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2. PI4KIIIβ is a therapeutic target in chromosome 1q–amplified lung adenocarcinoma

Author

Tan, Xiaochao, Banerjee, Priyam, Pham, Edward A, Rutaganira, Florentine UN, Basu, Kaustabh, Bota-Rabassedas, Neus, Guo, Hou-Fu, Grzeskowiak, Caitlin L, Liu, Xin, Yu, Jiang, Shi, Lei, Peng, David H, Rodriguez, B Leticia, Zhang, Jiaqi, Zheng, Veronica, Duose, Dzifa Y, Solis, Luisa M, Mino, Barbara, Raso, Maria Gabriela, Behrens, Carmen, Wistuba, Ignacio I, Scott, Kenneth L, Smith, Mark, Nguyen, Khanh, Lam, Grace, Choong, Ingrid, Mazumdar, Abhijit, Hill, Jamal L, Gibbons, Don L, Brown, Powel H, Russell, William K, Shokat, Kevan, Creighton, Chad J, Glenn, Jeffrey S, and Kurie, Jonathan M

Subjects
Lung Cancer, Cancer, Lung, Rare Diseases, Adenocarcinoma of Lung, Animals, Chromosomes, Human, Pair 1, Enzyme-Linked Immunosorbent Assay, Golgi Apparatus, Humans, In Vitro Techniques, Membrane Proteins, Mice, Phosphotransferases (Alcohol Group Acceptor), X-Ray Microtomography, Biological Sciences, Medical and Health Sciences
Abstract

Heightened secretion of protumorigenic effector proteins is a feature of malignant cells. Yet, the molecular underpinnings and therapeutic implications of this feature remain unclear. Here, we identify a chromosome 1q region that is frequently amplified in diverse cancer types and encodes multiple regulators of secretory vesicle biogenesis and trafficking, including the Golgi-dedicated enzyme phosphatidylinositol (PI)-4-kinase IIIβ (PI4KIIIβ). Molecular, biochemical, and cell biological studies show that PI4KIIIβ-derived PI-4-phosphate (PI4P) synthesis enhances secretion and accelerates lung adenocarcinoma progression by activating Golgi phosphoprotein 3 (GOLPH3)-dependent vesicular release from the Golgi. PI4KIIIβ-dependent secreted factors maintain 1q-amplified cancer cell survival and influence prometastatic processes in the tumor microenvironment. Disruption of this functional circuitry in 1q-amplified cancer cells with selective PI4KIIIβ antagonists induces apoptosis and suppresses tumor growth and metastasis. These results support a model in which chromosome 1q amplifications create a dependency on PI4KIIIβ-dependent secretion for cancer cell survival and tumor progression.

Published
2020

3. Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in RAS mutant cancers

Author

Sun, Chaoyang, Fang, Yong, Yin, Jun, Chen, Jian, Ju, Zhenlin, Zhang, Dong, Chen, Xiaohua, Vellano, Christopher P, Jeong, Kang Jin, Ng, Patrick Kwok-Shing, Eterovic, Agda Karina B, Bhola, Neil H, Lu, Yiling, Westin, Shannon N, Grandis, Jennifer R, Lin, Shiaw-Yih, Scott, Kenneth L, Peng, Guang, Brugge, Joan, and Mills, Gordon B

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Genetics, Cancer, Rare Diseases, Orphan Drug, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Animals, Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Cell Line, Tumor, DNA Damage, Drug Resistance, Neoplasm, Drug Synergism, Female, Forkhead Box Protein O3, Genes, ras, Homologous Recombination, MAP Kinase Signaling System, Mice, Mitogen-Activated Protein Kinase Kinases, Mutation, Neoplasms, Ovarian Neoplasms, Poly(ADP-ribose) Polymerase Inhibitors, Poly(ADP-ribose) Polymerases, Protein Kinase Inhibitors, Xenograft Model Antitumor Assays, Biological Sciences, Medical and Health Sciences, Medical biotechnology, Biomedical engineering
Abstract

Mutant RAS has remained recalcitrant to targeted therapy efforts. We demonstrate that combined treatment with poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors and mitogen-activated protein kinase (MAPK) kinase (MEK) inhibitors evokes unanticipated, synergistic cytotoxic effects in vitro and in vivo in multiple RAS mutant tumor models across tumor lineages where RAS mutations are prevalent. The effects of PARP and MEK inhibitor combinations are independent of BRCA1/2 and p53 mutation status, suggesting that the synergistic activity is likely to be generalizable. Synergistic activity of PARP and MEK inhibitor combinations in RAS mutant tumors is associated with (i) induction of BIM-mediated apoptosis, (ii) decrease in expression of components of the homologous recombination DNA repair pathway, (iii) decrease in homologous recombination DNA damage repair capacity, (iv) decrease in DNA damage checkpoint activity, (v) increase in PARP inhibitor-induced DNA damage, (vi) decrease in vascularity that could increase PARP inhibitor efficacy by inducing hypoxia, and (vii) elevated PARP1 protein, which increases trapping activity of PARP inhibitors. Mechanistically, enforced expression of FOXO3a, which is a target of the RAS/MAPK pathway, was sufficient to recapitulate the functional consequences of MEK inhibitors including synergy with PARP inhibitors. Thus, the ability of mutant RAS to suppress FOXO3a and its reversal by MEK inhibitors accounts, at least in part, for the synergy of PARP and MEK inhibitors in RAS mutant tumors. The rational combination of PARP and MEK inhibitors warrants clinical investigation in patients with RAS mutant tumors where there are few effective therapeutic options.

Published
2017

6. Bacteria-to-Human Protein Networks Reveal Origins of Endogenous DNA Damage

Author

Xia, Jun, Chiu, Li-Ya, Nehring, Ralf B., Bravo Núñez, María Angélica, Mei, Qian, Perez, Mercedes, Zhai, Yin, Fitzgerald, Devon M., Pribis, John P., Wang, Yumeng, Hu, Chenyue W., Powell, Reid T., LaBonte, Sandra A., Jalali, Ali, Matadamas Guzmán, Meztli L., Lentzsch, Alfred M., Szafran, Adam T., Joshi, Mohan C., Richters, Megan, Gibson, Janet L., Frisch, Ryan L., Hastings, P.J., Bates, David, Queitsch, Christine, Hilsenbeck, Susan G., Coarfa, Cristian, Hu, James C., Siegele, Deborah A., Scott, Kenneth L., Liang, Han, Mancini, Michael A., Herman, Christophe, Miller, Kyle M., and Rosenberg, Susan M.

Published
2019
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7. Literature-based automated discovery of tumor suppressor p53 phosphorylation and inhibition by NEK2

Author

Choi, Byung-Kwon, Dayaram, Tajhal, Parikh, Neha, Wilkins, Angela D., Nagarajan, Meena, Novikov, Ilya B., Bachman, Benjamin J., Jung, Sung Yun, Haas, Peter J., Labrie, Jacques L., Pickering, Curtis R., Adikesavan, Anbu K., Regenbogen, Sam, Kato, Linda, Lelescu, Ana, Buchovecky, Christie M., Zhang, Houyin, Bao, Sheng Hua, Boyer, Stephen, Weber, Griff, Scott, Kenneth L., Chen, Ying, Spangler, Scott, Donehower, Lawrence A., and Lichtarge, Olivier

Published
2018

8. Systematic Functional Annotation of Somatic Mutations in Cancer

Author

Ng, Patrick Kwok-Shing, Li, Jun, Jeong, Kang Jin, Shao, Shan, Chen, Hu, Tsang, Yiu Huen, Sengupta, Sohini, Wang, Zixing, Bhavana, Venkata Hemanjani, Tran, Richard, Soewito, Stephanie, Minussi, Darlan Conterno, Moreno, Daniela, Kong, Kathleen, Dogruluk, Turgut, Lu, Hengyu, Gao, Jianjiong, Tokheim, Collin, Zhou, Daniel Cui, Johnson, Amber M., Zeng, Jia, Ip, Carman Ka Man, Ju, Zhenlin, Wester, Matthew, Yu, Shuangxing, Li, Yongsheng, Vellano, Christopher P., Schultz, Nikolaus, Karchin, Rachel, Ding, Li, Lu, Yiling, Cheung, Lydia Wai Ting, Chen, Ken, Shaw, Kenna R., Meric-Bernstam, Funda, Scott, Kenneth L., Yi, Song, Sahni, Nidhi, Liang, Han, and Mills, Gordon B.

Published
2018
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9. A Pan-Cancer Proteogenomic Atlas of PI3K/AKT/mTOR Pathway Alterations

Author

Zhang, Yiqun, Kwok-Shing Ng, Patrick, Kucherlapati, Melanie, Chen, Fengju, Liu, Yuexin, Tsang, Yiu Huen, de Velasco, Guillermo, Jeong, Kang Jin, Akbani, Rehan, Hadjipanayis, Angela, Pantazi, Angeliki, Bristow, Christopher A., Lee, Eunjung, Mahadeshwar, Harshad S., Tang, Jiabin, Zhang, Jianhua, Yang, Lixing, Seth, Sahil, Lee, Semin, Ren, Xiaojia, Song, Xingzhi, Sun, Huandong, Seidman, Jonathan, Luquette, Lovelace J., Xi, Ruibin, Chin, Lynda, Protopopov, Alexei, Westbrook, Thomas F., Shelley, Carl Simon, Choueiri, Toni K., Ittmann, Michael, Van Waes, Carter, Weinstein, John N., Liang, Han, Henske, Elizabeth P., Godwin, Andrew K., Park, Peter J., Kucherlapati, Raju, Scott, Kenneth L., Mills, Gordon B., Kwiatkowski, David J., and Creighton, Chad J.

Published
2017
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11. The epithelial-to-mesenchymal transition activator ZEB1 initiates a prometastatic competing endogenous RNA network

Author

Tan, Xiaochao, Banerjee, Priyam, Liu, Xin, Yu, Jiang, Gibbons, Don L., Wu, Ping, Scott, Kenneth L., Diao, Lixia, Zheng, Xiaofeng, Wang, Jing, Jalali, Ali, Suraokar, Milind, Fujimoto, Junya, Behrens, Carmen, Liu, Xiuping, Liu, Chang-gong, Creighton, Chad J., Wistuba, Ignacio I., and Kurie, Jonathan M.

Subjects
Lung cancer -- Development and progression -- Prognosis, MicroRNA -- Health aspects -- Physiological aspects, Cancer metastasis -- Genetic aspects -- Development and progression, Transcription factors -- Health aspects, Health care industry
Abstract

Epithelial tumor cells undergo epithelial-to-mesenchymal transition (EMT) to gain metastatic activity. Competing endogenous RNAs (ceRNAs) have binding sites for a common set of microRNAs (miRs) and regulate each other's expression by sponging miRs. Here, we address whether ceRNAs govern metastasis driven by the EMT- activating transcription factor ZEB1. High miR-181b levels were correlated with an improved prognosis in human lung adenocarcinomas, and metastatic tumor cell lines derived from a murine lung adenocarcinoma model in which metastasis is ZEB1- driven were enriched in miR-181b targets. ZEB1 relieved a strong basal repression of [[alpha].sub.1] integrin (ITGA1) mRNA, which in turn upregulated adenylyl cyclase 9 mRNA (ADCY9) by sponging miR181b. Ectopic expression of the ITGA1 3'-untranslated region reversed miR-181b-mediated metastasis suppression and increased the levels of adenylyl cyclase 9 protein (AC9), which promoted tumor cell migration and metastasis. In human lung adenocarcinomas, ITGA1 and ADCY9 levels were positively correlated, and an AC9-activated transcriptomic signature had poor-prognostic value. Thus, ZEB1 initiates a miR-181b-regulated ceRNA network to drive metastasis., Introduction Metastasis is the primary cause of cancer-related death (1) and is driven by tumor cells that are uniquely capable of switching reversibly between epithelial and mesenchymal states in response [...]

Published
2018
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12. Combinatorial inhibition of PTPN12-regulated receptors leads to a broadly effective therapeutic strategy in triple-negative breast cancer

Author

Nair, Amritha, Chung, Hsiang-Ching, Sun, Tingting, Tyagi, Siddhartha, Dobrolecki, Lacey E, Dominguez-Vidana, Rocio, Kurley, Sarah J, Orellana, Mayra, Renwick, Alexander, Henke, David M, Katsonis, Panagiotis, Schmitt, Earlene, Chan, Doug W, Li, Hui, Mao, Sufeng, Petrovic, Ivana, Creighton, Chad J, Gutierrez, Carolina, Dubrulle, Julien, Stossi, Fabio, Tyner, Jeffrey W, Lichtarge, Olivier, Lin, Charles Y, Zhang, Bing, Scott, Kenneth L, Hilsenbeck, Susan G, Sun, Jinpeng, Yu, Xiao, Osborne, C Kent, Schiff, Rachel, Christensen, James G, Shields, David J, Rimawi, Mothaffar F, Ellis, Matthew J, Shaw, Chad A, Lewis, Michael T, and Westbrook, Thomas F

Subjects
Cell receptors -- Health aspects, Esterases -- Health aspects, Gene mutation -- Health aspects, Breast cancer -- Genetic aspects -- Development and progression -- Care and treatment, Gene expression -- Health aspects, Biological sciences, Health
Abstract

Author(s): Amritha Nair [1, 2]; Hsiang-Ching Chung [1, 2, 3]; Tingting Sun [1, 2]; Siddhartha Tyagi [1, 2]; Lacey E Dobrolecki [4]; Rocio Dominguez-Vidana [1, 2, 3]; Sarah J Kurley [...]

Published
2018
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15. Supplementary Tables from HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2+ Breast Cancer

Author

Xu, Xiaowei, primary, De Angelis, Carmine, primary, Burke, Kathleen A., primary, Nardone, Agostina, primary, Hu, Huizhong, primary, Qin, Lanfang, primary, Veeraraghavan, Jamunarani, primary, Sethunath, Vidyalakshmi, primary, Heiser, Laura M., primary, Wang, Nicholas, primary, Ng, Charlotte K.Y., primary, Chen, Edward S., primary, Renwick, Alexander, primary, Wang, Tao, primary, Nanda, Sarmistha, primary, Shea, Martin, primary, Mitchell, Tamika, primary, Rajendran, Mahitha, primary, Waters, Ian, primary, Zabransky, Daniel J., primary, Scott, Kenneth L., primary, Gutierrez, Carolina, primary, Nagi, Chandandeep, primary, Geyer, Felipe C., primary, Chamness, Gary C., primary, Park, Ben H., primary, Shaw, Chad A., primary, Hilsenbeck, Susan G., primary, Rimawi, Mothaffar F., primary, Gray, Joe W., primary, Weigelt, Britta, primary, Reis-Filho, Jorge S., primary, Osborne, C. Kent, primary, and Schiff, Rachel, primary

Published
2023
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16. Supplementary information from HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2+ Breast Cancer

Author

Xu, Xiaowei, primary, De Angelis, Carmine, primary, Burke, Kathleen A., primary, Nardone, Agostina, primary, Hu, Huizhong, primary, Qin, Lanfang, primary, Veeraraghavan, Jamunarani, primary, Sethunath, Vidyalakshmi, primary, Heiser, Laura M., primary, Wang, Nicholas, primary, Ng, Charlotte K.Y., primary, Chen, Edward S., primary, Renwick, Alexander, primary, Wang, Tao, primary, Nanda, Sarmistha, primary, Shea, Martin, primary, Mitchell, Tamika, primary, Rajendran, Mahitha, primary, Waters, Ian, primary, Zabransky, Daniel J., primary, Scott, Kenneth L., primary, Gutierrez, Carolina, primary, Nagi, Chandandeep, primary, Geyer, Felipe C., primary, Chamness, Gary C., primary, Park, Ben H., primary, Shaw, Chad A., primary, Hilsenbeck, Susan G., primary, Rimawi, Mothaffar F., primary, Gray, Joe W., primary, Weigelt, Britta, primary, Reis-Filho, Jorge S., primary, Osborne, C. Kent, primary, and Schiff, Rachel, primary

Published
2023
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17. Tables S1-S6 from Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of Cancer

Author

Lu, Hengyu, primary, Villafane, Nicole, primary, Dogruluk, Turgut, primary, Grzeskowiak, Caitlin L., primary, Kong, Kathleen, primary, Tsang, Yiu Huen, primary, Zagorodna, Oksana, primary, Pantazi, Angeliki, primary, Yang, Lixing, primary, Neill, Nicholas J., primary, Kim, Young Won, primary, Creighton, Chad J., primary, Verhaak, Roel G., primary, Mills, Gordon B., primary, Park, Peter J., primary, Kucherlapati, Raju, primary, and Scott, Kenneth L., primary

Published
2023
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18. Data from Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of Cancer

Author

Lu, Hengyu, primary, Villafane, Nicole, primary, Dogruluk, Turgut, primary, Grzeskowiak, Caitlin L., primary, Kong, Kathleen, primary, Tsang, Yiu Huen, primary, Zagorodna, Oksana, primary, Pantazi, Angeliki, primary, Yang, Lixing, primary, Neill, Nicholas J., primary, Kim, Young Won, primary, Creighton, Chad J., primary, Verhaak, Roel G., primary, Mills, Gordon B., primary, Park, Peter J., primary, Kucherlapati, Raju, primary, and Scott, Kenneth L., primary

Published
2023
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19. Figures S1-S4 from Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of Cancer

Author

Lu, Hengyu, primary, Villafane, Nicole, primary, Dogruluk, Turgut, primary, Grzeskowiak, Caitlin L., primary, Kong, Kathleen, primary, Tsang, Yiu Huen, primary, Zagorodna, Oksana, primary, Pantazi, Angeliki, primary, Yang, Lixing, primary, Neill, Nicholas J., primary, Kim, Young Won, primary, Creighton, Chad J., primary, Verhaak, Roel G., primary, Mills, Gordon B., primary, Park, Peter J., primary, Kucherlapati, Raju, primary, and Scott, Kenneth L., primary

Published
2023
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20. Supplementary Figures from HER2 Reactivation through Acquisition of the HER2 L755S Mutation as a Mechanism of Acquired Resistance to HER2-targeted Therapy in HER2+ Breast Cancer

Author

Xu, Xiaowei, primary, De Angelis, Carmine, primary, Burke, Kathleen A., primary, Nardone, Agostina, primary, Hu, Huizhong, primary, Qin, Lanfang, primary, Veeraraghavan, Jamunarani, primary, Sethunath, Vidyalakshmi, primary, Heiser, Laura M., primary, Wang, Nicholas, primary, Ng, Charlotte K.Y., primary, Chen, Edward S., primary, Renwick, Alexander, primary, Wang, Tao, primary, Nanda, Sarmistha, primary, Shea, Martin, primary, Mitchell, Tamika, primary, Rajendran, Mahitha, primary, Waters, Ian, primary, Zabransky, Daniel J., primary, Scott, Kenneth L., primary, Gutierrez, Carolina, primary, Nagi, Chandandeep, primary, Geyer, Felipe C., primary, Chamness, Gary C., primary, Park, Ben H., primary, Shaw, Chad A., primary, Hilsenbeck, Susan G., primary, Rimawi, Mothaffar F., primary, Gray, Joe W., primary, Weigelt, Britta, primary, Reis-Filho, Jorge S., primary, Osborne, C. Kent, primary, and Schiff, Rachel, primary

Published
2023
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21. Data from Identification of Variant-Specific Functions of PIK3CA by Rapid Phenotyping of Rare Mutations

Author

Dogruluk, Turgut, primary, Tsang, Yiu Huen, primary, Espitia, Maribel, primary, Chen, Fengju, primary, Chen, Tenghui, primary, Chong, Zechen, primary, Appadurai, Vivek, primary, Dogruluk, Armel, primary, Eterovic, Agna Karina, primary, Bonnen, Penelope E., primary, Creighton, Chad J., primary, Chen, Ken, primary, Mills, Gordon B., primary, and Scott, Kenneth L., primary

Published
2023
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22. Supplementary Tables S1-S5 from Identification of Variant-Specific Functions of PIK3CA by Rapid Phenotyping of Rare Mutations

Author

Dogruluk, Turgut, primary, Tsang, Yiu Huen, primary, Espitia, Maribel, primary, Chen, Fengju, primary, Chen, Tenghui, primary, Chong, Zechen, primary, Appadurai, Vivek, primary, Dogruluk, Armel, primary, Eterovic, Agna Karina, primary, Bonnen, Penelope E., primary, Creighton, Chad J., primary, Chen, Ken, primary, Mills, Gordon B., primary, and Scott, Kenneth L., primary

Published
2023
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23. Supplementary Figures S1-S2 from Identification of Variant-Specific Functions of PIK3CA by Rapid Phenotyping of Rare Mutations

Author

Dogruluk, Turgut, primary, Tsang, Yiu Huen, primary, Espitia, Maribel, primary, Chen, Fengju, primary, Chen, Tenghui, primary, Chong, Zechen, primary, Appadurai, Vivek, primary, Dogruluk, Armel, primary, Eterovic, Agna Karina, primary, Bonnen, Penelope E., primary, Creighton, Chad J., primary, Chen, Ken, primary, Mills, Gordon B., primary, and Scott, Kenneth L., primary

Published
2023
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24. The Genomic Landscape and Clinical Relevance of A-to-I RNA Editing in Human Cancers

Author

Han, Leng, Diao, Lixia, Yu, Shuangxing, Xu, Xiaoyan, Li, Jie, Zhang, Rui, Yang, Yang, Werner, Henrica M.J., Eterovic, A. Karina, Yuan, Yuan, Li, Jun, Nair, Nikitha, Minelli, Rosalba, Tsang, Yiu Huen, Cheung, Lydia W.T., Jeong, Kang Jin, Roszik, Jason, Ju, Zhenlin, Woodman, Scott E., Lu, Yiling, Scott, Kenneth L., Li, Jin Billy, Mills, Gordon B., and Liang, Han

Published
2015
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29. RNA editing derived epitopes function as cancer antigens to elicit immune responses

Author

Zhang, Minying, Fritsche, Jens, Roszik, Jason, Williams, Leila J., Peng, Xinxin, Chiu, Yulun, Tsou, Chih-Chiang, Hoffgaard, Franziska, Goldfinger, Valentina, Schoor, Oliver, Talukder, Amjad, Forget, Marie A., Haymaker, Cara, Bernatchez, Chantale, Han, Leng, Tsang, Yiu-Huen, Kong, Kathleen, Xu, Xiaoyan, Scott, Kenneth L., Singh-Jasuja, Harpreet, Lizee, Greg, Liang, Han, Weinschenk, Toni, Mills, Gordon B., and Hwu, Patrick

Published
2018
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30. A functional genomic screen in vivo identifies CEACAM5 as a clinically relevant driver of breast cancer metastasis

Author

Powell, Emily, Shao, Jiansu, Picon, Hector M., Bristow, Christopher, Ge, Zhongqi, Peoples, Michael, Robinson, Frederick, Jeter-Jones, Sabrina L., Schlosberg, Christopher, Grzeskowiak, Caitlin L., Yang, Fei, Wu, Yun, Wistuba, Ignacio, Moulder, Stacy L., Symmans, William F., Scott, Kenneth L., Edwards, John R., Liang, Han, Heffernan, Timothy P., and Piwnica-Worms, Helen

Published
2018
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31. Mutations in FBXL4 Cause Mitochondrial Encephalopathy and a Disorder of Mitochondrial DNA Maintenance

Author

Bonnen, Penelope E., Yarham, John W., Besse, Arnaud, Wu, Ping, Faqeih, Eissa A., Al-Asmari, Ali Mohammad, Saleh, Mohammad A.M., Eyaid, Wafaa, Hadeel, Alrukban, He, Langping, Smith, Frances, Yau, Shu, Simcox, Eve M., Miwa, Satomi, Donti, Taraka, Abu-Amero, Khaled K., Wong, Lee-Jun, Craigen, William J., Graham, Brett H., Scott, Kenneth L., McFarland, Robert, and Taylor, Robert W.

Published
2013
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33. Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma

Author

Chen, Yulong, Terajima, Masahiko, Yang, Yanan, Sun, Li, Ahn, Young-Ho, Pankova, Daniela, Puperi, Daniel S., Watanabe, Takeshi, Kim, Min P., Blackmon, Shanda H., Rodriguez, Jaime, Behrens, Carmen, Wistuba, Ignacio I., Minelli, Rosalba, Scott, Kenneth L., Sanchez-Adams, Johannah, Guilak, Farshid, Pati, Debananda, Thilaganathan, Nishan, Burns, Alan R., Creighton, Chad J., Martinez, Elisabeth D., Zal, Tomasz, Grande-Alien, K. Jane, Yamauchi, Mitsuo, and Kurie, Jonathan M.

Subjects
Crosslinked polymers -- Research, Hydroxylases -- Physiological aspects, Oncology, Experimental, Tumors -- Development and progression, Collagen -- Analysis -- Physiological aspects, Cancer -- Research, Health care industry
Abstract

Epithelial tumor metastasis Is preceded by an accumulation of collagen cross-links that heighten stromal stiffness and stimulate the Invasive properties of tumor cells. However, the biochemical nature of collagen cross-links in cancer is still unclear. Here, we postulated that epithelial tumorigenesis is accompanied by changes in the biochemical type of collagen crosslinks. Utilizing resected human lung cancertissues and a [p21.sup.CIP1/WAF1]-deficient, [K-ras.sup.G12D]-expressing murine metastatic lung cancer model, we showed that, relative to normal lung tissues, tumor stroma contains higher levels of hydroxylysine aldehyde-derived collagen cross-links (HLCCs) and lower levels of lysine aldehyde-derived cross-links (LCCs), which are the predominant types of collagen cross-links in skeletal tissues and soft tissues, respectively. Gain- and loss-of-function studies in tumor cells showed that lysyl hydroxylase 2 (LH2), which hydroxylates telopeptidyl lysine residues on collagen, shifted the tumor stroma toward a high-HLCC, low-LCC state, increased tumor stiffness, and enhanced tumor cell invasion and metastasis. Together, our data indicate that LH2 enhances the metastatic properties of tumor cells and functions as a regulatory switch that controls the relative abundance of biochemically distinct types of collagen cross-links in the tumor stroma., Introduction Collagen is the most abundant intrinsic matrix scaffolding protein and contributes to tissue tensile strength (1). Various aspects of collagen metabolism, including its expression, deposition, organization, and turnover, are [...]

Published
2015
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35. Proinvasion Metastasis Drivers in Early-Stage Melanoma Are Oncogenes

Author

Scott, Kenneth L., Nogueira, Cristina, Heffernan, Timothy P., van Doorn, Remco, Dhakal, Sabin, Hanna, Jason A., Min, Chengyin, Jaskelioff, Mariela, Xiao, Yonghong, Wu, Chang-Jiun, Cameron, Lisa A., Perry, Samuel R., Zeid, Rhamy, Feinberg, Tamar, Kim, Minjung, Vande Woude, George, Granter, Scott R., Bosenberg, Marcus, Chu, Gerald C., DePinho, Ronald A., Rimm, David L., and Chin, Lynda

Published
2011
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36. A functional genomic approach to actionable gene fusions for precision oncology

Author

Li, Jun, primary, Lu, Hengyu, additional, Ng, Patrick Kwok-Shing, additional, Pantazi, Angeliki, additional, Ip, Carman Ka Man, additional, Jeong, Kang Jin, additional, Amador, Bianca, additional, Tran, Richard, additional, Tsang, Yiu Huen, additional, Yang, Lixing, additional, Song, Xingzhi, additional, Dogruluk, Turgut, additional, Ren, Xiaojia, additional, Hadjipanayis, Angela, additional, Bristow, Christopher A., additional, Lee, Semin, additional, Kucherlapati, Melanie, additional, Parfenov, Michael, additional, Tang, Jiabin, additional, Seth, Sahil, additional, Mahadeshwar, Harshad S., additional, Mojumdar, Kamalika, additional, Zeng, Dong, additional, Zhang, Jianhua, additional, Protopopov, Alexei, additional, Seidman, Jonathan G., additional, Creighton, Chad J., additional, Lu, Yiling, additional, Sahni, Nidhi, additional, Shaw, Kenna R., additional, Meric-Bernstam, Funda, additional, Futreal, Andrew, additional, Chin, Lynda, additional, Scott, Kenneth L., additional, Kucherlapati, Raju, additional, Mills, Gordon B., additional, and Liang, Han, additional

Published
2022
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38. RET Fusion as a Novel Driver of Medullary Thyroid Carcinoma

Author

Grubbs, Elizabeth G., Ng, Patrick Kwok-Shing, Bui, Jacquelin, Busaidy, Naifa L., Chen, Ken, Lee, Jeffrey E., Lu, Xinyan, Lu, Hengyu, Meric-Bernstam, Funda, Mills, Gordon B., Palmer, Gary, Perrier, Nancy D., Scott, Kenneth L., Shaw, Kenna R., Waguespack, Steven G., Williams, Michelle D., Yelensky, Roman, and Cote, Gilbert J.

Published
2015

39. SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression

Author

Ding, Zhihu, Wii, Chang-Jiun, Chu, Gerald C., Xiao, Yonghong, Ho, Dennis, Zhang, Jingfang, Perry, Samuel R., Labrot, Emma S., Wu, Xiaoqiu, Lis, Rosina, Hoshida, Yujin, Hiller, David, Hu, Baoli, Jiang, Shan, Zheng, Hongwu, Stegh, Alexander H., Scott, Kenneth L., Signoretti, Sabina, Bardeesy, Nabeel, Wang, Y. Alan, Hill, David E., Golub, Todd R., Stampfer, Meir J., Wong, Wing H., Loda, Massimo, Mucci, Lorelei, Chin, Lynda, and DePinho, Ronald A.

Subjects
Prostate cancer -- Genetic aspects -- Care and treatment, Adenocarcinoma -- Genetic aspects -- Care and treatment, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Effective clinical management of prostate cancer (PCA) has been challenged by significant intratumoural heterogeneity on the genomic and pathological levels and limited understanding of the genetic elements governing disease progression (1). Here, we exploited the experimental merits of the mouse to test the hypothesis that pathways constraining progression might be activated in indolent Pten-null mouse prostate tumours and that inactivation of such progression barriers in mice would engender a metastasis-prone condition. Comparative transcriptomic and canonical pathway analyses, followed by biochemical confirmation, of normal prostate epithelium versus poorly progressive Pten-null prostate cancers revealed robust activation of the TGFβ/BMP-SMAD4 signalling axis. The functional relevance of SMAD4 was further supported by emergence of invasive, metastatic and lethal prostate cancers with 100% penetrance upon genetic deletion of Smad4 in the Pten-null mouse prostate. Pathological and molecular analysis as well as transcriptomic knowledge-based pathway profiling of emerging tumours identified cell proliferation and invasion as two cardinal tumour biological features in the metastatic Smad4/Pten-null PCA model. Follow-on pathological and functional assessment confirmed cyclin D1 and SPP1 as key mediators of these biological processes, which together with PTEN and SMAD4, form a four-gene signature that is prognostic of prostate-specific antigen (PSA) biochemical recurrence and lethal metastasis in human PCA. This model-informed progression analysis, together with genetic, functional and translational studies, establishes SMAD4 as a key regulator of PCA progression in mice and humans., Adenocarcinoma of the prostate (PCA) is the most common form of cancer and the second leading cause of cancer death in American men (2). Current methods of stratifying tumours to [...]

Published
2011
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40. GOLPH3 modulates mTOR signalling and rapamycin sensitivity in cancer

Author

Scott, Kenneth L., Kabbarah, Omar, Liang, Mei-Chih, Ivanova, Elena, Anagnostou, Valsamo, Wu, Joyce, Dhakal, Sabin, Wu, Min, Chen, Shujuan, Feinberg, Tamar, Huang, Joseph, Saci, Abdel, Widlund, Hans R., Fisher, David E., Xiao, Yonghong, Rimm, David L., Protopopov, Alexei, Wong, Kwok-Kin, and Chin, Lynda

Subjects
Oncology, Experimental -- Genetic aspects -- Health aspects, Binding proteins -- Health aspects -- Genetic aspects, Human genome -- Health aspects -- Genetic aspects, Cancer -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation, Genetic aspects, Health aspects
Abstract

Genome-wide copy number analyses of human cancers identified a frequent 5p13 amplification in several solid tumour types, including lung (56%), ovarian (38%), breast (32%), prostate (37%) and melanoma (32%). Here, using integrative analysis of a genomic profile of the region, we identify a Golgi protein, GOLPH3, as a candidate targeted for amplification. Gain- and loss-of-function studies in vitro and in vivo validated GOLPH3 as a potent oncogene. Physically, GOLPH3 localizes to the trans-Golgi network and interacts with components of the retromer complex, which in yeast has been linked to target of rapamycin (TOR) signalling. Mechanistically, GOLPH3 regulates cell size, enhances growth-factor-induced mTOR (also known as FRAP1) signalling in human cancer cells, and alters the response to an mTOR inhibitor in vivo. Thus, genomic and genetic, biological, functional and biochemical data in yeast and humans establishes GOLPH3 as a new oncogene that is commonly targeted for amplification in human cancer, and is capable of modulating the response to rapamycin, a cancer drug in clinical use., Cellular growth, proliferation and survival are regulated by a complex network of intracellular and extracellular signal transduction cascades. The growth-factor-responsive receptor tyrosine kinase (RTK)-phosphatidylinositol-3-kinase (PI3K) pathway has an important role [...]

Published
2009

41. POT1 Regulates Proliferation and Confers Sexual Dimorphism in Glioma

Author

Jalali, Ali, primary, Yu, Kwanha, additional, Beechar, Vivek, additional, Bosquez Huerta, Navish A., additional, Grichuk, Anthony, additional, Mehra, Deepika, additional, Lozzi, Brittney, additional, Kong, Kathleen, additional, Scott, Kenneth L., additional, Rao, Ganesh, additional, Bainbridge, Matthew N., additional, Bondy, Melissa L., additional, and Deneen, Benjamin, additional

Published
2021
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42. Differential expression of MAGEA6 toggles autophagy to promote pancreatic cancer progression

Author

Tsang, Yiu Huen, primary, Wang, Yumeng, additional, Kong, Kathleen, additional, Grzeskowiak, Caitlin, additional, Zagorodna, Oksana, additional, Dogruluk, Turgut, additional, Lu, Hengyu, additional, Villafane, Nicole, additional, Bhavana, Venkata Hemanjani, additional, Moreno, Daniela, additional, Elsea, Sarah H, additional, Liang, Han, additional, Mills, Gordon B, additional, and Scott, Kenneth L, additional

Published
2020
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43. Author response: Differential expression of MAGEA6 toggles autophagy to promote pancreatic cancer progression

Author

Tsang, Yiu Huen, primary, Wang, Yumeng, additional, Kong, Kathleen, additional, Grzeskowiak, Caitlin, additional, Zagorodna, Oksana, additional, Dogruluk, Turgut, additional, Lu, Hengyu, additional, Villafane, Nicole, additional, Bhavana, Venkata Hemanjani, additional, Moreno, Daniela, additional, Elsea, Sarah H, additional, Liang, Han, additional, Mills, Gordon B, additional, and Scott, Kenneth L, additional

Published
2020
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44. FTIR analysis of the SII (sub)540 intermediate of sensory rhodopsin II: Asp73 is the Schiff base proton acceptor

Author

Bergo, Vladislav, Spudich, Elena N., Scott, Kenneth L., Spudich, John L., and Rothschild, Kenneth J.

Subjects
Biochemistry -- Research, Fourier transform infrared spectroscopy -- Usage, Rhodopsin -- Research, Schiff bases -- Research, Protons -- Research, Biological sciences, Chemistry
Abstract

Research has been conducted on the sensory rhodopsin II (SRII) found in Halobacterium salinarum. The analysis of the wild-type SRII and the mutant D73E by means of FTIR difference spectroscopy has been carried out.

Published
2000

48. In vivo screening identifies GATAD2B as a metastasis driver in KRAS-driven lung cancer

Author

Grzeskowiak, Caitlin L., primary, Kundu, Samrat T., additional, Mo, Xiulei, additional, Ivanov, Andrei A., additional, Zagorodna, Oksana, additional, Lu, Hengyu, additional, Chapple, Richard H., additional, Tsang, Yiu Huen, additional, Moreno, Daniela, additional, Mosqueda, Maribel, additional, Eterovic, Karina, additional, Fradette, Jared J., additional, Ahmad, Sumreen, additional, Chen, Fengju, additional, Chong, Zechen, additional, Chen, Ken, additional, Creighton, Chad J., additional, Fu, Haian, additional, Mills, Gordon B., additional, Gibbons, Don L., additional, and Scott, Kenneth L., additional

Published
2018
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49. Bacteria-to-human protein networks reveal origins of endogenous DNA damage

Author

Xia, Jun, primary, Chiu, Li-Ya, additional, Nehring, Ralf B., additional, Bravo Núñez, María Angélica, additional, Mei, Qian, additional, Perez, Mercedes, additional, Zhai, Yin, additional, Fitzgerald, Devon M., additional, Pribis, John P., additional, Wang, Yumeng, additional, Hu, Chenyue W., additional, Powell, Reid T., additional, LaBonte, Sandra A., additional, Jalali, Ali, additional, Matadamas Guzmán, Meztli L., additional, Lentzsch, Alfred M., additional, Szafran, Adam T., additional, Joshi, Mohan C., additional, Richters, Megan, additional, Gibson, Janet L., additional, Frisch, Ryan L., additional, Hastings, P.J., additional, Bates, David, additional, Queitsch, Christine, additional, Hilsenbeck, Susan G., additional, Coarfa, Cristian, additional, Hu, James C., additional, Siegele, Deborah A., additional, Scott, Kenneth L., additional, Liang, Han, additional, Mancini, Michael A., additional, Herman, Christophe, additional, Miller, Kyle M., additional, and Rosenberg, Susan M., additional

Published
2018
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