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1. Dissecting the treatment-naive ecosystem of human melanoma brain metastasis

Author

Biermann, Jana, Melms, Johannes C, Amin, Amit Dipak, Wang, Yiping, Caprio, Lindsay A, Karz, Alcida, Tagore, Somnath, Barrera, Irving, Ibarra-Arellano, Miguel A, Andreatta, Massimo, Fullerton, Benjamin T, Gretarsson, Kristjan H, Sahu, Varun, Mangipudy, Vaibhav S, Nguyen, Trang TT, Nair, Ajay, Rogava, Meri, Ho, Patricia, Koch, Peter D, Banu, Matei, Humala, Nelson, Mahajan, Aayushi, Walsh, Zachary H, Shah, Shivem B, Vaccaro, Daniel H, Caldwell, Blake, Mu, Michael, Wünnemann, Florian, Chazotte, Margot, Berhe, Simon, Luoma, Adrienne M, Driver, Joseph, Ingham, Matthew, Khan, Shaheer A, Rapisuwon, Suthee, Slingluff, Craig L, Eigentler, Thomas, Röcken, Martin, Carvajal, Richard, Atkins, Michael B, Davies, Michael A, Agustinus, Albert, Bakhoum, Samuel F, Azizi, Elham, Siegelin, Markus, Lu, Chao, Carmona, Santiago J, Hibshoosh, Hanina, Ribas, Antoni, Canoll, Peter, Bruce, Jeffrey N, Bi, Wenya Linda, Agrawal, Praveen, Schapiro, Denis, Hernando, Eva, Macosko, Evan Z, Chen, Fei, Schwartz, Gary K, and Izar, Benjamin

Subjects
Cancer, Biotechnology, Neurosciences, Aetiology, 2.1 Biological and endogenous factors, Brain Neoplasms, CD8-Positive T-Lymphocytes, Ecosystem, Humans, Melanoma, RNA-Seq, brain metastasis, chromosomal instability, melanoma, neuronal-like cell state, single-cell genomics, spatial transcriptomics, tumor-microenvironment, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX+CD8+ T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration.

Published
2022

2. Multi-scale signaling and tumor evolution in high-grade gliomas

Author

Agarwal, Anupriya, Alnahhas, Iyad, Amin, Mitual, An, Eunkyung, Anderson, Matthew L., Andrews, David W., Anurag, Meenakshi, Barnholtz-Sloan, Jill S., Bauer, Thomas, Bavarva, Jasmin, Binder, Zev A., Birrer, Michael J., Borate, Uma, Borucki, Melissa, Bramer, Lisa M., Brem, Steven, Cai, Shuang, Cantley, Lewis C., Cao, Song, Caravan, Wagma, Carr, Steven A, Chan, Daniel W., Chen, Lijun, Chen, Lin S., Chen, Xi S., Chesla, David, Chheda, Milan G., Chinnaiyan, Arul M., Chowdhury, Shrabanti, Chu, Rosalie K., Cieślik, Marcin P., Clark, Natalie M., Clauser, Karl, Colaprico, Antonio, Cottingham, Sandra L., Couvillion, Sneha P., Crispen, Reese, Czernicki, Tomasz, D’Angelo, Fulvio, Demir, Emek, Dhanasekaran, Saravana Mohan, Ding, Li, Domagalski, Marcin J., Dou, Yongchao, Druker, Brian, Eder, Josie, Edwards, Nathan J., Eschbacher, Jennifer, Fenyő, David, Fillmore, Thomas H., Gabrovski, Nikolay, Gao, Yuqian, Garofano, Luciano, Geffen, Yifat, Getz, Gad, Gillette, Michael A., Golbin, Denis, Goldthwaite, Charles A., Jr., Gritsenko, Marina A., Gumus, Zeynep, Hanhan, Ziad, Hermes, Beth, Hiltke, Tara, Hostetter, Galen, Houston, Andrew, Huang, Chen, Iavarone, Antonio, Imbach, Kathleen J., Jaehnig, Eric, Jewell, Scott D., Johnson, Jared L., Judy, Kevin D., Karz, Alicia, Kaspera, Wojciech, Ketchum, Karen A., Kim, Lyndon, Kim, Young-Mo, Koptyra, Mateusz P, Kothadia, Ramani B, Kumar-Sinha, Chandan, Kyle, Jennifer E., Lee, John Y.K., Lei, Jonathan, Leprevost, Felipe D., Li, Kai, Li, Qing Kay, Li, Yize, Li, Zibo, Liao, Yuxing, Lih, Tung-Shing M., Lilly, Jena, Liu, Jingxian, Liu, Tao, Jui-Hsien Lu, Rita, Lu, Yin, Lubínski, Jan, Ma, Weiping, Maggio, William, Malovannaya, Anna, Mani, D.R., Martinez, Nina, McDermott, Jason E., McGarvey, Peter B., Mesri, Mehdi, Migliozzi, Simona, Monroe, Matthew E., Moore, Ronald J., Al Deen, Nataly Naser, Nasrallah, MacLean P., Nestor, Michael, Nesvizhskii, Alexey I., Newton, Chelsea J., O’Rourke, Donald M., Omenn, Gilbert S., Ozbek, Umut, Paklina, Oxana V., Paulovich, Amanda G., Payne, Samuel H., Petralia, Francesca, Petyuk, Vladislav A., Pico, Alexander R., Piehowski, Paul D., Pilozzi, Alexander, Placantonakis, Dmitris, Porta-Pardo, Eduard, Potapova, Olga, Pruetz, Barbara, Resnick, Adam C., Reva, Boris, Robles, Ana I., Rodland, Karin D., Rodriguez, Henry, Rohrer, Daniel C., Rood, Brian, Rossell, Larissa, Ruggles, Kelly V., Rykunov, Dmitry, Sagendorf, Tyler, Sarkar, Atom, Satpathy, Shankha, Savage, Sara R., Schadt, Eric E., Schepmoes, Athena A., Shepard, Scott R., Shi, Zhiao, Shutack, Yvonne, Smith, Richard D., Sokoll, Lori J., Song, Yingduo, Song, Yizhe, Southard-Smith, Austin N., Stawicki, Jakub, Storm, Phillip B., Stratton, Kelly G., Strunilin, Ilya, Szopa, Wojciech, Thangudu, Ratna R., Thiagarajan, Mathangi, Tognon, Cristina, Traer, Elie, Tsai, Chia-Feng, Tsang, Shirley, Turtz, Alan R., Tyner, Jeffrey, Vatanian, Negin, Wan, Weiqing, Wang, Liang-Bo, Wang, Pei, Wang, Yi-Ting, Weaver, Michael W., Weitz, Karl K., Wen, Bo, Whiteaker, Jeffrey R., Williams, Bart, Wilson, George D., Wiznerowicz, Maciej, Wu, Yige, Wyczalkowski, Matthew A., Yao, Lijun, Yaron, Tomer M., Zager, Eric L., Zhang, Bing, Zhang, Hui, Zhang, Xu, Zhang, Zhen, Zhao, Rui, Zhu, Jun, Yaron-Barir, Tomer M., Shinkle, Andrew, Naser Al Deen, Nataly, Simin, Faria Anjum, Storrs, Erik, Chen, Siqi, Illindala, Ritvik, Li, Yuping D., Jayasinghe, Reyka G., Fillmore, Thomas L., Li, Yang E., Fenyö, David, and Chen, Feng

Published
2024
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4. An epigenetic switch controls an alternative NR2F2 isoform that unleashes a metastatic program in melanoma

Author

Davalos, Veronica, Lovell, Claudia D., Von Itter, Richard, Dolgalev, Igor, Agrawal, Praveen, Baptiste, Gillian, Kahler, David J., Sokolova, Elena, Moran, Sebastian, Piqué, Laia, Vega-Saenz de Miera, Eleazar, Fontanals-Cirera, Barbara, Karz, Alcida, Tsirigos, Aristotelis, Yun, Chi, Darvishian, Farbod, Etchevers, Heather C., Osman, Iman, Esteller, Manel, Schober, Markus, and Hernando, Eva

Published
2023
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5. Feasibility of Health Literacy Tools for Older Patients in the Emergency Department

Author

McGuinness, Matthew J., Bucher, Joshua, Karz, James, Pardee, Carla, Patti, Laryssa, Ohman-Strickland, Pamela, and McCoy, Jonathan V.

Subjects
Health Literacy, Emergency Department, Newest Vital Sign, SAHL
Abstract

Introduction: This study evaluates the feasibility of using a volunteer research associate (RA) to administer two separate health literacy assessment tools in the emergency department (ED), specifically in an older population of patients. The outcomes measured were administration time and interruptions.Methods: Using a prospective, cross-sectional study with a convenience sample, adult patients over the age of 55 presenting between June–August 2018 to one urban, academic ED were evaluated by a volunteer RA using either the Newest Vital Sign (NVS) or the Short Assessment of Health Literacy (SAHL). All patients 55 years of age or older who consented to participate were included. We excluded from this study the following: patients with dementia or other disability involving reading, speech, or cognitive function, as noted in their medical record or by their attending physician; prisoners; and those subjectively deemed in extremis or too ill to participate by their attending physician.Results: Health literacy was assessed in 202 patients using either the NVS or SAHL. Mean time of administration was 214.0 seconds for the NVS, and 206.8 for the SAHL. The maximum time of administration for the NVS was 563 seconds, compared to 607 seconds for the SAHL. We found that 95.2% of NVS and 93.9% of SAHL tests incurred no interruptions during administration.Conclusion: No significant difference was found between the length of time needed to administer the NVS or SAHL to older patients in the ED. Both tools averaged an administration time of around three to four minutes, and neither incurred regular interruptions to its administration by a volunteer RA. Further study is needed to assess validity of these tools in an ED setting.

Published
2020

6. Material characterization of GPX®: A versatile in situ solidifying embolic platform technology

Author

Russell J. Stewart, Monika Sima, Jessica Karz, and Joshua P. Jones

Subjects
embolization, embolic agent, liquid embolic, chemoembolization (TACE), doxorubicin, polyelectrolytes, Biotechnology, TP248.13-248.65
Abstract

Endovascular embolization is a minimally invasive procedure during which blood flow to targeted tissues is selectively occluded. The list of clinical indications for embolization continues to expand. Liquid embolic agents are injectable compositions that transition into a solid or semi-solid form when introduced into blood vessels. The mechanism that triggers the liquid-to-solid transition is a key distinguishing feature of liquid embolic agents. GPX is a waterborne liquid embolic agent comprising oppositely charged polyelectrolytes: polyguanidinum and inorganic polyphoshate. In situ solidification is driven by electrostatic condensation of the polyelectrolytes, triggered by ionic strength differentials. We report in vitro characterization of the material properties of GPX, it is in vivo effectiveness in acute animal studies, and its potential for chemoembolization. The viscosity of GPX can be varied over a wide range by adjusting the polyguanidinium MW and/or concentration. Formulation of GPX with either tantalum microparticles (30 wt%) or iodinated radiocontrast agents (300 mgI ml−1) did not significantly change the flow behavior of GPX; the viscosity was independent of shear rate and remained within a clinically practical range (80–160 cP). Formulation of GPX with doxorubicin substantially increased viscosity at low shear rates and resulted in a power law dependence on shear rate. High contrast and effective vascular occlusion were demonstrated in both swine kidneys and rete mirabile. Contrast from iodinated compounds was temporary, dissipating within hours. The doxorubicin in vitro release profile was linear over 90 days. The results demonstrate that GPX is a versatile liquid embolic platform that can be formulated with a wide range of viscosities injectable at clinically practical flow rates, with either transient or permanent contrast, and that can provide prolonged zero-order delivery of doxorubicin to embolized tissues.

Published
2023
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7. Osborn Waves

Author

Karz, James Elliot, Wei, Grant, and Shah, Chirag

Published
2018

8. Are You Checked Out at Work?

Author

Horan, Rebecca and Karz, Melissa

Subjects
BUSINESS networks, BUSINESS schools, INTERNET forums, CORPORATE culture, WORKWEEK
Abstract

The article "Are You Checked Out at Work?" discusses strategies to combat disengagement in the workplace, which affects over half of U.S. workers. The authors emphasize the importance of purposeful interactions to reignite engagement, highlighting the benefits of collaboration, brainstorming sessions, seeking peer input, stepping away from the desk, and seeking out community. By implementing these small actions, individuals can break the withdrawal cycle, increase connection, and restore energy and creativity in their work. The article provides practical tips for individuals to re-engage at work and emphasizes the significance of leaning into connection to combat isolation. [Extracted from the article]

Published
2025

9. Proteogenomic and metabolomic characterization of human glioblastoma

Author

Agarwal, Anupriya, Amin, Mitual, An, Eunkyung, Anderson, Matthew L., Andrews, David W., Bauer, Thomas, Birger, Chet, Birrer, Michael J., Blumenberg, Lili, Bocik, William E., Borate, Uma, Borucki, Melissa, Burke, Meghan C., Cai, Shuang, Calinawan, Anna P., Carr, Steven A., Cerda, Sandra, Chan, Daniel W., Charamut, Alyssa, Chen, Lin S., Chesla, David, Chinnaiyan, Arul M., Chowdhury, Shrabanti, Cieślik, Marcin P., Clark, David J., Culpepper, Houston, Czernicki, Tomasz, D'Angelo, Fulvio, Day, Jacob, De Young, Stephanie, Demir, Emek, Dhanasekaran, Saravana Mohan, Dhir, Rajiv, Domagalski, Marcin J., Druker, Brian, Duffy, Elizabeth, Dyer, Maureen, Edwards, Nathan J., Edwards, Robert, Elburn, Kimberly, Ellis, Matthew J., Eschbacher, Jennifer, Francis, Alicia, Gabriel, Stacey, Gabrovski, Nikolay, Garofano, Luciano, Getz, Gad, Gillette, Michael A., Godwin, Andrew K., Golbin, Denis, Hanhan, Ziad, Hannick, Linda I., Hariharan, Pushpa, Hindenach, Barbara, Hoadley, Katherine A., Hostetter, Galen, Huang, Chen, Jaehnig, Eric, Jewell, Scott D., Ji, Nan, Jones, Corbin D., Karz, Alcida, Kaspera, Wojciech, Kim, Lyndon, Kothadia, Ramani B., Kumar-Sinha, Chandan, Lei, Jonathan, Leprevost, Felipe D., Li, Kai, Liao, Yuxing, Lilly, Jena, Liu, Hongwei, Lubínski, Jan, Madan, Rashna, Maggio, William, Malc, Ewa, Malovannaya, Anna, Mareedu, Sailaja, Markey, Sanford P., Marrero-Oliveras, Annette, Martinez, Nina, Maunganidze, Nicollette, McDermott, Jason E., McGarvey, Peter B., McGee, John, Mieczkowski, Piotr, Migliozzi, Simona, Modugno, Francesmary, Montgomery, Rebecca, Newton, Chelsea J., Omenn, Gilbert S., Ozbek, Umut, Paklina, Oxana V., Paulovich, Amanda G., Perou, Amy M., Pico, Alexander R., Piehowski, Paul D., Placantonakis, Dimitris G., Polonskaya, Larisa, Potapova, Olga, Pruetz, Barbara, Qi, Liqun, Ramkissoon, Shakti, Resnick, Adam, Richey, Shannon, Riggins, Gregory, Robinson, Karna, Roche, Nancy, Rohrer, Daniel C., Rood, Brian R., Rossell, Larissa, Savage, Sara R., Schadt, Eric E., Shi, Yan, Shi, Zhiao, Shutack, Yvonne, Singh, Shilpi, Skelly, Tara, Sokoll, Lori J., Stawicki, Jakub, Stein, Stephen E., Suh, James, Szopa, Wojciech, Tabor, Dave, Tan, Donghui, Tansil, Darlene, Thangudu, Ratna R., Tognon, Cristina, Traer, Elie, Tsang, Shirley, Tyner, Jeffrey, Um, Ki Sung, Valley, Dana R., Vasaikar, Suhas, Vatanian, Negin, Velvulou, Uma, Vernon, Michael, Wan, Weiqing, Wang, Junmei, Webster, Alex, Wen, Bo, Whiteaker, Jeffrey R., Wilson, George D., Zakhartsev, Yuriy, Zelt, Robert, Zhang, Hui, Zhang, Liwei, Zhang, Zhen, Zhao, Grace, Zhu, Jun, Wang, Liang-Bo, Karpova, Alla, Gritsenko, Marina A., Kyle, Jennifer E., Cao, Song, Li, Yize, Rykunov, Dmitry, Colaprico, Antonio, Rothstein, Joseph H., Hong, Runyu, Stathias, Vasileios, Cornwell, MacIntosh, Petralia, Francesca, Wu, Yige, Reva, Boris, Krug, Karsten, Pugliese, Pietro, Kawaler, Emily, Olsen, Lindsey K., Liang, Wen-Wei, Song, Xiaoyu, Dou, Yongchao, Wendl, Michael C., Caravan, Wagma, Liu, Wenke, Cui Zhou, Daniel, Ji, Jiayi, Tsai, Chia-Feng, Petyuk, Vladislav A., Moon, Jamie, Ma, Weiping, Chu, Rosalie K., Weitz, Karl K., Moore, Ronald J., Monroe, Matthew E., Zhao, Rui, Yang, Xiaolu, Yoo, Seungyeul, Krek, Azra, Demopoulos, Alexis, Zhu, Houxiang, Wyczalkowski, Matthew A., McMichael, Joshua F., Henderson, Brittany L., Lindgren, Caleb M., Boekweg, Hannah, Lu, Shuangjia, Baral, Jessika, Yao, Lijun, Stratton, Kelly G., Bramer, Lisa M., Zink, Erika, Couvillion, Sneha P., Bloodsworth, Kent J., Satpathy, Shankha, Sieh, Weiva, Boca, Simina M., Schürer, Stephan, Chen, Feng, Wiznerowicz, Maciej, Ketchum, Karen A., Boja, Emily S., Kinsinger, Christopher R., Robles, Ana I., Hiltke, Tara, Thiagarajan, Mathangi, Nesvizhskii, Alexey I., Zhang, Bing, Mani, D.R., Ceccarelli, Michele, Chen, Xi S., Cottingham, Sandra L., Li, Qing Kay, Kim, Albert H., Fenyö, David, Ruggles, Kelly V., Rodriguez, Henry, Mesri, Mehdi, Payne, Samuel H., Resnick, Adam C., Wang, Pei, Smith, Richard D., Iavarone, Antonio, Chheda, Milan G., Barnholtz-Sloan, Jill S., Rodland, Karin D., Liu, Tao, and Ding, Li

Published
2021
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10. Proteogenomic insights into the biology and treatment of HPV-negative head and neck squamous cell carcinoma

Author

Agarwal, Anupriya, Anderson, Matthew L., Avanessian, Shayan C., Avtonomov, Dmitry, Bathe, Oliver F., Birger, Chet, Birrer, Michael J., Blumenberg, Lili, Bocik, William E., Borate, Uma, Borucki, Melissa, Burke, Meghan C., Cai, Shuang, Calinawan, Anna Pamela, Cerda, Sandra, Charamut, Alyssa, Chen, Lin S., Chowdhury, Shrabanti, Clauser, Karl R., Culpepper, Houston, Czernicki, Tomasz, D'Angelo, Fulvio, Day, Jacob, De Young, Stephanie, Demir, Emek, Ding, Fei, Domagalski, Marcin J., Dort, Joseph C., Druker, Brian, Duffy, Elizabeth, Dyer, Maureen, Edwards, Nathan J., Elburn, Kimberly, Ermakova, Tatiana S., Fenyo, David, Ferrarotto, Renata, Francis, Alicia, Gabriel, Stacey, Garofano, Luciano, Geffen, Yifat, Getz, Gad, Goldthwaite, Charles A., Hannick, Linda I., Hariharan, Pushpa, Hayes, David N., Heiman, David, Hindenach, Barbara, Hoadley, Katherine A., Hostetter, Galen, Hyrcza, Martin, Jewell, Scott D., Jones, Corbin D., Kane, M. Harry, Karz, Alicia, Kothadia, Ramani B., Krek, Azra, Kumar-Sinha, Chandan, Liu, Tao, Liu, Hongwei, Ma, Weiping, Malc, Ewa, Malovannaya, Anna, Mareedu, Sailaja, Markey, Sanford P., Marrero-Oliveras, Annette, Maunganidze, Nicollette, McDermott, Jason E., McGarvey, Peter B., McGee, John, Mieczkowski, Piotr, Migliozzi, Simona, Montgomery, Rebecca, Newton, Chelsea J., Ozbek, Umut, Paulovich, Amanda G., Payne, Samuel H., Pazardzhikliev, Dimitar Dimitrov, Perou, Amy M., Petralia, Francesca, Petrenko, Lyudmila, Piehowski, Paul D., Placantonakis, Dmitris, Polonskaya, Larisa, Ponomareva, Elena V., Potapova, Olga, Qi, Liqun, Qu, Ning, Ramkissoon, Shakti, Reva, Boris, Richey, Shannon, Robinson, Karna, Roche, Nancy, Rodland, Karin, Rohrer, Daniel C., Rykunov, Dmitry, Schadt, Eric E., Shi, Yan, Shutack, Yvonne, Singh, Shilpi, Skelly, Tara, Smith, Richard, Sokoll, Lori J., Stawicki, Jakub, Stein, Stephen E., Suh, James, Szopa, Wojciech, Tabor, Dave, Tan, Donghui, Tansil, Darlene, Teo, Guo Ci, Thangudu, Ratna R., Tognon, Cristina, Traer, Elie, Tsang, Shirley, Tyner, Jeffrey, Um, Ki Sung, Valley, Dana R., Vasilev, Lyubomir Valkov, Vatanian, Negin, Velvulou, Uma, Vernon, Michael, Westbrook, Thomas F., Whiteaker, Jeffrey R., Wu, Yige, Xu, Midie, Yao, Lijun, Yi, Xinpei, Yu, Fengchao, Zaalishvili, Kakhaber, Zakhartsev, Yuriy, Zelt, Robert, Zhao, Grace, Zhu, Jun, Huang, Chen, Chen, Lijun, Savage, Sara R., Eguez, Rodrigo Vargas, Dou, Yongchao, Li, Yize, da Veiga Leprevost, Felipe, Jaehnig, Eric J., Lei, Jonathan T., Wen, Bo, Schnaubelt, Michael, Krug, Karsten, Song, Xiaoyu, Cieślik, Marcin, Chang, Hui-Yin, Wyczalkowski, Matthew A., Li, Kai, Colaprico, Antonio, Li, Qing Kay, Clark, David J., Hu, Yingwei, Cao, Liwei, Pan, Jianbo, Wang, Yuefan, Cho, Kyung-Cho, Shi, Zhiao, Liao, Yuxing, Jiang, Wen, Anurag, Meenakshi, Ji, Jiayi, Yoo, Seungyeul, Zhou, Daniel Cui, Liang, Wen-Wei, Wendl, Michael, Vats, Pankaj, Carr, Steven A., Mani, D.R., Zhang, Zhen, Qian, Jiang, Chen, Xi S., Pico, Alexander R., Wang, Pei, Chinnaiyan, Arul M., Ketchum, Karen A., Kinsinger, Christopher R., Robles, Ana I., An, Eunkyung, Hiltke, Tara, Mesri, Mehdi, Thiagarajan, Mathangi, Weaver, Alissa M., Sikora, Andrew G., Lubiński, Jan, Wierzbicka, Małgorzata, Wiznerowicz, Maciej, Satpathy, Shankha, Gillette, Michael A., Miles, George, Ellis, Matthew J., Omenn, Gilbert S., Rodriguez, Henry, Boja, Emily S., Dhanasekaran, Saravana M., Ding, Li, Nesvizhskii, Alexey I., El-Naggar, Adel K., Chan, Daniel W., Zhang, Hui, and Zhang, Bing

Published
2021
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12. MetFinder: A Tool for Automated Quantitation of Metastatic Burden in Histological Sections From Preclinical Models.

Author

Karz, Alcida, Coudray, Nicolas, Bayraktar, Erol, Galbraith, Kristyn, Jour, George, Shadaloey, Arman Alberto Sorin, Eskow, Nicole, Rubanov, Andrey, Navarro, Maya, Moubarak, Rana, Baptiste, Gillian, Levinson, Grace, Mezzano, Valeria, Alu, Mark, Loomis, Cynthia, Lima, Daniel, Rubens, Adam, Jilaveanu, Lucia, Tsirigos, Aristotelis, and Hernando, Eva

Subjects
*ARTIFICIAL neural networks, *DEEP learning, *COLLEGE laboratories, *RESEARCH personnel, *ANIMAL models in research
Abstract

ABSTRACT As efforts to study the mechanisms of melanoma metastasis and novel therapeutic approaches multiply, researchers need accurate, high‐throughput methods to evaluate the effects on tumor burden resulting from specific interventions. We show that automated quantification of tumor content from whole slide images is a compelling solution to assess in vivo experiments. In order to increase the outflow of data collection from preclinical studies, we assembled a large dataset with annotations and trained a deep neural network for the quantitative analysis of melanoma tumor content on histopathological sections of murine models. After assessing its performance in segmenting these images, the tool obtained consistent results with an orthogonal method (bioluminescence) of measuring metastasis in an experimental setting. This AI‐based algorithm, made freely available to academic laboratories through a web‐interface called MetFinder, promises to become an asset for melanoma researchers and pathologists interested in accurate, quantitative assessment of metastasis burden. [ABSTRACT FROM AUTHOR]

Published
2024
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13. HNRNPM controls circRNA biogenesis and splicing fidelity to sustain cancer cell fitness

Author

Jessica SY Ho, Federico Di Tullio, Megan Schwarz, Diana Low, Danny Incarnato, Florence Gay, Tommaso Tabaglio, JingXian Zhang, Heike Wollmann, Leilei Chen, Omer An, Tim Hon Man Chan, Alexander Hall Hickman, Simin Zheng, Vladimir Roudko, Sujun Chen, Alcida Karz, Musaddeque Ahmed, Housheng Hansen He, Benjamin D Greenbaum, Salvatore Oliviero, Michela Serresi, Gaetano Gargiulo, Karen M Mann, Eva Hernando, David Mulholland, Ivan Marazzi, Dave Keng Boon Wee, and Ernesto Guccione

Subjects
splicing, antisense oligonucleotides, circular RNA, Medicine, Science, Biology (General), QH301-705.5
Abstract

High spliceosome activity is a dependency for cancer cells, making them more vulnerable to perturbation of the splicing machinery compared to normal cells. To identify splicing factors important for prostate cancer (PCa) fitness, we performed pooled shRNA screens in vitro and in vivo. Our screens identified heterogeneous nuclear ribonucleoprotein M (HNRNPM) as a regulator of PCa cell growth. RNA- and eCLIP-sequencing identified HNRNPM binding to transcripts of key homeostatic genes. HNRNPM binding to its targets prevents aberrant exon inclusion and backsplicing events. In both linear and circular mis-spliced transcripts, HNRNPM preferentially binds to GU-rich elements in long flanking proximal introns. Mimicry of HNRNPM-dependent linear-splicing events using splice-switching-antisense-oligonucleotides was sufficient to inhibit PCa cell growth. This suggests that PCa dependence on HNRNPM is likely a result of mis-splicing of key homeostatic coding and non-coding genes. Our results have further been confirmed in other solid tumors. Taken together, our data reveal a role for HNRNPM in supporting cancer cell fitness. Inhibition of HNRNPM activity is therefore a potential therapeutic strategy in suppressing growth of PCa and other solid tumors.

Published
2021
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14. Feasibility of Health Literacy Tools for Older Patients in the Emergency Department

Author

Matthew J. McGuinness, Joshua Bucher, James Karz, Carla Pardee, Laryssa Patti, Pamela Ohman-Strickland, and Jonathan V. McCoy

Subjects
Medicine, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Introduction: This study evaluates the feasibility of using a volunteer research associate (RA) to administer two separate health literacy assessment tools in the emergency department (ED), specifically in an older population of patients. The outcomes measured were administration time and interruptions. Methods: Using a prospective, cross-sectional study with a convenience sample, adult patients over the age of 55 presenting between June–August 2018 to one urban, academic ED were evaluated by a volunteer RA using either the Newest Vital Sign (NVS) or the Short Assessment of Health Literacy (SAHL). All patients 55 years of age or older who consented to participate were included. We excluded from this study the following: patients with dementia or other disability involving reading, speech, or cognitive function, as noted in their medical record or by their attending physician; prisoners; and those subjectively deemed in extremis or too ill to participate by their attending physician. Results: Health literacy was assessed in 202 patients using either the NVS or SAHL. Mean time of administration was 214.0 seconds for the NVS, and 206.8 for the SAHL. The maximum time of administration for the NVS was 563 seconds, compared to 607 seconds for the SAHL. We found that 95.2% of NVS and 93.9% of SAHL tests incurred no interruptions during administration. Conclusion: No significant difference was found between the length of time needed to administer the NVS or SAHL to older patients in the ED. Both tools averaged an administration time of around three to four minutes, and neither incurred regular interruptions to its administration by a volunteer RA. Further study is needed to assess validity of these tools in an ED setting.

Published
2020
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16. Melanoma central nervous system metastases: An update to approaches, challenges, and opportunities

Author

Alcida Karz, Maya Dimitrova, Kevin Kleffman, Christopher Alvarez‐Breckenridge, Michael B. Atkins, Adrienne Boire, Marcus Bosenberg, Priscilla Brastianos, Daniel P. Cahill, Qing Chen, Sherise Ferguson, Peter Forsyth, Isabella C. Glitza Oliva, Sarah B. Goldberg, Sheri L. Holmen, Jonathan P. S. Knisely, Glenn Merlino, Don X. Nguyen, Michael E. Pacold, Eva Perez‐Guijarro, Keiran S. M. Smalley, Hussein A. Tawbi, Patrick Y. Wen, Michael A. Davies, Harriet M. Kluger, Janice M. Mehnert, and Eva Hernando

Subjects
Brain Neoplasms, Brain, Disease Management, Neoplasms, Second Primary, Dermatology, Article, General Biochemistry, Genetics and Molecular Biology, Central Nervous System Neoplasms, Oncology, Tumor Microenvironment, Humans, Immunotherapy, Molecular Targeted Therapy, Melanoma, Ecosystem
Abstract

Brain metastases are the most common brain malignancy. This review discusses the studies presented at the third annual meeting of the Melanoma Research Foundation in the context of other recent reports on the biology and treatment of melanoma brain metastases (MBM). Although symptomatic MBM patients were historically excluded from immunotherapy trials, efforts from clinicians and patient advocates have resulted in more inclusive and even dedicated clinical trials for MBM patients. The results of checkpoint inhibitor trials were discussed in conversation with current standards of care for MBM patients, including steroids, radiotherapy, and targeted therapy. Advances in the basic scientific understanding of MBM, including the role of astrocytes and metabolic adaptations to the brain microenvironment, are exposing new vulnerabilities which could be exploited for therapeutic purposes. Technical advances including single-cell omics and multiplex imaging are expanding our understanding of the MBM ecosystem and its response to therapy. This unprecedented level of spatial and temporal resolution is expected to dramatically advance the field in the coming years and render novel treatment approaches that might improve MBM patient outcomes.

Published
2022
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17. Supplementary Data from Melanoma-Secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Author

Kleffman, Kevin, primary, Levinson, Grace, primary, Rose, Indigo V.L., primary, Blumenberg, Lili M., primary, Shadaloey, Sorin A.A., primary, Dhabaria, Avantika, primary, Wong, Eitan, primary, Galán-Echevarría, Francisco, primary, Karz, Alcida, primary, Argibay, Diana, primary, Von Itter, Richard, primary, Floristán, Alfredo, primary, Baptiste, Gillian, primary, Eskow, Nicole M., primary, Tranos, James A., primary, Chen, Jenny, primary, Vega y Saenz de Miera, Eleazar C., primary, Call, Melissa, primary, Rogers, Robert, primary, Jour, George, primary, Wadghiri, Youssef Zaim, primary, Osman, Iman, primary, Li, Yue-Ming, primary, Mathews, Paul, primary, DeMattos, Ronald B., primary, Ueberheide, Beatrix, primary, Ruggles, Kelly V., primary, Liddelow, Shane A., primary, Schneider, Robert J., primary, and Hernando, Eva, primary

Published
2023
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18. Supplementary Table from Melanoma-Secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Author

Kleffman, Kevin, primary, Levinson, Grace, primary, Rose, Indigo V.L., primary, Blumenberg, Lili M., primary, Shadaloey, Sorin A.A., primary, Dhabaria, Avantika, primary, Wong, Eitan, primary, Galán-Echevarría, Francisco, primary, Karz, Alcida, primary, Argibay, Diana, primary, Von Itter, Richard, primary, Floristán, Alfredo, primary, Baptiste, Gillian, primary, Eskow, Nicole M., primary, Tranos, James A., primary, Chen, Jenny, primary, Vega y Saenz de Miera, Eleazar C., primary, Call, Melissa, primary, Rogers, Robert, primary, Jour, George, primary, Wadghiri, Youssef Zaim, primary, Osman, Iman, primary, Li, Yue-Ming, primary, Mathews, Paul, primary, DeMattos, Ronald B., primary, Ueberheide, Beatrix, primary, Ruggles, Kelly V., primary, Liddelow, Shane A., primary, Schneider, Robert J., primary, and Hernando, Eva, primary

Published
2023
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19. Supplementary Figure from Melanoma-Secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Author

Kleffman, Kevin, primary, Levinson, Grace, primary, Rose, Indigo V.L., primary, Blumenberg, Lili M., primary, Shadaloey, Sorin A.A., primary, Dhabaria, Avantika, primary, Wong, Eitan, primary, Galán-Echevarría, Francisco, primary, Karz, Alcida, primary, Argibay, Diana, primary, Von Itter, Richard, primary, Floristán, Alfredo, primary, Baptiste, Gillian, primary, Eskow, Nicole M., primary, Tranos, James A., primary, Chen, Jenny, primary, Vega y Saenz de Miera, Eleazar C., primary, Call, Melissa, primary, Rogers, Robert, primary, Jour, George, primary, Wadghiri, Youssef Zaim, primary, Osman, Iman, primary, Li, Yue-Ming, primary, Mathews, Paul, primary, DeMattos, Ronald B., primary, Ueberheide, Beatrix, primary, Ruggles, Kelly V., primary, Liddelow, Shane A., primary, Schneider, Robert J., primary, and Hernando, Eva, primary

Published
2023
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20. Data from Melanoma-Secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Author

Kleffman, Kevin, primary, Levinson, Grace, primary, Rose, Indigo V.L., primary, Blumenberg, Lili M., primary, Shadaloey, Sorin A.A., primary, Dhabaria, Avantika, primary, Wong, Eitan, primary, Galán-Echevarría, Francisco, primary, Karz, Alcida, primary, Argibay, Diana, primary, Von Itter, Richard, primary, Floristán, Alfredo, primary, Baptiste, Gillian, primary, Eskow, Nicole M., primary, Tranos, James A., primary, Chen, Jenny, primary, Vega y Saenz de Miera, Eleazar C., primary, Call, Melissa, primary, Rogers, Robert, primary, Jour, George, primary, Wadghiri, Youssef Zaim, primary, Osman, Iman, primary, Li, Yue-Ming, primary, Mathews, Paul, primary, DeMattos, Ronald B., primary, Ueberheide, Beatrix, primary, Ruggles, Kelly V., primary, Liddelow, Shane A., primary, Schneider, Robert J., primary, and Hernando, Eva, primary

Published
2023
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21. Data from Melanoma-Secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Author

Eva Hernando, Robert J. Schneider, Shane A. Liddelow, Kelly V. Ruggles, Beatrix Ueberheide, Ronald B. DeMattos, Paul Mathews, Yue-Ming Li, Iman Osman, Youssef Zaim Wadghiri, George Jour, Robert Rogers, Melissa Call, Eleazar C. Vega y Saenz de Miera, Jenny Chen, James A. Tranos, Nicole M. Eskow, Gillian Baptiste, Alfredo Floristán, Richard Von Itter, Diana Argibay, Alcida Karz, Francisco Galán-Echevarría, Eitan Wong, Avantika Dhabaria, Sorin A.A. Shadaloey, Lili M. Blumenberg, Indigo V.L. Rose, Grace Levinson, and Kevin Kleffman

Abstract

Brain metastasis is a significant cause of morbidity and mortality in multiple cancer types and represents an unmet clinical need. The mechanisms that mediate metastatic cancer growth in the brain parenchyma are largely unknown. Melanoma, which has the highest rate of brain metastasis among common cancer types, is an ideal model to study how cancer cells adapt to the brain parenchyma. Our unbiased proteomics analysis of melanoma short-term cultures revealed that proteins implicated in neurodegenerative pathologies are differentially expressed in melanoma cells explanted from brain metastases compared with those derived from extracranial metastases. We showed that melanoma cells require amyloid beta (Aβ) for growth and survival in the brain parenchyma. Melanoma-secreted Aβ activates surrounding astrocytes to a prometastatic, anti-inflammatory phenotype and prevents phagocytosis of melanoma by microglia. Finally, we demonstrate that pharmacologic inhibition of Aβ decreases brain metastatic burden.Significance:Our results reveal a novel mechanistic connection between brain metastasis and Alzheimer's disease, two previously unrelated pathologies; establish Aβ as a promising therapeutic target for brain metastasis; and demonstrate suppression of neuroinflammation as a critical feature of metastatic adaptation to the brain parenchyma.This article is highlighted in the In This Issue feature, p. 1171

Published
2023
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22. Supplementary Table from Melanoma-Secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Author

Eva Hernando, Robert J. Schneider, Shane A. Liddelow, Kelly V. Ruggles, Beatrix Ueberheide, Ronald B. DeMattos, Paul Mathews, Yue-Ming Li, Iman Osman, Youssef Zaim Wadghiri, George Jour, Robert Rogers, Melissa Call, Eleazar C. Vega y Saenz de Miera, Jenny Chen, James A. Tranos, Nicole M. Eskow, Gillian Baptiste, Alfredo Floristán, Richard Von Itter, Diana Argibay, Alcida Karz, Francisco Galán-Echevarría, Eitan Wong, Avantika Dhabaria, Sorin A.A. Shadaloey, Lili M. Blumenberg, Indigo V.L. Rose, Grace Levinson, and Kevin Kleffman

Abstract

Supplementary Table from Melanoma-Secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Published
2023
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23. Supplementary Data from Melanoma-Secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Author

Eva Hernando, Robert J. Schneider, Shane A. Liddelow, Kelly V. Ruggles, Beatrix Ueberheide, Ronald B. DeMattos, Paul Mathews, Yue-Ming Li, Iman Osman, Youssef Zaim Wadghiri, George Jour, Robert Rogers, Melissa Call, Eleazar C. Vega y Saenz de Miera, Jenny Chen, James A. Tranos, Nicole M. Eskow, Gillian Baptiste, Alfredo Floristán, Richard Von Itter, Diana Argibay, Alcida Karz, Francisco Galán-Echevarría, Eitan Wong, Avantika Dhabaria, Sorin A.A. Shadaloey, Lili M. Blumenberg, Indigo V.L. Rose, Grace Levinson, and Kevin Kleffman

Abstract

Supplementary Data from Melanoma-Secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Published
2023
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24. Supplementary Figure from Melanoma-Secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Author

Eva Hernando, Robert J. Schneider, Shane A. Liddelow, Kelly V. Ruggles, Beatrix Ueberheide, Ronald B. DeMattos, Paul Mathews, Yue-Ming Li, Iman Osman, Youssef Zaim Wadghiri, George Jour, Robert Rogers, Melissa Call, Eleazar C. Vega y Saenz de Miera, Jenny Chen, James A. Tranos, Nicole M. Eskow, Gillian Baptiste, Alfredo Floristán, Richard Von Itter, Diana Argibay, Alcida Karz, Francisco Galán-Echevarría, Eitan Wong, Avantika Dhabaria, Sorin A.A. Shadaloey, Lili M. Blumenberg, Indigo V.L. Rose, Grace Levinson, and Kevin Kleffman

Abstract

Supplementary Figure from Melanoma-Secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Published
2023
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25. Melanoma-Secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Author

Kevin Kleffman, Grace Levinson, Indigo V.L. Rose, Lili M. Blumenberg, Sorin A.A. Shadaloey, Avantika Dhabaria, Eitan Wong, Francisco Galán-Echevarría, Alcida Karz, Diana Argibay, Richard Von Itter, Alfredo Floristán, Gillian Baptiste, Nicole M. Eskow, James A. Tranos, Jenny Chen, Eleazar C. Vega y Saenz de Miera, Melissa Call, Robert Rogers, George Jour, Youssef Zaim Wadghiri, Iman Osman, Yue-Ming Li, Paul Mathews, Ronald B. DeMattos, Beatrix Ueberheide, Kelly V. Ruggles, Shane A. Liddelow, Robert J. Schneider, and Eva Hernando

Subjects
Amyloid beta-Peptides, Oncology, Brain Neoplasms, Astrocytes, Neuroinflammatory Diseases, Humans, Neoplasm Metastasis, Melanoma, Article
Abstract

Brain metastasis is a significant cause of morbidity and mortality in multiple cancer types and represents an unmet clinical need. The mechanisms that mediate metastatic cancer growth in the brain parenchyma are largely unknown. Melanoma, which has the highest rate of brain metastasis among common cancer types, is an ideal model to study how cancer cells adapt to the brain parenchyma. Our unbiased proteomics analysis of melanoma short-term cultures revealed that proteins implicated in neurodegenerative pathologies are differentially expressed in melanoma cells explanted from brain metastases compared with those derived from extracranial metastases. We showed that melanoma cells require amyloid beta (Aβ) for growth and survival in the brain parenchyma. Melanoma-secreted Aβ activates surrounding astrocytes to a prometastatic, anti-inflammatory phenotype and prevents phagocytosis of melanoma by microglia. Finally, we demonstrate that pharmacologic inhibition of Aβ decreases brain metastatic burden. Significance: Our results reveal a novel mechanistic connection between brain metastasis and Alzheimer's disease, two previously unrelated pathologies; establish Aβ as a promising therapeutic target for brain metastasis; and demonstrate suppression of neuroinflammation as a critical feature of metastatic adaptation to the brain parenchyma. This article is highlighted in the In This Issue feature, p. 1171

Published
2022
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26. An epigenetic switch controls an alternative NR2F2 isoform 2 that unleashes a metastatic program in melanoma

Author

Davalos, Verónica, Lovell, Claudia, von Itter, Richard, Dolgalev, Igor, Agrawal, Praveen, Baptiste, Gillian, Kahler, David, Sokolova, Elena, Moran, Sebastian, Piqué, Laia, Vega-Saenz de Miera, Eleazar, Fontanals-Cirera, Barbara, Karz, Alcida, Tsirigos, Aristotelis, Yun, Chi, Darvishian, Farbod, Etchevers, Heather, Osman, Iman, Esteller, Manel, Schober, Markus, Hernando, Eva, Department of Pathology, New York University Grossman School of Medicine, NY 10016, USA, Applied Bioinformatics Laboratories, New York University Grossman School of Medicine, NY 10016, USA, Bellvitge Biomedical Research Institute, Partenaires INRAE, Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain, New York University School of Medicine (NYU Grossman School of Medicine), National Tsing Hua University [Hsinchu] (NTHU), City University of Hong Kong [Hong Kong] (CUHK), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Marseille Maladies Rares (MarMaRa), Aix Marseille Université (AMU), Interdisciplinary Melanoma Cooperative Group, Perlmutter Cancer Center, New York University School of Medicine, NY 10016, USA (NYUSM), Institució Catalana de Recerca i Estudis Avançats (ICREA), Josep Carreras Leukaemia Research Institute (IJC), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Universitat de Barcelona (UB), New York University [New York] (NYU), NYU System (NYU), and We thank the NYU Experimental Pathology Core, the NYU Genome Technology Center, the NYUCenter for Biospecimen Research and Development, and the Small Animal Imaging core, all partially supported by the Laura and Isaac Perlmutter Cancer Center Support Grant (CCSG) NIH/NCI P30CA016087 (NIH/NCI), and National Institute of Health S10 Grants NIH/ORIP S10OD01058 and S10OD018338. We thank the High Throughput Biology Core partially funded by P30CA16087 and NYSTEM Contract C026719. V.D. was supported by the People Program (Marie Curie Actions) of the European Union's Seventh Framework Program (FP7-PEOPLE30 2013-IOF) under REA grant agreement n° PIOF-GA-2013-623443. This work was funded by NCI/NIH R01CA202027, R01CA274100, P01CA206980 and NYU Melanoma SPOREP50CA225450 (PI: I.O).

Subjects
[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV]Life Sciences [q-bio], [SDV.CAN]Life Sciences [q-bio]/Cancer, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.MHEP.DERM]Life Sciences [q-bio]/Human health and pathology/Dermatology
Abstract

International audience; Metastatic melanoma develops once transformed melanocytic cells begin to de-differentiate into migratory and invasive melanoma cells with neural crest cell (NCC)-like and epithelial-tomesenchymal transition (EMT)-like features. However, it is still unclear how transformed melanocytes assume a metastatic melanoma cell state. Here, we define DNA methylation changes that accompany metastatic progression in melanoma patients and discover Nuclear Receptor Subfamily 2 Group F, Member 2 – isoform 2 (NR2F2-Iso2) as an epigenetically regulated metastasis driver. NR2F2-Iso2 is transcribed from an alternative transcriptional start site (TSS) and it is truncated at the N-terminal end which encodes the NR2F2 DNA-bindingdomain. We find that NR2F2-Iso2 expression is turned off by DNA methylation when NCCs differentiate into melanocytes. Conversely, this process is reversed during metastatic melanoma progression, when NR2F2-Iso2 becomes increasingly hypomethylated and re-expressed. Our functional and molecular studies suggest that NR2F2-Iso2 drives metastatic melanomaprogression by modulating the activity of full-length NR2F2 (Isoform 1) over EMT- and NCC-associated target genes. Our findings indicate that DNA methylation changes play a crucial role during metastatic melanoma progression, and their control of NR2F2 activity allows transformed melanocytes to acquire NCC-like and EMT-like features. This epigenetically regulated transcriptional plasticity facilitates cell state transitions and metastatic spread.

Published
2023
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30. Osborn Waves in a Severely Hypothermic Patient

Author

James Elliot Karz, DO, Grant Wei, MD, and Chirag Shah, MD

Subjects
EKG, Osborn wave, J wave, ECG, cardiology, environmental, hypothermia, ECMO, Education, Special aspects of education, LC8-6691
Abstract

History of present illness: An 88-year-old female was found lying prone and unresponsive outside of her home with an unknown downtime. She was intubated in the field by medics and brought to the emergency department (ED). In the ED, she had a core temperature of 78 degrees Fahrenheit (°F) with a heart rate of 21 beats per minute. Active rewarming and resuscitation were started and serial electrocardiograms (ECGs) were performed; two hours later, her core temperature had increased to 86°F. Significant findings: The initial ECG shows a junctional rhythm with Osborn waves (or J point elevations/J waves) in the lateral precordial leads, as well as the limb leads (Image 1). The second ECG, 49 minutes later, shows an improving ventricular rate and Osborn wave height decrease of approximately 50% (Image 2). Discussion: Differentiating between mild, moderate and severe hypothermia can help guide resuscitation efforts in these patients. Patients with mild hypothermia have core temperatures between 90-95°F and present with shivering, tachypnea, and tachycardia. Those with moderate hypothermia have core temperatures between 82-90°F and present with muscle rigidity, altered mental status, bradycardia and hypoventilation. Severe hypothermia is defined as a core temperature below 82°F. These patients are often comatose, hypotensive, and apneic.1 Patients with primary hypothermia and cardiac stability who have been treated with active external and minimally invasive rewarming techniques have a rate of neurologically intact survival of approximately 100%.2 For patients with primary hypothermia and cardiac instability or cardiac arrest, extracorporeal membrane oxygenation (ECMO) may be the best treatment option. The rate of neurologically intact survival for patients with cardiac arrest treated with extracorporeal rewarming is approximately 50%. If ECMO or cardiopulmonary bypass is not available and transport to a facility with these capabilities is not possible, circulation should be supported with CPR while the patient is rewarmed with an alternative internal rewarming technique. Topics: EKG, Osborn wave, J wave, ECG, cardiology, environmental, hypothermia, ECMO

Published
2018
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31. Melanoma central nervous system metastases: An update to approaches, challenges, and opportunities

Author

Karz, Alcida, primary, Dimitrova, Maya, additional, Kleffman, Kevin, additional, Alvarez‐Breckenridge, Christopher, additional, Atkins, Michael B., additional, Boire, Adrienne, additional, Bosenberg, Marcus, additional, Brastianos, Priscilla, additional, Cahill, Daniel P., additional, Chen, Qing, additional, Ferguson, Sherise, additional, Forsyth, Peter, additional, Glitza Oliva, Isabella C., additional, Goldberg, Sarah B., additional, Holmen, Sheri L., additional, Knisely, Jonathan P. S., additional, Merlino, Glenn, additional, Nguyen, Don X., additional, Pacold, Michael E., additional, Perez‐Guijarro, Eva, additional, Smalley, Keiran S. M., additional, Tawbi, Hussein A., additional, Wen, Patrick Y., additional, Davies, Michael A., additional, Kluger, Harriet M., additional, Mehnert, Janice M., additional, and Hernando, Eva, additional

Published
2022
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33. Abstract LB052: Melanoma-secreted amyloid beta suppresses neuroinflammation and promotes brain metastasis

Author

Kleffman, Kevin, primary, Levinson, Grace, additional, Rose, Indigo V., additional, Blumenberg, Lili, additional, Shadaloey, Sorin A., additional, Dhabaria, Avantika, additional, Wong, Eitan, additional, Galán-Echevarría, Francisco, additional, Karz, Alcida, additional, Argibay, Diana, additional, Von-Itter, Richard, additional, Floristán, Alfredo, additional, Baptiste, Gillian, additional, Eskow, Nicole, additional, Tranos, James, additional, Chen, Jenny, additional, de Miera, Eleazar C. Vega Saenz, additional, Call, Melissa, additional, Rogers, Robert, additional, Jour, George, additional, Wadghiri, Youssef Zaim, additional, Osman, Iman, additional, Li, Yue Ming, additional, Mathews, Paul, additional, Demattos, Ronald, additional, Ueberheide, Beatrix, additional, Ruggles, Kelly, additional, Liddelow, Shane A., additional, Schneider, Robert J., additional, and Hernando, Eva, additional

Published
2022
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34. A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis

Author

Arman Alberto Sorin, Shadaloey, Alcida, Karz, Rana S, Moubarak, Praveen, Agrawal, Grace, Levinson, Kevin, Kleffman, Orlando, Aristizabal, Iman, Osman, Youssef Z, Wadghiri, and Eva, Hernando

Subjects
Mice, General Immunology and Microbiology, General Chemical Engineering, General Neuroscience, Animals, Humans, Neoplasm Metastasis, Melanoma, General Biochemistry, Genetics and Molecular Biology, Cell Line
Abstract

Metastasis is a complex process, requiring cells to overcome barriers that are only incompletely modeled by in vitro assays. A systematic workflow was established using robust, reproducible in vivo models and standardized methods to identify novel players in melanoma metastasis. This approach allows for data inference at specific experimental stages to precisely characterize a gene's role in metastasis. Models are established by introducing genetically modified melanoma cells via intracardiac, intradermal, or subcutaneous injections into mice, followed by monitoring with serial in vivo imaging. Once preestablished endpoints are reached, primary tumors and/or metastases-bearing organs are harvested and processed for various analyses. Tumor cells can be sorted and subjected to any of several 'omics' platforms, including single-cell RNA sequencing. Organs undergo imaging and immunohistopathological analyses to quantify the overall burden of metastases and map their specific anatomic location. This optimized pipeline, including standardized protocols for engraftment, monitoring, tissue harvesting, processing, and analysis, can be adopted for patient-derived, short-term cultures and established human and murine cell lines of various solid cancer types.

Published
2022
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35. The histone demethylase PHF8 regulates TGFβ signaling and promotes melanoma metastasis

Author

Rana S. Moubarak, Ana de Pablos-Aragoneses, Vanessa Ortiz-Barahona, Yixiao Gong, Michael Gowen, Igor Dolgalev, Sorin A. A. Shadaloey, Diana Argibay, Alcida Karz, Richard Von Itter, Eleazar Carmelo Vega-Sáenz de Miera, Elena Sokolova, Farbod Darvishian, Aristotelis Tsirigos, Iman Osman, and Eva Hernando

Subjects
Histone Demethylases, Homeodomain Proteins, Multidisciplinary, Transforming Growth Factor beta, Humans, Melanoma, Cell Proliferation, Epigenesis, Genetic, Transcription Factors
Abstract

The contribution of epigenetic dysregulation to metastasis remains understudied. Through a meta-analysis of gene expression datasets followed by a mini-screen, we identified Plant Homeodomain Finger protein 8 (PHF8), a histone demethylase of the Jumonji C protein family, as a previously unidentified prometastatic gene in melanoma. Loss- and gain-of-function approaches demonstrate that PHF8 promotes cell invasion without affecting proliferation in vitro and increases dissemination but not subcutaneous tumor growth in vivo, thus supporting its specific contribution to the acquisition of metastatic potential. PHF8 requires its histone demethylase activity to enhance melanoma cell invasion. Transcriptomic and epigenomic analyses revealed that PHF8 orchestrates a molecular program that directly controls the TGFβ signaling pathway and, as a consequence, melanoma invasion and metastasis. Our findings bring a mechanistic understanding of epigenetic regulation of metastatic fitness in cancer, which may pave the way for improved therapeutic interventions.

Published
2022

36. Proteogenomic and metabolomic characterization of human glioblastoma

Author

Cristina E. Tognon, Larisa Polonskaya, Tara Skelly, Shuang Cai, Francesmary Modugno, Larissa Rossell, Nancy Roche, Chen Huang, Jessika Baral, Fulvio D'Angelo, Wen-Wei Liang, Chia-Feng Tsai, Sneha P. Couvillion, Karin D. Rodland, Jun Zhu, Liang-Bo Wang, Paul D. Piehowski, Antonio Colaprico, Anupriya Agarwal, Matthew A. Wyczalkowski, Umut Ozbek, Francesca Petralia, Alexis Demopoulos, William W. Maggio, Lin Chen, Katherine A. Hoadley, Richard D. Smith, Sandra Cottingham, John McGee, Marcin J. Domagalski, Houxiang Zhu, Emek Demir, Rebecca I. Montgomery, Jamie Moon, Rashna Madan, George D. Wilson, Luciano Garofano, Ewa P. Malc, Chelsea J. Newton, Steven A. Carr, Chandan Kumar-Sinha, Donghui Tan, Christopher R. Kinsinger, Oxana Paklina, Weiqing Wan, Stephanie De Young, Sandra Cerda, Shankha Satpathy, Wojciech Kaspera, Linda Hannick, Gad Getz, Runyu Hong, Shuangjia Lu, Ziad Hanhan, Daniel C. Rohrer, Annette Marrero-Oliveras, Wojciech Szopa, Yuxing Liao, Amanda G. Paulovich, Jiayi Ji, Denis A. Golbin, Tara Hiltke, Weiva Sieh, Piotr A. Mieczkowski, Matthew E. Monroe, Gilbert S. Omenn, Jill S. Barnholtz-Sloan, Azra Krek, Bing Zhang, Brittany Henderson, Peter B. McGarvey, Ratna R. Thangudu, Maciej Wiznerowicz, Saravana M. Dhanasekaran, Alex Webster, Kai Li, Karna Robinson, Nan Ji, Karl K. Weitz, Simina M. Boca, Xiaoyu Song, Anna Calinawan, Adam C. Resnick, Brian J. Druker, Dana R. Valley, David J. Clark, Tao Liu, Eric J. Jaehnig, Alicia Francis, Michele Ceccarelli, Rui Zhao, Dmitry Rykunov, Boris Reva, Elizabeth R. Duffy, Antonio Iavarone, Dave Tabor, Joshua F. McMichael, Daniel Cui Zhou, Maureen Dyer, Kimberly Elburn, Scott D. Jewell, Negin Vatanian, Shirley Tsang, Seungyeul Yoo, Alexander R. Pico, Grace Zhao, Kent J. Bloodsworth, Chet Birger, Jena Lilly, Eunkyung An, Jeffrey R. Whiteaker, Albert H. Kim, Yige Wu, Karen A. Ketchum, Felipe D. Leprevost, Alcida Karz, Uma Borate, Nathan Edwards, Uma Velvulou, Melissa Borucki, Vasileios Stathias, Sanford P. Markey, Corbin D. Jones, Ronald J. Moore, MacIntosh Cornwell, Karsten Krug, Michael J. Birrer, James Suh, Tomasz Czernicki, Jason E. McDermott, Emily S. Boja, Pei Wang, Nina Martinez, Wenke Liu, Yan Shi, Lili Blumenberg, Emily Kawaler, Jeffrey W. Tyner, Feng Chen, Jakub Stawicki, Ki Sung Um, Arul M. Chinnaiyan, Robert Zelt, Jacob J. Day, Zhen Zhang, Caleb M. Lindgren, Li Ding, Nikolay Gabrovski, Hongwei Liu, Jonathan T. Lei, Alla Karpova, Ramani B. Kothadia, Sailaja Mareedu, Mitual Amin, Hannah Boekweg, Jennifer E. Kyle, Sara R. Savage, Brian R. Rood, Yuriy Zakhartsev, Matthew L. Anderson, Alyssa Charamut, Wagma Caravan, Shakti Ramkissoon, Junmei Wang, Song Cao, Samuel H. Payne, Rosalie K. Chu, Rajiv Dhir, David W. Andrews, Galen Hostetter, Liqun Qi, Zhiao Shi, Milan G. Chheda, Robert Edwards, Hui Zhang, Weiping Ma, Jennifer M. Eschbacher, Stacey Gabriel, Jan Lubinski, Lijun Yao, Erika M. Zink, Kelly L. Stratton, William Bocik, Mathangi Thiagarajan, Shilpi Singh, Michael A. Gillette, Lisa M. Bramer, Thomas L. Bauer, Michael Vernon, Henry Rodriguez, Dimitris G. Placantonakis, Eric E. Schadt, Alexey I. Nesvizhskii, Vladislav A. Petyuk, Ana I. Robles, Yvonne Shutack, Anna Malovannaya, Stephen E. Stein, Xi Chen, Lyndon Kim, Yize Li, Shannon Richey, Stephan C. Schürer, Barbara Hindenach, Matthew J. Ellis, Yongchao Dou, David Fenyö, Amy M. Perou, Olga Potapova, Shrabanti Chowdhury, Andrew K. Godwin, Marcin Cieślik, Michael C. Wendl, Marina A. Gritsenko, Pietro Pugliese, Elie Traer, Simona Migliozzi, D. R. Mani, Houston Culpepper, Gregory J. Riggins, Xiaolu Yang, Mehdi Mesri, David Chesla, Lindsey K. Olsen, Lori J. Sokoll, Suhas Vasaikar, Liwei Zhang, Meghan C. Burke, Kelly V. Ruggles, Qing Kay Li, Daniel W. Chan, Bo Wen, Nicollette Maunganidze, Darlene Tansil, Joseph H. Rothstein, Barbara Pruetz, Pushpa Hariharan, Wang, L. -B., Karpova, A., Gritsenko, M. A., Kyle, J. E., Cao, S., Li, Y., Rykunov, D., Colaprico, A., Rothstein, J. H., Hong, R., Stathias, V., Cornwell, M., Petralia, F., Wu, Y., Reva, B., Krug, K., Pugliese, P., Kawaler, E., Olsen, L. K., Liang, W. -W., Song, X., Dou, Y., Wendl, M. C., Caravan, W., Liu, W., Cui Zhou, D., Ji, J., Tsai, C. -F., Petyuk, V. A., Moon, J., Ma, W., Chu, R. K., Weitz, K. K., Moore, R. J., Monroe, M. E., Zhao, R., Yang, X., Yoo, S., Krek, A., Demopoulos, A., Zhu, H., Wyczalkowski, M. A., Mcmichael, J. F., Henderson, B. L., Lindgren, C. M., Boekweg, H., Lu, S., Baral, J., Yao, L., Stratton, K. G., Bramer, L. M., Zink, E., Couvillion, S. P., Bloodsworth, K. J., Satpathy, S., Sieh, W., Boca, S. M., Schurer, S., Chen, F., Wiznerowicz, M., Ketchum, K. A., Boja, E. S., Kinsinger, C. R., Robles, A. I., Hiltke, T., Thiagarajan, M., Nesvizhskii, A. I., Zhang, B., Mani, D. R., Ceccarelli, M., Chen, X. S., Cottingham, S. L., Li, Q. K., Kim, A. H., Fenyo, D., Ruggles, K. V., Rodriguez, H., Mesri, M., Payne, S. H., Resnick, A. C., Wang, P., Smith, R. D., Iavarone, A., Chheda, M. G., Barnholtz-Sloan, J. S., Rodland, K. D., Liu, T., Ding, L., Agarwal, A., Amin, M., An, E., Anderson, M. L., Andrews, D. W., Bauer, T., Birger, C., Birrer, M. J., Blumenberg, L., Bocik, W. E., Borate, U., Borucki, M., Burke, M. C., Cai, S., Calinawan, A. P., Carr, S. A., Cerda, S., Chan, D. W., Charamut, A., Chen, L. S., Chesla, D., Chinnaiyan, A. M., Chowdhury, S., Cieslik, M. P., Clark, D. J., Culpepper, H., Czernicki, T., D'Angelo, F., Day, J., De Young, S., Demir, E., Dhanasekaran, S. M., Dhir, R., Domagalski, M. J., Druker, B., Duffy, E., Dyer, M., Edwards, N. J., Edwards, R., Elburn, K., Ellis, M. J., Eschbacher, J., Francis, A., Gabriel, S., Gabrovski, N., Garofano, L., Getz, G., Gillette, M. A., Godwin, A. K., Golbin, D., Hanhan, Z., Hannick, L. I., Hariharan, P., Hindenach, B., Hoadley, K. A., Hostetter, G., Huang, C., Jaehnig, E., Jewell, S. D., Ji, N., Jones, C. D., Karz, A., Kaspera, W., Kim, L., Kothadia, R. B., Kumar-Sinha, C., Lei, J., Leprevost, F. D., Li, K., Liao, Y., Lilly, J., Liu, H., Lubinski, J., Madan, R., Maggio, W., Malc, E., Malovannaya, A., Mareedu, S., Markey, S. P., Marrero-Oliveras, A., Martinez, N., Maunganidze, N., Mcdermott, J. E., Mcgarvey, P. B., Mcgee, J., Mieczkowski, P., Migliozzi, S., Modugno, F., Montgomery, R., Newton, C. J., Omenn, G. S., Ozbek, U., Paklina, O. V., Paulovich, A. G., Perou, A. M., Pico, A. R., Piehowski, P. D., Placantonakis, D. G., Polonskaya, L., Potapova, O., Pruetz, B., Qi, L., Ramkissoon, S., Resnick, A., Richey, S., Riggins, G., Robinson, K., Roche, N., Rohrer, D. C., Rood, B. R., Rossell, L., Savage, S. R., Schadt, E. E., Shi, Y., Shi, Z., Shutack, Y., Singh, S., Skelly, T., Sokoll, L. J., Stawicki, J., Stein, S. E., Suh, J., Szopa, W., Tabor, D., Tan, D., Tansil, D., Thangudu, R. R., Tognon, C., Traer, E., Tsang, S., Tyner, J., Um, K. S., Valley, D. R., Vasaikar, S., Vatanian, N., Velvulou, U., Vernon, M., Wan, W., Wang, J., Webster, A., Wen, B., Whiteaker, J. R., Wilson, G. D., Zakhartsev, Y., Zelt, R., Zhang, H., Zhang, L., Zhang, Z., Zhao, G., and Zhu, J.

Subjects
Proteomics, 0301 basic medicine, Cancer Research, CPTAC, Histone H2B acetylation, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Computational biology, Biology, Article, 03 medical and health sciences, lipidome, 0302 clinical medicine, Metabolomics, proteogenomic, Humans, Phosphorylation, EP300, proteomic, Proteogenomics, acetylome, single nuclei RNA-seq, Brain Neoplasms, Phospholipase C gamma, glioblastoma, Computational Biology, Lipidome, 030104 developmental biology, Histone, Oncology, Acetylation, 030220 oncology & carcinogenesis, Mutation, biology.protein, metabolome, signaling
Abstract

Glioblastoma (GBM) is the most aggressive nervous system cancer. Understanding its molecular pathogenesis is crucial to improving diagnosis and treatment. Integrated analysis of genomic, proteomic, post-translational modification and metabolomic data on 99 treatment-naive GBMs provides insights to GBM biology. We identify key phosphorylation events (e.g., phosphorylated PTPN11 and PLCG1) as potential switches mediating oncogenic pathway activation, as well as potential targets for EGFR-, TP53-, and RB1-altered tumors. Immune subtypes with distinct immune cell types are discovered using bulk omics methodologies, validated by snRNA-seq, and correlated with specific expression and histone acetylation patterns. Histone H2B acetylation in classical-like and immune-low GBM is driven largely by BRDs, CREBBP, and EP300. Integrated metabolomic and proteomic data identify specific lipid distributions across subtypes and distinct global metabolic changes in IDH-mutated tumors. This work highlights biological relationships that could contribute to stratification of GBM patients for more effective treatment. Wang et al. perform integrated proteogenomic analysis of adult glioblastoma (GBM), including metabolomics, lipidomics, and single nuclei RNA-Seq, revealing insights into the immune landscape of GBM, cell-specific nature of EMT signatures, histone acetylation in classical GBM, and the existence of signaling hubs which could provide therapeutic vulnerabilities.

Published
2021

37. Melanoma-Secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis

Author

Kleffman, Kevin, primary, Levinson, Grace, additional, Rose, Indigo V.L., additional, Blumenberg, Lili M., additional, Shadaloey, Sorin A.A., additional, Dhabaria, Avantika, additional, Wong, Eitan, additional, Galán-Echevarría, Francisco, additional, Karz, Alcida, additional, Argibay, Diana, additional, Von Itter, Richard, additional, Floristán, Alfredo, additional, Baptiste, Gillian, additional, Eskow, Nicole M., additional, Tranos, James A., additional, Chen, Jenny, additional, Vega y Saenz de Miera, Eleazar C., additional, Call, Melissa, additional, Rogers, Robert, additional, Jour, George, additional, Wadghiri, Youssef Zaim, additional, Osman, Iman, additional, Li, Yue-Ming, additional, Mathews, Paul, additional, DeMattos, Ronald B., additional, Ueberheide, Beatrix, additional, Ruggles, Kelly V., additional, Liddelow, Shane A., additional, Schneider, Robert J., additional, and Hernando, Eva, additional

Published
2022
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39. The histone demethylase PHF8 regulates TGFβ signaling and promotes melanoma metastasis

Author

Moubarak, Rana S., primary, de Pablos-Aragoneses, Ana, additional, Ortiz-Barahona, Vanessa, additional, Gong, Yixiao, additional, Gowen, Michael, additional, Dolgalev, Igor, additional, Shadaloey, Sorin A. A., additional, Argibay, Diana, additional, Karz, Alcida, additional, Von Itter, Richard, additional, Vega-Sáenz de Miera, Eleazar Carmelo, additional, Sokolova, Elena, additional, Darvishian, Farbod, additional, Tsirigos, Aristotelis, additional, Osman, Iman, additional, and Hernando, Eva, additional

Published
2022
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40. HNRNPM controls circRNA biogenesis and splicing fidelity to sustain cancer cell fitness

Author

Ernesto Guccione, Heike Wollmann, Gaetano Gargiulo, Federico Di Tullio, Tim Chan, Diana Low, Danny Incarnato, David J. Mulholland, Leilei Chen, Vladimir Roudko, Sujun Chen, Benjamin Greenbaum, Simin Zheng, Omer An, Musaddeque Ahmed, Megan C. Schwarz, Ivan Marazzi, Michela Serresi, Tommaso Tabaglio, Jingxian Zhang, Alexander Hall Hickman, Eva Hernando, Karen M Mann, Jessica Sy Ho, Dave Keng Boon Wee, Alcida Karz, Housheng Hansen He, Salvatore Oliviero, Molecular Genetics, and School of Biological Sciences

Subjects
Male, Cancer Research, Mice, SCID, Exon, 0302 clinical medicine, Tumor Cells, Cultured, Biology (General), 0303 health sciences, General Neuroscience, Biological sciences [Science], Hep G2 Cells, General Medicine, Tumor Burden, Cell biology, Gene Expression Regulation, Neoplastic, 030220 oncology & carcinogenesis, PC-3 Cells, RNA splicing, Medicine, antisense oligonucleotides, Research Article, Human, Spliceosome, QH301-705.5, RNA Splicing, Science, Adenocarcinoma, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, splicing, Circular RNA, Animals, Humans, Gene, Cell Proliferation, 030304 developmental biology, General Immunology and Microbiology, Cell growth, Circular Ribonucleic Acid, Intron, Prostatic Neoplasms, Genetics and Genomics, circular RNA, RNA, Circular, Animal Experiment, Heterogeneous-Nuclear Ribonucleoprotein Group M, Cancer cell
Abstract

High spliceosome activity is a dependency for cancer cells, making them more vulnerable to perturbation of the splicing machinery compared to normal cells. To identify splicing factors important for prostate cancer (PCa) fitness, we performed pooled shRNA screens in vitro and in vivo. Our screens identified heterogeneous nuclear ribonucleoprotein M (HNRNPM) as a regulator of PCa cell growth. RNA- and eCLIP-sequencing identified HNRNPM binding to transcripts of key homeostatic genes. HNRNPM binding to its targets prevents aberrant exon inclusion and backsplicing events. In both linear and circular mis-spliced transcripts, HNRNPM preferentially binds to GU-rich elements in long flanking proximal introns. Mimicry of HNRNPM-dependent linear-splicing events using splice-switching-antisense-oligonucleotides was sufficient to inhibit PCa cell growth. This suggests that PCa dependence on HNRNPM is likely a result of mis-splicing of key homeostatic coding and non-coding genes. Our results have further been confirmed in other solid tumors. Taken together, our data reveal a role for HNRNPM in supporting cancer cell fitness. Inhibition of HNRNPM activity is therefore a potential therapeutic strategy in suppressing growth of PCa and other solid tumors. Published version EG and DW acknowledge support from NMRC/OFIRG/0032/2017 and NRF-CRP17-2017-06. Research reported in this publication was supported in part by National Cancer Institute of the NIH (R01CA249204) and ISMMS seed fund to EG and Melanoma Research Alliance MRA Team Science Award to EH and EG. SZ was supported by the Lee Kuan Yew Endowment Fund Postdoctoral Fellowship. The authors gratefully acknowledge the use of the services and facilities of the Tisch Cancer Institute supported by the NCI Cancer Center Support Grant (P30 CA196521). MS was supported by a NCI training grant (T32CA078207). GG lab was supported by the MDC, the Helmholtz Association, and the ERC. DM was supported by NCI-R01CA197910.

Published
2021

41. Author response: HNRNPM controls circRNA biogenesis and splicing fidelity to sustain cancer cell fitness

Author

Megan C. Schwarz, Eva Hernando, Gaetano Gargiulo, Alcida Karz, Housheng Hansen He, Jingxian Zhang, Ernesto Guccione, Federico Di Tullio, Sujun Chen, Musaddeque Ahmed, Heike Wollmann, Michela Serresi, Karen M Mann, Dave Keng Boon Wee, Benjamin Greenbaum, Alexander Hall Hickman, David J. Mulholland, Ivan Marazzi, Danny Incarnato, Tim Chan, Diana Low, Omer An, Salvatore Oliviero, Leilei Chen, Vladimir Roudko, Jessica Sy Ho, Simin Zheng, and Tommaso Tabaglio

Subjects
media_common.quotation_subject, Cancer cell, RNA splicing, Fidelity, Biology, Biogenesis, media_common, Cell biology
Published
2021
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42. Abstract LB052: Melanoma-secreted amyloid beta suppresses neuroinflammation and promotes brain metastasis

Author

Kevin Kleffman, Grace Levinson, Indigo V. Rose, Lili Blumenberg, Sorin A. Shadaloey, Avantika Dhabaria, Eitan Wong, Francisco Galán-Echevarría, Alcida Karz, Diana Argibay, Richard Von-Itter, Alfredo Floristán, Gillian Baptiste, Nicole Eskow, James Tranos, Jenny Chen, Eleazar C. Vega Saenz de Miera, Melissa Call, Robert Rogers, George Jour, Youssef Zaim Wadghiri, Iman Osman, Yue Ming Li, Paul Mathews, Ronald Demattos, Beatrix Ueberheide, Kelly Ruggles, Shane A. Liddelow, Robert J. Schneider, and Eva Hernando

Subjects
Cancer Research, Oncology
Abstract

Brain metastasis is a significant cause of morbidity and mortality in multiple cancer types and represents an unmet clinical need. The mechanisms that mediate metastatic cancer growth in the brain parenchyma are largely unknown. Melanoma, which has the highest rate of brain metastasis among common cancer types, is an ideal model to study how cancer cells adapt to the brain parenchyma. Our unbiased proteomics analysis of melanoma short-term cultures revealed that proteins implicated in neurodegenerative pathologies are differentially expressed in melanoma cells explanted from brain metastases compared to those derived from extracranial metastases. We showed that melanoma cells require amyloid beta (Aβ) for growth and survival in the brain parenchyma. Melanoma-secreted Aβ activates surrounding astrocytes to a prometastatic, anti-inflammatory phenotype and prevents phagocytosis of melanoma by microglia. Finally, we demonstrate that pharmacological inhibition of Aβ decreases brain metastatic burden. Our results reveal a novel mechanistic connection between brain metastasis and Alzheimer’s disease - two previously unrelated pathologies, establish Aβ as a promising therapeutic target for brain metastasis, and demonstrate suppression of neuroinflammation as a critical feature of metastatic adaptation to the brain parenchyma. Citation Format: Kevin Kleffman, Grace Levinson, Indigo V. Rose, Lili Blumenberg, Sorin A. Shadaloey, Avantika Dhabaria, Eitan Wong, Francisco Galán-Echevarría, Alcida Karz, Diana Argibay, Richard Von-Itter, Alfredo Floristán, Gillian Baptiste, Nicole Eskow, James Tranos, Jenny Chen, Eleazar C. Vega Saenz de Miera, Melissa Call, Robert Rogers, George Jour, Youssef Zaim Wadghiri, Iman Osman, Yue Ming Li, Paul Mathews, Ronald Demattos, Beatrix Ueberheide, Kelly Ruggles, Shane A. Liddelow, Robert J. Schneider, Eva Hernando. Melanoma-secreted amyloid beta suppresses neuroinflammation and promotes brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB052.

Published
2022
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44. HNRNPM controls circRNA biogenesis and splicing fidelity to sustain cancer cell fitness

Author

Ho, Jessica SY, primary, Di Tullio, Federico, additional, Schwarz, Megan, additional, Low, Diana, additional, Incarnato, Danny, additional, Gay, Florence, additional, Tabaglio, Tommaso, additional, Zhang, JingXian, additional, Wollmann, Heike, additional, Chen, Leilei, additional, An, Omer, additional, Chan, Tim Hon Man, additional, Hall Hickman, Alexander, additional, Zheng, Simin, additional, Roudko, Vladimir, additional, Chen, Sujun, additional, Karz, Alcida, additional, Ahmed, Musaddeque, additional, He, Housheng Hansen, additional, Greenbaum, Benjamin D, additional, Oliviero, Salvatore, additional, Serresi, Michela, additional, Gargiulo, Gaetano, additional, Mann, Karen M, additional, Hernando, Eva, additional, Mulholland, David, additional, Marazzi, Ivan, additional, Wee, Dave Keng Boon, additional, and Guccione, Ernesto, additional

Published
2021
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45. Author response: HNRNPM controls circRNA biogenesis and splicing fidelity to sustain cancer cell fitness

Author

Ho, Jessica SY, primary, Di Tullio, Federico, additional, Schwarz, Megan, additional, Low, Diana, additional, Incarnato, Danny, additional, Gay, Florence, additional, Tabaglio, Tommaso, additional, Zhang, JingXian, additional, Wollmann, Heike, additional, Chen, Leilei, additional, An, Omer, additional, Chan, Tim Hon Man, additional, Hall Hickman, Alexander, additional, Zheng, Simin, additional, Roudko, Vladimir, additional, Chen, Sujun, additional, Karz, Alcida, additional, Ahmed, Musaddeque, additional, He, Housheng Hansen, additional, Greenbaum, Benjamin D, additional, Oliviero, Salvatore, additional, Serresi, Michela, additional, Gargiulo, Gaetano, additional, Mann, Karen M, additional, Hernando, Eva, additional, Mulholland, David, additional, Marazzi, Ivan, additional, Wee, Dave Keng Boon, additional, and Guccione, Ernesto, additional

Published
2021
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46. Proteogenomic and metabolomic characterization of human glioblastoma

Author

Wang, Liang-Bo, primary, Karpova, Alla, additional, Gritsenko, Marina A., additional, Kyle, Jennifer E., additional, Cao, Song, additional, Li, Yize, additional, Rykunov, Dmitry, additional, Colaprico, Antonio, additional, Rothstein, Joseph H., additional, Hong, Runyu, additional, Stathias, Vasileios, additional, Cornwell, MacIntosh, additional, Petralia, Francesca, additional, Wu, Yige, additional, Reva, Boris, additional, Krug, Karsten, additional, Pugliese, Pietro, additional, Kawaler, Emily, additional, Olsen, Lindsey K., additional, Liang, Wen-Wei, additional, Song, Xiaoyu, additional, Dou, Yongchao, additional, Wendl, Michael C., additional, Caravan, Wagma, additional, Liu, Wenke, additional, Cui Zhou, Daniel, additional, Ji, Jiayi, additional, Tsai, Chia-Feng, additional, Petyuk, Vladislav A., additional, Moon, Jamie, additional, Ma, Weiping, additional, Chu, Rosalie K., additional, Weitz, Karl K., additional, Moore, Ronald J., additional, Monroe, Matthew E., additional, Zhao, Rui, additional, Yang, Xiaolu, additional, Yoo, Seungyeul, additional, Krek, Azra, additional, Demopoulos, Alexis, additional, Zhu, Houxiang, additional, Wyczalkowski, Matthew A., additional, McMichael, Joshua F., additional, Henderson, Brittany L., additional, Lindgren, Caleb M., additional, Boekweg, Hannah, additional, Lu, Shuangjia, additional, Baral, Jessika, additional, Yao, Lijun, additional, Stratton, Kelly G., additional, Bramer, Lisa M., additional, Zink, Erika, additional, Couvillion, Sneha P., additional, Bloodsworth, Kent J., additional, Satpathy, Shankha, additional, Sieh, Weiva, additional, Boca, Simina M., additional, Schürer, Stephan, additional, Chen, Feng, additional, Wiznerowicz, Maciej, additional, Ketchum, Karen A., additional, Boja, Emily S., additional, Kinsinger, Christopher R., additional, Robles, Ana I., additional, Hiltke, Tara, additional, Thiagarajan, Mathangi, additional, Nesvizhskii, Alexey I., additional, Zhang, Bing, additional, Mani, D.R., additional, Ceccarelli, Michele, additional, Chen, Xi S., additional, Cottingham, Sandra L., additional, Li, Qing Kay, additional, Kim, Albert H., additional, Fenyö, David, additional, Ruggles, Kelly V., additional, Rodriguez, Henry, additional, Mesri, Mehdi, additional, Payne, Samuel H., additional, Resnick, Adam C., additional, Wang, Pei, additional, Smith, Richard D., additional, Iavarone, Antonio, additional, Chheda, Milan G., additional, Barnholtz-Sloan, Jill S., additional, Rodland, Karin D., additional, Liu, Tao, additional, Ding, Li, additional, Agarwal, Anupriya, additional, Amin, Mitual, additional, An, Eunkyung, additional, Anderson, Matthew L., additional, Andrews, David W., additional, Bauer, Thomas, additional, Birger, Chet, additional, Birrer, Michael J., additional, Blumenberg, Lili, additional, Bocik, William E., additional, Borate, Uma, additional, Borucki, Melissa, additional, Burke, Meghan C., additional, Cai, Shuang, additional, Calinawan, Anna P., additional, Carr, Steven A., additional, Cerda, Sandra, additional, Chan, Daniel W., additional, Charamut, Alyssa, additional, Chen, Lin S., additional, Chesla, David, additional, Chinnaiyan, Arul M., additional, Chowdhury, Shrabanti, additional, Cieślik, Marcin P., additional, Clark, David J., additional, Culpepper, Houston, additional, Czernicki, Tomasz, additional, D'Angelo, Fulvio, additional, Day, Jacob, additional, De Young, Stephanie, additional, Demir, Emek, additional, Dhanasekaran, Saravana Mohan, additional, Dhir, Rajiv, additional, Domagalski, Marcin J., additional, Druker, Brian, additional, Duffy, Elizabeth, additional, Dyer, Maureen, additional, Edwards, Nathan J., additional, Edwards, Robert, additional, Elburn, Kimberly, additional, Ellis, Matthew J., additional, Eschbacher, Jennifer, additional, Francis, Alicia, additional, Gabriel, Stacey, additional, Gabrovski, Nikolay, additional, Garofano, Luciano, additional, Getz, Gad, additional, Gillette, Michael A., additional, Godwin, Andrew K., additional, Golbin, Denis, additional, Hanhan, Ziad, additional, Hannick, Linda I., additional, Hariharan, Pushpa, additional, Hindenach, Barbara, additional, Hoadley, Katherine A., additional, Hostetter, Galen, additional, Huang, Chen, additional, Jaehnig, Eric, additional, Jewell, Scott D., additional, Ji, Nan, additional, Jones, Corbin D., additional, Karz, Alcida, additional, Kaspera, Wojciech, additional, Kim, Lyndon, additional, Kothadia, Ramani B., additional, Kumar-Sinha, Chandan, additional, Lei, Jonathan, additional, Leprevost, Felipe D., additional, Li, Kai, additional, Liao, Yuxing, additional, Lilly, Jena, additional, Liu, Hongwei, additional, Lubínski, Jan, additional, Madan, Rashna, additional, Maggio, William, additional, Malc, Ewa, additional, Malovannaya, Anna, additional, Mareedu, Sailaja, additional, Markey, Sanford P., additional, Marrero-Oliveras, Annette, additional, Martinez, Nina, additional, Maunganidze, Nicollette, additional, McDermott, Jason E., additional, McGarvey, Peter B., additional, McGee, John, additional, Mieczkowski, Piotr, additional, Migliozzi, Simona, additional, Modugno, Francesmary, additional, Montgomery, Rebecca, additional, Newton, Chelsea J., additional, Omenn, Gilbert S., additional, Ozbek, Umut, additional, Paklina, Oxana V., additional, Paulovich, Amanda G., additional, Perou, Amy M., additional, Pico, Alexander R., additional, Piehowski, Paul D., additional, Placantonakis, Dimitris G., additional, Polonskaya, Larisa, additional, Potapova, Olga, additional, Pruetz, Barbara, additional, Qi, Liqun, additional, Ramkissoon, Shakti, additional, Resnick, Adam, additional, Richey, Shannon, additional, Riggins, Gregory, additional, Robinson, Karna, additional, Roche, Nancy, additional, Rohrer, Daniel C., additional, Rood, Brian R., additional, Rossell, Larissa, additional, Savage, Sara R., additional, Schadt, Eric E., additional, Shi, Yan, additional, Shi, Zhiao, additional, Shutack, Yvonne, additional, Singh, Shilpi, additional, Skelly, Tara, additional, Sokoll, Lori J., additional, Stawicki, Jakub, additional, Stein, Stephen E., additional, Suh, James, additional, Szopa, Wojciech, additional, Tabor, Dave, additional, Tan, Donghui, additional, Tansil, Darlene, additional, Thangudu, Ratna R., additional, Tognon, Cristina, additional, Traer, Elie, additional, Tsang, Shirley, additional, Tyner, Jeffrey, additional, Um, Ki Sung, additional, Valley, Dana R., additional, Vasaikar, Suhas, additional, Vatanian, Negin, additional, Velvulou, Uma, additional, Vernon, Michael, additional, Wan, Weiqing, additional, Wang, Junmei, additional, Webster, Alex, additional, Wen, Bo, additional, Whiteaker, Jeffrey R., additional, Wilson, George D., additional, Zakhartsev, Yuriy, additional, Zelt, Robert, additional, Zhang, Hui, additional, Zhang, Liwei, additional, Zhang, Zhen, additional, Zhao, Grace, additional, and Zhu, Jun, additional

Published
2021
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47. Proteogenomic insights into the biology and treatment of HPV-negative head and neck squamous cell carcinoma

Author

Huang, Chen, primary, Chen, Lijun, additional, Savage, Sara R., additional, Eguez, Rodrigo Vargas, additional, Dou, Yongchao, additional, Li, Yize, additional, da Veiga Leprevost, Felipe, additional, Jaehnig, Eric J., additional, Lei, Jonathan T., additional, Wen, Bo, additional, Schnaubelt, Michael, additional, Krug, Karsten, additional, Song, Xiaoyu, additional, Cieślik, Marcin, additional, Chang, Hui-Yin, additional, Wyczalkowski, Matthew A., additional, Li, Kai, additional, Colaprico, Antonio, additional, Li, Qing Kay, additional, Clark, David J., additional, Hu, Yingwei, additional, Cao, Liwei, additional, Pan, Jianbo, additional, Wang, Yuefan, additional, Cho, Kyung-Cho, additional, Shi, Zhiao, additional, Liao, Yuxing, additional, Jiang, Wen, additional, Anurag, Meenakshi, additional, Ji, Jiayi, additional, Yoo, Seungyeul, additional, Zhou, Daniel Cui, additional, Liang, Wen-Wei, additional, Wendl, Michael, additional, Vats, Pankaj, additional, Carr, Steven A., additional, Mani, D.R., additional, Zhang, Zhen, additional, Qian, Jiang, additional, Chen, Xi S., additional, Pico, Alexander R., additional, Wang, Pei, additional, Chinnaiyan, Arul M., additional, Ketchum, Karen A., additional, Kinsinger, Christopher R., additional, Robles, Ana I., additional, An, Eunkyung, additional, Hiltke, Tara, additional, Mesri, Mehdi, additional, Thiagarajan, Mathangi, additional, Weaver, Alissa M., additional, Sikora, Andrew G., additional, Lubiński, Jan, additional, Wierzbicka, Małgorzata, additional, Wiznerowicz, Maciej, additional, Satpathy, Shankha, additional, Gillette, Michael A., additional, Miles, George, additional, Ellis, Matthew J., additional, Omenn, Gilbert S., additional, Rodriguez, Henry, additional, Boja, Emily S., additional, Dhanasekaran, Saravana M., additional, Ding, Li, additional, Nesvizhskii, Alexey I., additional, El-Naggar, Adel K., additional, Chan, Daniel W., additional, Zhang, Hui, additional, Zhang, Bing, additional, Agarwal, Anupriya, additional, Anderson, Matthew L., additional, Avanessian, Shayan C., additional, Avtonomov, Dmitry, additional, Bathe, Oliver F., additional, Birger, Chet, additional, Birrer, Michael J., additional, Blumenberg, Lili, additional, Bocik, William E., additional, Borate, Uma, additional, Borucki, Melissa, additional, Burke, Meghan C., additional, Cai, Shuang, additional, Calinawan, Anna Pamela, additional, Cerda, Sandra, additional, Charamut, Alyssa, additional, Chen, Lin S., additional, Chowdhury, Shrabanti, additional, Clauser, Karl R., additional, Culpepper, Houston, additional, Czernicki, Tomasz, additional, D'Angelo, Fulvio, additional, Day, Jacob, additional, De Young, Stephanie, additional, Demir, Emek, additional, Ding, Fei, additional, Domagalski, Marcin J., additional, Dort, Joseph C., additional, Druker, Brian, additional, Duffy, Elizabeth, additional, Dyer, Maureen, additional, Edwards, Nathan J., additional, Elburn, Kimberly, additional, Ermakova, Tatiana S., additional, Fenyo, David, additional, Ferrarotto, Renata, additional, Francis, Alicia, additional, Gabriel, Stacey, additional, Garofano, Luciano, additional, Geffen, Yifat, additional, Getz, Gad, additional, Goldthwaite, Charles A., additional, Hannick, Linda I., additional, Hariharan, Pushpa, additional, Hayes, David N., additional, Heiman, David, additional, Hindenach, Barbara, additional, Hoadley, Katherine A., additional, Hostetter, Galen, additional, Hyrcza, Martin, additional, Jewell, Scott D., additional, Jones, Corbin D., additional, Kane, M. Harry, additional, Karz, Alicia, additional, Kothadia, Ramani B., additional, Krek, Azra, additional, Kumar-Sinha, Chandan, additional, Liu, Tao, additional, Liu, Hongwei, additional, Ma, Weiping, additional, Malc, Ewa, additional, Malovannaya, Anna, additional, Mareedu, Sailaja, additional, Markey, Sanford P., additional, Marrero-Oliveras, Annette, additional, Maunganidze, Nicollette, additional, McDermott, Jason E., additional, McGarvey, Peter B., additional, McGee, John, additional, Mieczkowski, Piotr, additional, Migliozzi, Simona, additional, Montgomery, Rebecca, additional, Newton, Chelsea J., additional, Ozbek, Umut, additional, Paulovich, Amanda G., additional, Payne, Samuel H., additional, Pazardzhikliev, Dimitar Dimitrov, additional, Perou, Amy M., additional, Petralia, Francesca, additional, Petrenko, Lyudmila, additional, Piehowski, Paul D., additional, Placantonakis, Dmitris, additional, Polonskaya, Larisa, additional, Ponomareva, Elena V., additional, Potapova, Olga, additional, Qi, Liqun, additional, Qu, Ning, additional, Ramkissoon, Shakti, additional, Reva, Boris, additional, Richey, Shannon, additional, Robinson, Karna, additional, Roche, Nancy, additional, Rodland, Karin, additional, Rohrer, Daniel C., additional, Rykunov, Dmitry, additional, Schadt, Eric E., additional, Shi, Yan, additional, Shutack, Yvonne, additional, Singh, Shilpi, additional, Skelly, Tara, additional, Smith, Richard, additional, Sokoll, Lori J., additional, Stawicki, Jakub, additional, Stein, Stephen E., additional, Suh, James, additional, Szopa, Wojciech, additional, Tabor, Dave, additional, Tan, Donghui, additional, Tansil, Darlene, additional, Teo, Guo Ci, additional, Thangudu, Ratna R., additional, Tognon, Cristina, additional, Traer, Elie, additional, Tsang, Shirley, additional, Tyner, Jeffrey, additional, Um, Ki Sung, additional, Valley, Dana R., additional, Vasilev, Lyubomir Valkov, additional, Vatanian, Negin, additional, Velvulou, Uma, additional, Vernon, Michael, additional, Westbrook, Thomas F., additional, Whiteaker, Jeffrey R., additional, Wu, Yige, additional, Xu, Midie, additional, Yao, Lijun, additional, Yi, Xinpei, additional, Yu, Fengchao, additional, Zaalishvili, Kakhaber, additional, Zakhartsev, Yuriy, additional, Zelt, Robert, additional, Zhao, Grace, additional, and Zhu, Jun, additional

Published
2021
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48. Abstract PR04: Epigenetic silencing of CDR1as drives IGF2BP3-mediated melanoma invasion and metastasis

Author

Hanniford, Douglas, primary, Ulloa-Morales, Alejandro, additional, Sánchez-Sendra, Beatriz, additional, Karz, Alcida, additional, Moubarak, Rana, additional, Tabaglio, Tommaso, additional, Berzoti-Coelho, Maria Gabriela, additional, Davalos, Veronica, additional, Wu, Pamela, additional, Vasudevaraja, Varshini, additional, Kloetgen, Andreas, additional, Lilja, Karin, additional, Imig, Jochen, additional, Monteagudo, Carlos, additional, Guccione, Ernesto, additional, Tsirigos, Aristotelis, additional, Osman, Iman, additional, Aifantis, Iannis, additional, and Hernando, Eva, additional

Published
2020
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49. Epigenetic Silencing of CDR1as Drives IGF2BP3-Mediated Melanoma Invasion and Metastasis

Author

Hanniford D, Ulloa-Morales A, Karz A, Berzoti-Coelho M, Moubarak R, Sanchez-Sendra B, Kloetgen A, Davalos V, Imig J, Wu P, Vasudevaraja V, Argibay D, Lilja K, Tabaglio T, Monteagudo C, Guccione E, Tsirigos A, Osman I, Aifantis I, and Hernando E

Abstract

Metastasis is the primary cause of death of cancer patients. Dissecting mechanisms governing metastatic spread may uncover important tumor biology and/or yield promising therapeutic insights. Here, we investigated the role of circular RNAs (circRNA) in metastasis, using melanoma as a model aggressive tumor. We identified silencing of cerebellar degeneration-related 1 antisense (CDR1as), a regulator of miR-7, as a hallmark of melanoma progression. CDR1as depletion results from epigenetic silencing of LINC00632, its originating long non-coding RNA (lncRNA) and promotes invasion in vitro and metastasis in vivo through a miR-7-independent, IGF2BP3-mediated mechanism. Moreover, CDR1as levels reflect cellular states associated with distinct therapeutic responses. Our study reveals functional, prognostic, and predictive roles for CDR1as and expose circRNAs as key players in metastasis.

Published
2020

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