bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B013: Tumor-derived CCL5 recruits’ cancer-associated fibroblasts and promotes tumor cell proliferation in esophageal carcinomas
Authors: Dunbar Karen J. , Tang Qiaosi , Karakasheva Tatiana A. , Rustgi Anil K. 
Published: January 2023

Abstract
The tumor microenvironment (TME), at both the primary tumor and sites of metastases, is a key determinant in the success of metastatic colonization. Cancer-associated fibroblasts (CAFs) are a predominant cell type in the TME that, through deposition and remodeling of extracellular matrix (ECM) components, can mediate the TME and promote cancer progression. In addition to cancer progression and metastasis, CAFs have also been shown to mediate resistance to chemotherapy and radiotherapy. Therefore, there is a need to identify the factors which activate and recruit CAFs to solid tumors. Though cytokine arrays, we identified CC motif chemokine ligand 5 (CCL5) as a secreted factor which is increased upon co-culture of esophageal cancer cell lines and CAFs. Using CRISPR/Cas9 technology, we determined that CCL5 is predominantly tumor-cell derived and loss of tumor-cell derived CCL5 reduced esophageal carcinoma cell proliferation in vitro and in vivo. We propose that this reduction in cell proliferation is mediated by ERK1/2 signaling as loss of tumor-cell derived CCL5 reduces expression of p-ERK1/2 and cyclin D1, an ERK1/2 target gene which is essential for cell cycle progression. Interestingly, the loss of tumor-derived CCL5 also reduced the percentage of CAFs, identified by αSMA positivity, recruited to xenograft tumors in vivo. CCL5 is a ligand for the CC motif receptor 5 (CCR5), for which a clinically approved inhibitor exists called Maraviroc. We treated xenografts generated from esophageal carcinoma cell lines or patient derived tumor fragments with Maraviroc. Maraviroc treated xenografts had reduced tumor volume, CAF recruitment and ERK1/2 signaling. Thus, mimicking the effects of the genetic loss of CCL5. Analysis of the TCGA database, identified that high CCL5 or CCR5 expression is associated with poorer prognosis in low grade esophageal carcinomas. Together, we propose that this data highlights the importance of CCL5 in esophageal carcinomas with regards to CAF recruitment and tumor cell proliferation, and that the maraviroc in vivo experiments suggest that targeting the CCL5-CCR5 axis may have therapeutic potential in esophageal carcinomas.
Citation Format: Karen J. Dunbar, Qiaosi Tang, Tatiana A. Karakasheva, Anil K. Rustgi. Tumor-derived CCL5 recruits’ cancer-associated fibroblasts and promotes tumor cell proliferation in esophageal carcinomas [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 B013.
Abstract B016: Pleiotrophin drives a pro-metastatic immune niche within the breast tumor microenvironment
Authors: Ganguly Debolina , Schmidt Marcel , Coleman Morgan , Ngo Tuong-Vi , Sorrelle Noah , Dominguez Adrian , Toombs Jason , Lewis Cheryl , Fang Yisheng , Mora Fatima , Ortega David , Wellstein Anton , Brekken Rolf 
Published: January 2023

Abstract
Metastatic cancer cells adapt to thrive in secondary organs. To investigate metastatic adaptation, we performed transcriptomic analysis of metastatic and non-metastatic murine breast cancer cells. We found that pleiotrophin (PTN), a neurotrophic cytokine, is a metastasis-associated factor that is expressed highly by aggressive breast cancers. Moreover, elevated PTN in plasma correlated significantly with metastasis and reduced survival of breast cancer patients. Mechanistically, we find that PTN activates NF-kB in cancer cells leading to altered cytokine production, subsequent neutrophil recruitment and an immune suppressive microenvironment. Consequently, inhibition of PTN, pharmacologically or genetically, reduces the accumulation of tumor associated neutrophils and reverts local immune suppression resulting in increased T cell activation and attenuated metastasis. Furthermore, inhibition of PTN significantly enhanced the efficacy of immune checkpoint blockade + chemotherapy in reducing metastatic burden in mice. These findings establish PTN as a previously unrecognized driver of a pro-metastatic immune niche and thus represents a promising therapeutic target for the treatment of metastatic breast cancer.
Citation Format: Debolina Ganguly, Marcel Schmidt, Morgan Coleman, Tuong-Vi Ngo, Noah Sorrelle, Adrian Dominguez, Jason Toombs, Cheryl Lewis, Yisheng Fang, Fatima Mora, David Ortega, Anton Wellstein, Rolf Brekken. Pleiotrophin drives a pro-metastatic immune niche within the breast tumor microenvironment [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 B016.
Abstract B021: Piezo1 and ROCK2 promote fast amoeboid migration in confined environments
Authors: Caruso Alexa , Kar Neelakshi , Logue Jeremy 
Published: January 2023

Abstract
Cell migration through confined environments may induce a phenotypic transition to fast amoeboid (leader bleb-based) migration. However, the molecular mechanism(s) controlling this phenotypic transition remain poorly understood. Here, we show that regulation of intracellular calcium levels by the plasma membrane tension sensor, Piezo1, promotes the Leader Bleb-Based Migration (LBBM) of melanoma cells. Using a ratiometric assay, intracellular calcium is shown to rise with increasing levels of confinement. Chelation of extracellular and intracellular calcium by BAPTA and BAPTA-AM, respectively, inhibits LBBM. Moreover, in highly motile cells, we found intracellular calcium levels to be dramatically increased at the cell rear. Using the Piezo1 inhibitor, GsMTx4, and RNAi, we can inhibit the phenotypic transition to fast amoeboid (leader bleb-based) migration. Therefore, we wondered if Piezo1 through calcium/calmodulin activates Myosin Light Chain Kinase (MLCK) to promote actomyosin contractility and amoeboid migration. Using a microchannel based assay, we find that ROCK2 and not MLCK, promotes amoeboid migration. Altogether, our work reveals an unanticipated collaboration between Piezo1 and ROCK2 in amoeboid migrating melanoma cells.
Citation Format: Alexa Caruso, Neelakshi Kar, Jeremy Logue. Piezo1 and ROCK2 promote fast amoeboid migration in confined environments [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 B021.
Abstract B024: TBX2highmiR-375-3plowRBPJhigh signaling drives prostate cancer bone metastatic phenotype via exosomes
Authors: Patel Girijesh Kumar , Dutta Sayanika , Khedmatgozar Hamed , Tripathi Manisha , Nandana Srinivas 
Published: January 2023

Abstract
Recent studies have shown that exosome secretion by prostate cancer (PCa) cells fosters multiple facets of PCa progression and metastasis, mediated in particular through exosomal micro RNAs (miRs) that dictate gene expression changes. However, the molecular mechanisms through which exosomal miRs orchestrate bone remodeling that facilitates the establishment of a pre-metastatic niche (PMN) at the distant metastatic site i.e. bone remain elusive. We have identified that TBX2, a transcription factor that we previously reported plays a key role in PCa metastasis, represses miR-375-3p thereby resulting in de-repression/upregulation of its target RBPJ, an effector of Notch signaling and an established driver of PCa metastasis. Further, the unbiased identification of miR-375-3p as the topmost miR repressed by TBX2, in combination with experiments that genetically manipulate miR-375-3p in the context of TBX2 modulation, point to a crucial biological function of miR-375-3p as a key mediator in RBPJ regulation exerted by TBX2. In addition, the study highlights a dual level of RBPJ regulation by TBX2/miR-375-3p signaling i.e. via: a) gene expression changes at the intra-cellular or autocrine level, and b) gene expression changes at the distant site of bone metastasis through inter-cellular/endocrine communication via exosomes. Further, the study implicates TBX2high primary PCa cells in directing bone remodeling activity at the distant metastatic site in a paracrine mode via exosomes in addition to our previously reported role of TBX2 in mediating bone remodeling in an autocrine mode that occurs following metastatic dissemination. Taken together, our study unravels the role of TBX2/miR-375-3p/RBPJ signaling in PCa bone metastatic progression.
Citation Format: Girijesh Kumar Patel, Sayanika Dutta, Hamed Khedmatgozar, Manisha Tripathi, Srinivas Nandana. TBX2highmiR-375-3plowRBPJhigh signaling drives prostate cancer bone metastatic phenotype via exosomes [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 B024.
Abstract B049: Breast cancer-derived angiopoietin-like 7 regulates necrotic core formation and metastasis from the tumor interior
Authors: Yamamoto Ami , Huang Yin , Krajina Brad A. , McBirney Margaux , Doak Andrea E. , Wang Carolyn L. , Haffner Michael C. , Cheung Kevin J. 
Published: January 2023

Abstract
Necrosis in the tumor interior is a common feature of aggressive cancers that is associated with poor clinical prognosis and the development of metastasis. However, how the necrotic core promotes tumor cell dissemination and metastasis remains unclear. Foundational models for cancer metastasis research include mouse, zebrafish, and chick embryo, but identifying tumor cells in transit is painstaking. Here we used a rat model of breast cancer metastasis to increase detection of dissemination events. Owing to the large size and higher blood volume of rats, we collected 10 times more circulating tumor cells (CTCs) than from mice. In the rat model, tumor dissemination was temporally correlated with the emergence of necrosis in the tumor interior. These findings were corroborated by longitudinal study of CTC abundance and tissue necrosis markers in blood plasma from patients with metastatic breast cancer. Further, we observed that dilated blood vessels were located next to necrotic regions of the tumor and that their increase was concurrent with the initiation of intratumoral necrosis and increase in CTC abundance. Bulk RNA sequencing of mouse-to-rat xenograft tumor necrotic core compared to the non-necrotic rim revealed distinct tumor-specific and host-specific transcripts in the necrotic interior. We identified angiopoietin-like 7 (Angptl7) as a tumor-specific factor localized to the peri-necrotic zone. Functional studies showed that Angptl7 loss normalizes central necrosis, peri-necrotic dilated vessels, metastasis, and reduces circulating tumor cell counts to nearly zero. Mechanistically, Angptl7 promoted vascular permeability and supported vascular remodeling in the peri-necrotic zone. Taken together, these findings show that breast tumors actively produce factors controlling central necrosis formation and metastatic dissemination from the tumor core. Tumor dissemination events are localized spatially to dilated peri-necrotic vessels in the tumor interior, and tumor dissemination is dependent functionally on the expression of a factor, Angptl7, produced by peri-necrotic tumor cells. Our findings in breast cancer models, in conjunction with recent clinical observations, provide strong evidence for tumor dissemination from the tumor interior.
Citation Format: Ami Yamamoto, Yin Huang, Brad A. Krajina, Margaux McBirney, Andrea E. Doak, Carolyn L. Wang, Michael C. Haffner, Kevin J. Cheung. Breast cancer-derived angiopoietin-like 7 regulates necrotic core formation and metastasis from the tumor interior [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 B049.
Abstract IA009: Biology and vulnerabilities of circulating tumor cell clusters
Authors: Aceto Nicola 
Published: January 2023

Abstract
The metastatic spread of cancer occurs through the generation and hematogenous dissemination of circulating tumor cells (CTCs). Among these, CTC clusters have recently emerged as key players in the metastatic process. With a combination of microfluidic technologies and single cell-resolution molecular analysis applied to cancer patients and mouse models, we gained fundamental insights into the biology, vulnerabilities, and clinical implications of CTC clusters. For instance, we found that their physical features enable molecular changes that promote stemness and metastasis, allowing us to define new treatment concepts aimed at suppressing their metastatic potential. Further, we investigated CTC heterogeneity at the single cell level, revealing fundamental interactions that occur between CTCs and immune cells and that accelerate metastasis formation, as well as microenvironment signals that impact on CTC generation. More recently, we also gained important insights into CTC generation dynamics and signals that trigger intravasation. Together, our findings support a model whereby upon defined microenvironmental cues, CTCs form multicellular aggregates to expand their metastatic ability, providing a new rationale for targeting these interactions in cancer.
Citation Format: Nicola Aceto. Biology and vulnerabilities of circulating tumor cell clusters [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 IA009.
Abstract IA022: Cell archetypes in human brain metastases: Connecting programs in tumor cells with the microenvironment
Authors: Gonzalez Hugo , Mei Wenbin , Robles Isabella , Hagerling Catharina , Allen Breanna , Okholm Trine Hauge , Nanjaraj Ankitha , Verbeek Tamara , Kalavacherla Sandhya , Gogh Merel van , Georgiou Stephen , Daras Mariza , Phillips Joanna J. , Spitzer Matthew H. , Roose Jeroen P. , Werb Zena 
Published: January 2023

Abstract
Brain metastasis (BrM) is the most common form of brain cancer, characterized by neurologic disability and an abysmal prognosis. Unfortunately, our understanding of the biology underlying human BrMs remains rudimentary. Here, we present an integrative analysis of &gt;100,000 malignant and non-malignant cells from 15 human parenchymal BrMs, generated by single-cell transcriptomics, mass cytometry, and complemented with mouse model- and in silico approaches. Specific single-cell interrogation of metastatic tumor cells provides a framework of 8 functional cell programs that coexist or anticorrelate. Collectively, these programs delineate two functional BrM archetypes, that co-exist within each metastatic tumor, one proliferative and the other inflammatory, that are evidently shaped through tumor-immune interactions. Our study provides a foundation to understand the molecular basis of BrM in patients with tumor cell-intrinsic and host environmental traits. For more details please refer to the original study: H. Gonzalez, et al. Cellular architecture of human brain metastases Cell, 185 (2022), pp. 729-745.
Citation Format: Hugo Gonzalez, Wenbin Mei, Isabella Robles, Catharina Hagerling, Breanna Allen, Trine Hauge Okholm, Ankitha Nanjaraj, Tamara Verbeek, Sandhya Kalavacherla, Merel van Gogh, Stephen Georgiou, Mariza Daras, Joanna J. Phillips, Matthew H. Spitzer, Jeroen P. Roose, Zena Werb. Cell archetypes in human brain metastases: Connecting programs in tumor cells with the microenvironment [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 IA022.
Abstract IA026: Chromosomal instability as a driver of cancer metastasis
Authors: Bakhoum Samuel F. 
Published: January 2023

Abstract
Chromosomal instability (CIN) is a hallmark of human cancer that is associated with metastasis and immune evasion. Yet, how CIN shapes the tumor microenvironment (TME) to facilitate tumor progression remains poorly understood. We undertook a systems level approach to better define the impact of CIN on cancer cell states as well as TME phenotypes and found that cancer cell CIN engenders a pro-metastatic TME that is markedly enriched for immune-suppressive macrophages, a granulocytic infiltrate, and dysfunctional T cells. We then developed a novel computational tool to infer conditionally dependent cell-cell interactions from single cell RNA sequence data to define tumor-derived factors that shape the TME and promote metastatic dissemination. This work led to the identification of novel therapeutic targets in chromosomally unstable tumors and sheds light on key mechanisms by which CIN cooperates with the immune system to drive disease progression.
Citation Format: Samuel F. Bakhoum. Chromosomal instability as a driver of cancer 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 IA026.
Abstract PR001: Codon-bias and tRNA modifications as drivers of melanoma metastasis
Authors: Piskounova Elena 
Published: January 2023

Abstract
Only tumor cells that are able to enhance their stress response pathways, are able to successfully metastasize and colonize distant organs. In yeast, reprogramming of translation through modification of the tRNA anticodon loop in response to stress has been shown to be a central adaptive mechanism of survival. Distinct tRNA modifications increase translational efficiency of certain codons. These modifications are upregulated and are essential for survival under a range of stressors, including oxidative stress. The adaptive proteome is therefore encoded by specific transcripts with a distinct codon bias and regulated by these tRNA modifications. We have identified several stress-induced tRNA anticodon loop modifications in metastasizing melanoma cells that drive codon-biased translation of the adaptive pro-metastatic proteome. One of these modifications specifically regulates stress-induced translation of selenocysteine-containing proteins. Selenoproteins are central to stress resistance including oxidative and proteotoxic stress. We have identified and characterized the methyltransferase that regulates this modification and enables translation of the metastatic selenoproteome. More broadly, by combining biochemical approaches with in vivo models of melanoma metastasis, we have now identified several other enzymes responsible for multiple tRNA anticodon modifications as novel and targetable drivers of metastatic disease. Our work aims to establish how tRNA anticodon modifications and a distinct codon bias reprogram the metastatic proteome as a therapeutically targetable stress response mechanism.
Citation Format: Elena Piskounova. Codon-bias and tRNA modifications as drivers of melanoma 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 PR001.
Abstract PR017: Differences in melanoma lipid metabolism among distinct metastatic sites
Authors: Mathews Thomas P. , Muh Sarah , Aurora Arin B. , Morrison Sean J. 
Published: January 2023

Abstract
Metastasis is a very inefficient process in which few disseminated cancer cells survive. We developed a patient-derived xenograft assay in which melanomas engraft and spontaneously metastasize (Quintana Nature 456:593-598). Using this assay, we discovered that melanoma cells experience a spike in reactive oxygen species during metastasis and that distant metastasis is limited by oxidative stress (Piskounova Nature 527:186-191). Successfully metastasizing cells undergo reversible metabolic changes during metastasis that increase oxidative stress resistance. For example, melanoma cells in lymph experience less oxidative stress and form more metastases than melanoma cells in the blood (Ubellacker Nature 585:113-120). This is true in both patient-derived melanomas growing in immunocompromised mice and mouse melanomas growing in syngeneic immunocompetent mice. Cells metastasizing through blood, but not lymph, appear to undergo ferroptosis, a form of cell death marked by lipid oxidation. Multiple differences between lymph fluid and blood plasma may contribute to this difference in oxidative stress, including higher levels of oleic acid in lymph. Oleic acid is a monounsaturated fatty acid that protects melanoma cells from ferroptosis, apparently by reducing the abundance of oxidizable polyunsaturated fatty acids (PUFAs) in phospholipids. In the current study we found that some PUFAs sensitize melanoma cells to lipid peroxidation and cell death more than others. Moreover, we analyzed the lipid profiles of common sites of distant metastasis – liver, brain, kidney, pancreas, bone marrow, lung, and liver – and found that the PUFA compositions of these tissues varies significantly. This raises the possibility that metastasizing melanoma cells may incorporate more PUFAs into their phospholipid membranes and exhibit increased ferroptosis sensitivity in some metastatic sites as compared to others. We found that melanoma cells isolated from metastatic sites by flow cytometry had higher levels of PUFAs in their phospholipid membranes compared to those isolated from subcutaneous tissues. These cells isolated from distal sites also exhibited higher levels of lipid ROS and contained higher levels of oxidized lipid species compared to subcutaneous tumors. These data suggest that the lipid metabolism of metastatic tumors reflects both lipid availability in the metastatic site as well as cell-intrinsic differences in lipid metabolism, both of which contribute to lipid ROS. Both cell-intrinsic and cell-extrinsic lipid metabolism likely influence the ability of melanoma cells to survive in distinct metastatic sites during metastasis.
Citation Format: Thomas P. Mathews, Sarah Muh, Arin B. Aurora, Sean J. Morrison. Differences in melanoma lipid metabolism among distinct metastatic sites [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 PR017.
The Relationship between Horizontal and Vertical Velocity Wavenumber Spectra in Global Storm-Resolving Simulations
Authors: Morfa Yanmichel A. , Stephan Claudia C. 
Published: January 2023

Abstract
Several studies have reported vertical kinetic energy spectra almost white in horizontal wavenumber space with evidence of two maxima at synoptic scales and mesoscales, leaving the explanation of these maxima open. Processes known to influence the shape of the horizontal kinetic energy spectra include the superposition of quasi-linear inertia–gravity waves (IGWs), quasigeostrophic turbulence, and moist convection. In contrast, vertical kinetic energy has been discussed much less, as measuring vertical velocity remains challenging. This study compares the horizontal and vertical kinetic energy spectra and their relationships in global storm-resolving simulations from the DYAMOND experiment. The consistency of these relationships with linear IGW theory is tested by diagnosing horizontal wind fluctuations associated with IGW modes. Furthermore, it is shown that hydrostatic IGW polarization relations provide a quantitative prediction of the spectral slopes of vertical kinetic energy at large scales and mesoscales, where the intrinsic frequencies are inferred from the linearized vorticity equation. Our results suggest that IGW modes dominate the vertical kinetic energy spectra at most horizontal scales, whereas an incompressible, isotropic scaling of the continuity equation captures the relationship between horizontal and vertical kinetic energy spectra at small scales.