytokines in cancer tissues, irrespective of cancer types. These results suggest that cancer associated macrophage is a major source of peripheral inflammatory molecules and may mobilize immunity well before a clinical diagnosis in the elderly.
Citation Format: Guangbo Chen, Hong Zheng, Yael Rosenberg-Hasson, Saron Araya, Cindy Padilla, Kavita Sarin, Cornelia L. Dekker, Philip Grant, Holden T. Maecker, David Furman, Shai Shen-Orr, Purvesh Khatri, Mark M. Davis. Cytokines surge in the blood years prior to a cancer diagnosis in elderly individuals [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr PR002.
Abstract A004: The role of calcium in metastatic progression
Authors: Morris Kenise , Papa Anne-Laure 
Published: January 2023

Abstract
Calcium is essential to the structural stability of integrin proteins implicated in platelet–cancer cell interactions, namely integrins GPIIb/IIIa and avb3, which share a common beta subunit (Pelletier et al., J Biol Chem, 1996), (Zhang and Chen, Cell Adh Migr, 2012). Additionally, calcium is essential for ligand binding to these integrins (e.g., fibrinogen) that bridge platelets and cancer cells (Raborn et al., Biochemistry, 2011) and for the downstream signaling following mechanical and chemical stimulation in the integrin microenvironment (Michelson, Platelets, 2013). Platelet-cancer cell interactions are key players in cancer progression as platelets support metastatic dissemination (Morris et al., Biochim. Biophys. Acta BBA - Rev. Cancer, 2022). Despite previous studies recognizing calcium’s role in integrin stability and function, calcium’s importance for platelet support in cancer progression is not well understood. Therefore, we aim to (1) characterize the receptor expression and ligand binding ability of GPIIb/IIIa and avb3 on respective cells via anti-CD41a (for platelets and breast cancer MDA-MB-231 cells) and anti-avb3 antibody (for lung cancer A549 cells), (2) characterize platelet function by assessing platelet aggregation using light transmission aggregometry and platelet adhesion on a thrombogenic surface, (3) characterize platelet-cancer cell interaction via flow cytometry, and (4) assess cancer cell invasion in the presence of platelets via transwell assay; all in the presence of an environment with calcium chelation and hypercalcemic conditions. Our results demonstrate that platelet GPIIb/IIIa, cancer cell GPIIb/IIIa (MDA-MB-231) and cancer cell integrin avb3 (A549) are modulated with calcium chelation. Additionally, platelet function, specifically aggregation is significantly decreased with calcium chelation and significantly increased with hypercalcemia. We also observed that the interaction between platelets and cancer cells is reduced with calcium chelation, platelet-MDA-MB-231 interaction specifically being significantly reduced in the presence of sodium citrate. Our overall hypothesis is that the observed effect of calcium levels of platelet and cancer cell integrins could have a significant influence on platelet-cancer cell interactions and cancer cell migration in hypercalcemia, often seen in patients with malignancy. A greater understanding of these interactions could have impact for the design of specific inhibitors with anti-metastatic effects and potentially lead to novel targeted therapies to combat metastatic dissemination.
Citation Format: Kenise Morris, Anne-Laure Papa. The role of calcium in metastatic progression [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A004.
Abstract A005: Adherent-to-suspension transition by hematopoietic factors promotes metastatic dissemination
Authors: Huh Hyunbin D. , Gee Heon Yung , Park Hyun Woo 
Published: January 2023

Abstract
How primary tumor cells reprogram their anchorage dependency to disseminate into the bloodstream remain elusive. Here, we discover a biological phenomenon referred to as “Adherent-to-Suspension Transition” (AST) that reprograms adherent cells into suspension cells by introducing four hematopoietic transcriptional regulators, which we designated AST factors. Induction of AST factors in adherent cells suppress Hippo transducers YAP-TEAD and upregulate globin genes that evoke spontaneous cell-matrix dissociation and anoikis resistance in the absence of lineage differentiation. During dissemination, we uncover the aberrant induction of AST factors in circulating tumor cells (CTCs) derived from de novo metastatic breast cancer patients and mouse models in vivo. Pharmacological blockade of AST factors in breast cancer cells abrogates CTC formation and suppresses lung metastases without affecting the primary tumor growth. Collectively, we demonstrate that suspension cells can directly arise from adherent cells by the addition of defined factors that confer metastatic traits. Furthermore, our data expand the prevailing cancer treatment paradigm toward direct intervention within the metastatic spread of cancer.
Citation Format: Hyunbin D. Huh, Heon Yung Gee, Hyun Woo Park. Adherent-to-suspension transition by hematopoietic factors promotes metastatic dissemination [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A005.
Abstract A010: MYC as a master regulator of dormancy in triple negative breast cancer
Authors: Roelofs Charlotte , Mouchemore Kellie A. , Chakrabarti Anannya , Redvers Richard P. , Anderson Robin L. 
Published: January 2023

Abstract
Dormancy is a major clinical problem in breast cancer. Although the five-year survival rate is high, 15% of the patients will relapse. Cancer cells that disseminate from the tumor (DTCs) can enter a dormant state that allows survival in the face of standard-of-care therapies. These DTCs are the source of cancer recurrence. Currently little is known about the molecular drivers that initiate dormancy. MYC is a well-known oncogene that is aberrantly regulated in many cancers, including breast cancer. It is involved in proliferation, tumorigenesis, and diapause. We propose that MYC is also a master regulator of dormancy. To investigate its role in dormancy, we generated cell lines with regulatable levels of MYC expression. Using an in vitro dormancy assay, we have shown that reduced MYC levels induce dormancy in otherwise aggressive cell lines. In mice bearing human breast tumors, the loss of MYC activity following primary tumor removal greatly reduces the extent of metastasis. The DTCs in lungs, livers, spine, and femurs are maintained as small clusters with few cells, while control mice have many and large metastases. MYC reduction maintains the DTCs in this dormant-like state for at least 32 days after primary tumor removal. Importantly, when MYC levels are restored, the DTCs exit the dormant state, and overt metastasis ensues. Currently, we are comparing the transcriptomes of dormant DTCs to actively growing metastatic cells to generate a MYC-driven dormancy signature that will elucidate potential dormancy genes to target therapeutically in the clinic. To complement our genetic studies, we are investigating pharmacological suppression of MYC activity. The bromodomain inhibitor I-BET151 reduces MYC protein levels and induces dormancy in our in vitro assay. Mice treated with I-BET151 after primary tumor removal had significantly reduced levels of metastasis in lung, liver, and spine when compared to their non-treated counterparts. Testing of this compound in an immune-competent preclinical model is currently underway. Our data imply that MYC is an important regulator of dormancy in breast cancer. Our future experiments will elucidate dormancy genes as potential targets that could lead to life-saving therapies in the clinic.
Citation Format: Charlotte Roelofs, Kellie A. Mouchemore, Anannya Chakrabarti, Richard P. Redvers, Robin L. Anderson. MYC as a master regulator of dormancy in triple negative breast cancer [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A010.
Abstract A012: NAT10 promotes metastasis through enhancer remodeling of cancer cells
Authors: Amin Ruhul , Ha Ngoc-Han , Meier Jordan L. , Hunter Kent W. 
Published: January 2023

Abstract
Distant organ metastases account for the majority of the cancer-related death. However, the detailed mechanism underlying the metastatic potential of cancer cells is poorly understood. We have previously shown than NUP210-dependent nuclear pore-associated chromatin-bound protein complex is involved in cellular mechanotransduction and metastasis in breast cancer. Although NAT10, an RNA cytidine acetyl transferase has been shown to interact with this protein complex, specific function of NAT10 in metastasis is not well understood. Using allograft and genetically engineered highly metastatic PyMT mouse model, we found that the loss of NAT10 significantly decreases lung metastasis in mice. NAT10 is mainly localized to the nucleolus and nucleoplasmic compartment of the cancer cells. Current understanding suggests a role of NAT10 in acetylation of mRNAs and ribosomal RNAs. In contrast to its role as an RNA acetylase, we uncovered a new mechanism of NAT10 in cancer cells. Using co-immunoprecipitation followed by mass spectrometry and chromatin immunoprecipitation followed by high throughput sequencing (ChIP-seq), we found that NAT10 is interacting with super-enhancer associated protein complex. RNA-seq analysis revealed that the loss of NAT10 leads to dramatic transcriptional suppression of super-enhancer driven genes including MYC. Mechanistically, using mass spectrometry-based quantification of protein acetylation, we showed that the loss of NAT10 leads to decreased acetylation of enhancer-associated Histone H4 and H3 modification. NAT10 loss also leads to increased heterochromatin-forming histone methylation within the cell nuclei. Our study revealed a distinct role of NAT10 as an enhancer remodeler in metastatic cancer cells. Therefore, NAT10 could be a potential therapeutic target in preventing metastatic disease.
Citation Format: Ruhul Amin, Ngoc-Han Ha, Jordan L. Meier, Kent W. Hunter. NAT10 promotes metastasis through enhancer remodeling of cancer cells [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A012.
Abstract A022: Role of imaging mass cytometry in studying hepatoblastoma vascular invasion
Authors: Espinoza Andres F. , Patel Roma , Woodfield Sarah , Vasudevan Sanjeev A. 
Published: January 2023

Abstract
Introduction: Hepatoblastoma (HB) is the most common liver cancer in children with a survival rate of less than 50% in patients with high-risk disease, especially those with vascular invasion (VI). Patients with VI receive aggressive therapies that are toxic and ineffective; therefore, a better understanding of the biomarkers and biology of VI in HB is urgently needed. Methods: Using imaging mass cytometry (IMC) we analyzed 18 pre-validated protein targets on two of our formalin-fixed paraffin embedded (FFPE) HB patient samples; one with VI and one without VI. For confirmation of the proteins of interest, we performed immunohistochemistry (IHC) on primary and metastatic lesions from a separate patient. We performed RNA sequencing of one of our primary liver tumor and two sub-clones of that tumor, one inside an intrahepatic vessel and one sample representing tumor vessel thrombus. Results: By IMC, we found that protein expression of c-Myc and YAP-1 are increased in the areas of VI as the tumor invades the neighboring blood vessel. YAP-1 and c-Myc expression were low in the patient without VI. When examining the IHC of the separate patient with metastatic lung disease, we noted clear nuclear positivity of YAP-1 and c-Myc in the metastatic cells, compared to the negative nature of the primary liver tumor. Our RNA sequencing data showed that the average gene expression of c-Myc of the tumor in intrahepatic vessel and tumor vessel thrombus was 1.61 times higher than the primary tumor. The tumor found in the intrahepatic vessel and tumor vessel was found to have 1.29 times higher expression of Yap-1 compared to the primary tumor. Conclusions: YAP-1 and c-Myc had higher expression in hepatoblastoma as the tumor cells progress to invade the vasculature and metastasize. YAP-1 and c-Myc expression appears to play a role in vascular invasion that is maintained when tumors grow in the metastatic sites.
Citation Format: Andres F. Espinoza, Roma Patel, Sarah Woodfield, Sanjeev A. Vasudevan. Role of imaging mass cytometry in studying hepatoblastoma vascular invasion [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A022.
Abstract A043: A novel role for Mitochondrial Rho GTPase 2 in tumor cell invasion and metastasis
Authors: Boulton Dillon P. , Furnish Madison , Caino M. Cecilia 
Published: January 2023

Abstract
Metastasis of cancer cells to secondary sites remains the leading cause of cancer related deaths, emphasizing a strong need for actionable targets in advanced stage cancer. To address this, we study novel dysregulated signaling mechanisms that cells utilize to metastasize to distal sites. Here, we focus on how outer mitochondrial membrane protein—Mitochondrial Rho GTPase 2 (MIRO2)—promotes tumor cell invasion and metastasis through a negative regulation of RhoA. Our previous work identified higher MIRO2 mRNA expression in cancer vs. normal patient samples, which correlated with worse patient outcomes. Furthermore, in the context of prostate cancer we demonstrated that MIRO2 was critical for 2D cell growth, anchorage-dependent and -independent colony formation, and tumor growth in vivo. However, it remains completely unknown if MIRO2 affects primary tumor growth or if this protein is important throughout tumor progression. Using siRNA mediated knockdown (KD) of MIRO2 we clearly show that MIRO2 KD ubiquitously reduces tumor cell invasion in breast, melanoma, pancreatic, and prostate cancer cell lines. Preliminary experiments modeling late-stage metastasis showed that tail vein injection of PC3 cells stably expressing MIRO2 targeting shRNA had reduced kidney and liver metastatic burden in comparison to PC3 cells with control shRNA. In further mechanistic studies, we identified novel MIRO2 binding partners and used siRNA to KD the top hits and observe changes in invasive capacity. We found that atypical myosin IX B (MYO9B) reduced the invasion of cells to the largest extent. MYO9B is a plus-end direct atypical myosin known to control cell motility through spatially inactivating RhoA at the leading edge of migrating cells. Excitingly, MIRO2 KD showed an increase in active RhoA phenocopying MYO9B KD. Lastly, in pilot experiments we found that dual KD of MIRO2 and RhoA rescued invasive capacity in comparison to MIRO2 KD alone. Taken together, we propose a novel signaling mechanism by which MIRO2 broadly promotes invasion and metastasis through MYO9B dependent inactivation of RhoA.
Citation Format: Dillon P. Boulton, Madison Furnish, M. Cecilia Caino. A novel role for Mitochondrial Rho GTPase 2 in tumor cell invasion and metastasis [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A043.
Abstract A046: Heterogenous nuclear ribonucleoprotein E1 regulates leukemia inhibitory factor receptor (LIFR) expression through FAM3C in mammary epithelial cells
Authors: Streitfeld William S. , Dalton Annamarie C. , Howe Philip H. 
Published: January 2023

Abstract
Leukemia inhibitory factor receptor (LIFR) signals through signal transducer and activator of transcription 3 (STAT3), a transcription factor that is associated with poor prognosis due to its overexpression and/or hyperactivity in 40% of breast cancer cases. LIFR has been defined as either a promoter or suppressor of metastasis in mammary carcinoma, and recently we have shown that its expression is significantly upregulated following loss of the RNA-binding protein heterogenous nuclear ribonucleoprotein E1 (hnRNP E1, “E1”). We have further shown that E1 is a regulator of the epithelial-to-mesenchymal transition (EMT) and of differentiation in mammary epithelium. Mechanistically, E1 acts as a tumor suppressor by binding to and inhibiting translation of mRNAs involved in EMT and cellular self-renewal, including the cytokine FAM3C. We have demonstrated that FAM3C binds to LIFR in the extracellular space and activates STAT3. Herein, we characterize induction of LIFR expression in response to FAM3C/LIFR signaling, and show that E1 upregulates LIFR transcription through FAM3C, involving initiation at the LIFR promoter locus. Induction of LIFR expression in mammary epithelial cells has been shown to be associated with tumor initiation, breast cancer stem cells, and metastasis. Additionally, our bioinformatic analysis reveals a signature of transcriptional regulation associated with FAM3C/LIFR interaction. Comparison between RNA-sequencing data from our mouse model of mammary carcinoma and human mammary carcinoma cell lines reveals common biological pathways and potential therapeutic targets. Future directions will be aimed at investigating the effect of modulation of LIFR expression during tumor dissemination in vivo.
Citation Format: William S. Streitfeld, Annamarie C. Dalton, Philip H. Howe. Heterogenous nuclear ribonucleoprotein E1 regulates leukemia inhibitory factor receptor (LIFR) expression through FAM3C in mammary epithelial cells [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A046.