bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B019: Identify features of fibroblast and macrophage which regulate metastasis of triple-negative breast cancer
Authors: Lee Woochan , Chung Hyewon , Heo Woohang , Moon Hyeong-Gon , Seok Seung Hyeok , Kim Jong-Il 
Published: January 2023

Abstract
The tumor microenvironment (TME), which the cancer is known to remodel, can interact with cancer in various ways, such as promoting or hindering metastasis. The challenge with comprehending TME is that each patient's individual variance makes it difficult to carry out a consistent analysis. We used the PDX model to analyze the alterations entirely brought about by cancer cells of each patient in the same environment exclusively. In 121 breast cancer patients, we created a PDX model and performed WES and RNA-seq. We repeatedly performed metastatic induction tests on the models of 26 TNBC patients among the PDX models we generated. The replicated experiments confirmed that cancer cells with frequent metastasis usually spread well, while cancer cells with seldom metastases rarely metastasize. For each of the five samples that had the greatest and worst rates of metastasis, the pre-metastatic xenograft tumor was analyzed using scRNA-seq. Metastasis could not be predicted by only cancer cells because there was no difference between the two groups. Still, fibroblasts and macrophages had distinct gene markers before metastasis which can predict metastasis. To explore TME that develops pre-metastatic niches (PMN) in organs that would be metastasis targets, we developed a metastatic model using 4T1 cell lines. Daily lung macrophage RNA-seq, lung WES, and lung scRNA-seq procedures were carried out for four weeks to examine the precise timing of metastasis and the daily changes in the transcriptome. Surprisingly, a few days before the presence of any cancer cells, the gene expression of lung macrophages had already undergone significant modification. Additionally, only injections of tumor-conditioned media that mimicked metastasis could activate PMN in lung macrophages.
Citation Format: Woochan Lee, Hyewon Chung, Woohang Heo, Hyeong-Gon Moon, Seung Hyeok Seok, Jong-Il Kim. Identify features of fibroblast and macrophage which regulate metastasis of 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 B019.
Abstract B043: Tissue Factor Pathway Inhibitor (TFPI), a novel invasion and therapy target in glioblastoma multiforme
Authors: Dang Tuyen T. , Morales Julio C. 
Published: January 2023

Abstract
Glioblastoma multiforme (GBM) is a deadly brain cancer with a 4-10% five-year survival rate. Even with the advent of temozolomide and tumor treating fields, at best GBM patients can hope for a median survival of approximately 25 months. The major cause of poor survivorship is the recurrence of inoperable therapy resistant secondary tumors. With the poor survivorship, there is an urgent need for novel therapy regimens. We propose a novel therapy and metastatic target for GBM treatment. Tissue Factor Pathway Inhibitor (TFPI) is a serine proteinase inhibitor. Classically, TFPI inhibits FXa and/or TF-VIIa to reduce blood coagulation. Recently, TFPI expression have been correlated with solid tumors such as breast, pancreatic, colorectal and brain tumors. However, it is unknown how TFPI contributes to cancer disease. We observed that TFPI increased expression correlated with GBM tumor samples. Additionally, GBM patients with high expression of TFPI had a poorer survivorship than those with low expression of TFPI. Using live cell imaging, we found that TFPI is required for cell motility, an initial and required step in cancer cell invasion. Additionally, we found that loss of TFPI increased 53bp1 foci formation. Increased 53bp1 foci formation is an indication of defunct DNA double stranded break repair. We found that loss of TFPI sensitizes cells to ionizing radiation another indication of a dysfunctional DNA double stranded break repair program. We found that loss of TFPI sensitizes cells to Parp-1 inhibition, a hallmark of a defunct homologous recombination repair program. Homologous recombination and non-homologous end-joining are the two major repair pathways for DNA double stranded breaks. Based on these preliminary data, we hypothesize that TFPI plays role in motility/invasion and DNA repair, which leads to therapy resistance and metastasis in GBM. TFPI is an attractive radio-sensitizer for GBM treatment since radiation is a first-line therapy modality. Additionally, Parp-1 inhibition is currently in clinical trials for GBM treatments. Lastly, there is an FDA approved inhibitor for TFPI, ANDEXXA and several TFPI antibodies in clinical trials. Our future endeavors are to elucidate the mechanisms by which TFPI regulates DNA repair and cancer cell invasion. These findings will lay down the foundation for using TFPI inhibitors as a concurrent treatment plan to standard of care.
Citation Format: Tuyen T. Dang, Julio C. Morales. Tissue Factor Pathway Inhibitor (TFPI), a novel invasion and therapy target in glioblastoma multiforme [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 B043.
Abstract IA008: Biology of metastasis-competent circulating tumor cells
Authors: Alix-Panabières Catherine 
Published: January 2023

Abstract
The characterization of circulating tumor cells (CTCs) holds promises for precision medicine because these cells are an important clinical indicator of treatment efficacy. We established the first and still only nine permanent colon CTC lines from peripheral blood samples of a patient with metastatic colon cancer collected at different time points during treatment and cancer progression. The study objectives were (i) to compare the gene expression profiles of these CTC lines, and (ii) to determine the main features acquired during treatment. The number of upregulated genes was higher in the CTC lines obtained after treatment, indicating that they acquired properties to escape treatment pressure. Among these upregulated genes, some are involved in the mTOR and PI3K/AKT signaling pathways. Moreover, cytidine deaminase expression was significantly increased in the CTC lines obtained after failure of the first- and second-line 5-fluorouracile-based treatments, suggesting that these CTCs can eliminate this specific drug and resist to therapy. Several enzymes involved in xenobiotic metabolism also were upregulated after treatment, suggesting the activation of detoxification mechanisms in response to chemotherapy. Finally, the significant higher expression of aldolase B in four of the six CTC lines obtained after treatment withdrawal and cancer progression indicated that these clones originated from liver metastases. In conclusion, these CTC lines generated at different time points during treatment of metastatic colon cancer in a single patient are characterized by the deregulation of different genes that promote (i) drug resistance, (ii) xenobiotic and energy metabolism, and (iii) stem cell properties and plasticity.
Citation Format: Catherine Alix-Panabières. Biology of metastasis-competent circulating tumor 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 IA008.
Abstract IA010: Hypomethylation of immune-related loci contribute to prostate tumorigenesis
Authors: Haber Daniel A. , Guo Hongshan , Wittner Ben S. , Vuille Joanna A , Lawrence Michael S. , Wu Chin-Lee , Toner Mehmet , Miyamoto David T. , Maheswaran Shyamala 
Published: January 2023

Abstract
Cancer-associated alterations in DNA methylation include hypermethylation of focal CpG islands within promoters, as well as hypomethylation of large stretches of gene-poor chromosomal domains, so called Partially Methylated Domains (PMDs). While CpG island hypermethylation is associated with silencing of tumor suppressor genes, the functional consequences of hypomethylation are uncertain. PMDs may be cause or consequence of cancer cell proliferation, and they have been associated with transcriptional de-repression of repetitive sequences, as well as histone modification-triggered silencing of rare protein encoding genes within these domains. In studying Circulating Tumor Cells (CTCs) isolated from blood specimens of patients with prostate cancer, we mapped PMDs at the single cell level, identifying a set of 40 “core PMDs” that are shared across cancer cells, within and across different individuals, as well as in prostate cancer cell lines. By analyzing single nuclei from micro-dissected early-stage prostate tumors, we find that hypomethylation of these core PMDs occurs early during prostate tumorigenesis. Core PMDs are highly enriched for immune-related genes, many of which are co-located within a single chromosomal locus targeted for hypomethylation-associated silencing. Nested between adjacent PMDs, we also identify domains that have retained DNA methylation (Preserved Methylation Islands; PMIs), which have sharply demarcated borders, spanning one or a small number of genes. In contrast to PMDs, PMIs are enriched for cell proliferation-associated genes. Together, these observations suggest that hypomethylation-associated silencing of immune-related genes, with sparing of adjacent proliferation-associated genes, is an early event in prostate cancer development. These large-scale chromosomal modifications are detectable within CTCs and may present diagnostic opportunities.
Citation Format: Daniel A. Haber, Hongshan Guo, Ben S. Wittner, Joanna A Vuille, Michael S. Lawrence, Chin-Lee Wu, Mehmet Toner, David T. Miyamoto, Shyamala Maheswaran. Hypomethylation of immune-related loci contribute to prostate tumorigenesis [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 IA010.
Abstract IA014: Effects of fluid shear stress on circulating tumor cells
Authors: Henry Michael 
Published: January 2023

Abstract
To colonize distant organ sites, cancer cells originating in solid tissues must traverse the circulatory system. How circulating tumor cells (CTCs) survive various biological and mechanical insults during this journey remains unclear. Mechanical challenges to CTCs include exposure to fluid shear stress (FSS) which ranges over several orders of magnitude throughout the circulatory system. To assess the effects of FSS on cancer cells, we developed a simple model to apply brief pulses of fluid shear stress to cancer cells in suspension. Surprisingly, we found that cancer cell lines, originating from many different tissues are more resistant to destruction by FSS than normal epithelial counterparts. FSS resistance is conferred on normal epithelial cells by transforming oncogenes and is evident in cancer cells acutely isolated from primary tumor tissues from mice and humans. Thus, FSS resistance is a conserved phenotype of viable transformed cells. FSS resistance is an active biological mechanism in viable cancer cells, dead and dying cancer cells are readily destroyed by FSS. In cancer cells, initial exposure to FSS results in rapid cell stiffening unlike non-transformed cells. This change in contractility of cancer cells exposed to FSS is associated with activation of RhoA/C GTPases. Correspondingly, in cancer cells exposed to FSS, there is a rapid increase in cortical F-actin that depends on formin activity, and myosin II activity is elevated. Both F-actin remodeling and myosin II activity are required for FSS resistance in vitro. Myosin II activity is also required for required for FSS resistance of experimental CTCs in vivo. Treatment of PC-3 cells with blebbistatin, a myosin II inhibitor, reduced the number of intact CTCs lodged in the lung and increased the number of CTCs destroyed immediately following tail vein injection. Moreover, treatment of mice bearing orthotopic prostate tumors with a non-toxic dose of blebbistatin reduced the levels of CTCs over 20-fold within 3h of treatment. As FSS exposure activates Rho GTPases, which are known to influence invasive and proliferative capacity of metastatic cells, more recently we have been investigating how FSS exposure may prime CTCs for metastasis. Exposure of both PC-3 and MDA-MB-231 cancer cell lines to FSS enhances metastatic colonization, invasive behavior in vitro and anchorage-independent proliferation. Ongoing efforts are to define the mechanisms that underly these emergent behaviors in response to FSS. In summary, we have found that viable CTCs actively resist destruction by FSS via a RhoA-dependent mechano-adaptive mechanism and that surviving cancer cells exposed to FSS exhibit enhanced metastatic potential.
Citation Format: Michael Henry. Effects of fluid shear stress on circulating tumor 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 IA014.
Abstract IA023: Tailored investigation and treatment of the brain metastasis micronich
Authors: Gephart Melanie Hayden 
Published: January 2023

Abstract
Brain metastases are highly aggressive, treatment-resistant malignancies with debilitating neurological sequelae and a grave prognosis. Common intrinsic features of the tumor and extrinsic features of the brain microenvironment, are relevant for cancer brain tropism and response to therapies. Efforts to understand, modulate, and target the metastatic brain tumor microenvironment have tremendous therapeutic potential.
Citation Format: Melanie Hayden Gephart. Tailored investigation and treatment of the brain metastasis micronich [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 IA023.
Abstract IA024: Cellular plasticity during metastatic colony formation in patients
Authors: Werner-Klein Melanie 
Published: January 2023

Abstract
Systemic cancer spread is a process whose complexity is only poorly understood. We have learned over the past years that metastatic dissemination starts very early in the evolution of a malignant clone of most cancers and that disseminated cancer cells (DCC) continue to acquire genomic alterations at the distant site. Consequently, it seems plausible that cellular phenotypes change during metastatic colony formation as well, although the impact of genotype changes on the cellular phenotypes is not clear at all. We studied this process in malignant melanoma, exploiting the unique chance that routine sentinel lymph node (SLN) biopsies provide for a cancer that is diagnosed much earlier and at smaller size than most other cancers. Moreover, mouse models suggest that lymph nodes serve as exit routes for systemic dissemination of cancer cells and that their colonization indues tumor-immune tolerance promoting distal metastasis. Melanoma DCC enter SLNs and may or may not give rise to a metastatic colony. We therefore first assessed in a large patient cohort comprising more than 500 early-stage melanoma patients, which melanoma marker is best suited to identify candidate metastasis founder cells and then progressed to provide their detailed molecular characterization. We found that melanoma cellular phenotypes indeed change over metastatic colony formation, indicating that differential molecular stage-specific targeting may be required to prevent metastasis formation. Of note, we observed mechanisms of very early immune suppression via DCC-derived EVs suggesting early DCC must find immune-escape strategies at the metastatic site.
Citation Format: Melanie Werner-Klein. Cellular plasticity during metastatic colony formation in patients [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 IA024.
Abstract PR004: Mechanistic basis for TGF-β-induced fibrogenic EMTs in metastasis
Authors: Lee Jun Ho , Basnet Harihar , Sánchez-Rivera Francisco , Wang Zhenghan , Li Liangji , Massagué Joan 
Published: January 2023

Abstract
The cytokine TGF-β is a central regulator of tissue homeostasis and regeneration through multiple coordinated effects on epithelial, immune, and mesenchymal stromal systems. Malfunctions of TGF-β signaling cause fibrosis, immune dysfunction, and cancer. As part of its multifunctional program, TGF-β induces epithelial-mesenchymal transitions (EMTs). Carcinoma cells use TGF-β to undergo EMT and adopt a highly plastic phenotype that facilitates tumor growth and metastasis. Notably, TGF-β-induced EMTs in epithelial progenitor cells are accompanied by the expression of fibrogenic factors that activate fibroblasts to produce and remodel the extracellular matrix. This not only occurs during wound healing but also in lung adenocarcinoma (LUAD) and pancreatic adenocarcinoma (PDAC) cells, suggesting that EMT and fibrogenesis are parts of an orchestrated program. We recently showed that the transcription factor RAS-Responsive Element-Binding Protein 1 (RREB1) activated by RAS-MAPK signaling synergizes with SMADs to coordinately activate the expression of EMT transcription factor Snai1 and fibrogenic genes in carcinoma progenitors (Su et al Nature 2020). Using metastasis transplantation models, we have now found that both arms of the RREB1-dependent TGF-β responses are important for metastasis. Knockout of individual fibrogenic genes in cancer cells inhibited metastasis without altering the induction of EMT by TGF-β. To address why these TGF-β target genes specifically require KRAS-activated RREB1 for transcriptional induction, we employed proteomics approaches coupled with a CRISPR-based genetic screen. With this approach we identified DXH9 and INO80 as RREB1-interacting factors essential for TGF-β activation of fibrogenic EMT programs in PDAC and LUAD cells. DXH9 and INO80 are helicases that interact and SMAD3 and RREB1 in response to TGF-β. Knockout of Dhx9 or Ino80 abolished the induction of Snai1 and fibrogenic genes by TGF-β, inhibited the LUAD metastasis, and decreased intratumoral fibrosis, thus phenocopying the knockout of Rreb1. The helicase domain of DHX9 is required for TGF-β gene responses and metastasis. Our evidence indicates that RREB1, DXH9, and INO80 function to remodel the chromatin at specific loci that constitute a TGF-β-dependent fibrogenic EMT program. This work illuminates a previously unknown cooperation between TGF-β and RAS-MAPK pathways during epithelial tissue regeneration and its cooption in carcinoma metastasis.
Citation Format: Jun Ho Lee, Harihar Basnet, Francisco Sánchez-Rivera, Zhenghan Wang, Liangji Li, Joan Massagué. Mechanistic basis for TGF-β-induced fibrogenic EMTs in 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 PR004.
Abstract PR008: Timing complex copy number gains in whole genome duplicated tumors
Authors: Baker Toby M. , Lai Siqi , Dentro Stefan , Tarabichi Maxime , Loo Peter Van 
Published: January 2023

Abstract
The accumulation of genetic copy number aberrations is a process common to the development of many cancers. Tumors that have undergone a whole genome duplication (WGD) are known to have high degrees of genomic instability and often contain genomic regions that have undergone a series of copy number gains resulting in multiple copies of both alleles. Metastases are known to have an even greater rate of WGDs and general genomic instability. WGDs provide a powerful handle to time genetic events, such as single nucleotide variants or copy-number aberrations, in tumor evolution. However, the relative timing of copy number gains in whole genome duplicated tumors is complicated by the fact that there are multiple plausible route histories that could give rise to them. Typically, the most parsimonious event history is assumed to take place but this has never been validated. Here we describe a method, GRITIC, that overcomes this problem by evaluating all possible histories that could result in a given copy number state and determining the timing of the most likely series of gains. GRITIC allows the gains leading to any copy number state to be inferred. On a representative simulated cohort, it accurately measures the timing of complex copy number gains. By applying GRITIC to 6,010 primary and metastatic tumor samples from the Pan-Cancer Analysis of Whole Genomes and Hartwig Medical Foundation datasets, we find that the principle of maximum parsimony is violated in at least 25% of all copy number gains in whole genome duplicated tumors, with gains occurring both much earlier and later than thought under this assumption. We also find evidence for punctuated bursts of gains in WGD tumors, independent of the duplication itself. Finally, GRITIC allows us to look at the influence of WGD on copy-number events by comparing pre- and post-WGD copy number aberration landscapes. We find that the frequency with which different chromosome arms are gained before a WGD is highly correlated with the frequency that they are gained post-WGD. In contrast, the correlation between pre- and post-WGD losses is much smaller. We suggest that this indicates that a genome duplication changes the evolutionary trajectories of copy number losses but not gains. As an exception to this trend, chromosome 8 was disproportionately likely to be gained pre-WGD in metastatic prostate cancer as well as 1q in both breast and liver cancers. Altogether, GRITIC allows for a more accurate inference of evolutionary histories in different cancer types and better insights into the early genomic events that occur in tumors that underwent a WGD.
Citation Format: Toby M. Baker, Siqi Lai, Stefan Dentro, Maxime Tarabichi, Peter Van Loo. Timing complex copy number gains in whole genome duplicated tumors [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 PR008.