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4. Supplementary Figures from MACROD2 Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors

Author

Sakthianandeswaren, Anuratha, primary, Parsons, Marie J., primary, Mouradov, Dmitri, primary, MacKinnon, Ruth N., primary, Catimel, Bruno, primary, Liu, Sheng, primary, Palmieri, Michelle, primary, Love, Christopher, primary, Jorissen, Robert N., primary, Li, Shan, primary, Whitehead, Lachlan, primary, Putoczki, Tracy L., primary, Preaudet, Adele, primary, Tsui, Cary, primary, Nowell, Cameron J., primary, Ward, Robyn L., primary, Hawkins, Nicholas J., primary, Desai, Jayesh, primary, Gibbs, Peter, primary, Ernst, Matthias, primary, Street, Ian, primary, Buchert, Michael, primary, and Sieber, Oliver M., primary

Published
2024
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5. Inhibition of the SRC Kinase HCK Impairs STAT3-Dependent Gastric Tumor Growth in Mice

Author

Poh, Ashleigh R, Dwyer, Amy R, Eissmann, Moritz F, Chand, Ashwini L, Baloyan, David, Boon, Louis, Murrey, Michael W, Whitehead, Lachlan, O'Brien, Megan, Lowell, Clifford A, Putoczki, Tracy L, Pixley, Fiona J, O'Donoghue, Robert JJ, and Ernst, Matthias

Subjects
Genetics, Rare Diseases, Cancer, Animals, Female, Humans, Macrophage Activation, Male, Mice, Mice, Transgenic, Phosphorylation, Proto-Oncogene Proteins c-hck, Pyrimidines, Pyrroles, STAT3 Transcription Factor, Stomach Neoplasms, Survival Rate, Immunology, Oncology and Carcinogenesis, Pharmacology and Pharmaceutical Sciences
Abstract

Persistent activation of the latent transcription factor STAT3 is observed in gastric tumor epithelial and immune cells and is associated with a poor patient prognosis. Although targeting STAT3-activating upstream kinases offers therapeutically viable targets with limited specificity, direct inhibition of STAT3 remains challenging. Here we provide functional evidence that myeloid-specific hematopoietic cell kinase (HCK) activity can drive STAT3-dependent epithelial tumor growth in mice and is associated with alternative macrophage activation alongside matrix remodeling and tumor cell invasion. Accordingly, genetic reduction of HCK expression in bone marrow-derived cells or systemic pharmacologic inhibition of HCK activity suppresses alternative macrophage polarization and epithelial STAT3 activation, and impairs tumor growth. These data validate HCK as a molecular target for the treatment of human solid tumors harboring excessive STAT3 activity.

Published
2020

10. Inhibition of Hematopoietic Cell Kinase Activity Suppresses Myeloid Cell-Mediated Colon Cancer Progression

Author

Poh, Ashleigh R, Love, Christopher G, Masson, Frederick, Preaudet, Adele, Tsui, Cary, Whitehead, Lachlan, Monard, Simon, Khakham, Yelena, Burstroem, Lotta, Lessene, Guillaume, Sieber, Oliver, Lowell, Clifford, Putoczki, Tracy L, O'Donoghue, Robert JJ, and Ernst, Matthias

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Biological Sciences, Immunology, Oncology and Carcinogenesis, Colo-Rectal Cancer, Hematology, Rare Diseases, Digestive Diseases, Cancer, Aetiology, 2.1 Biological and endogenous factors, Animals, Colonic Neoplasms, Colorectal Neoplasms, Female, Gene Expression Regulation, Neoplastic, Humans, Macrophage Activation, Mice, Inbred C57BL, Mice, Knockout, Proto-Oncogene Proteins c-hck, Pyrimidines, Pyrroles, STAT3 Transcription Factor, Signal Transduction, Stromal Cells, Xenograft Model Antitumor Assays, SRC family kinases, alternative macrophage polarization, colitis-associated colon cancer, colorectal cancer, hematopoietic cell kinase, mouse model, stat3, tumor microenvironment, tyrosine kinase inhibitor, xenograft, Neurosciences, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Aberrant activation of the SRC family kinase hematopoietic cell kinase (HCK) triggers hematological malignancies as a tumor cell-intrinsic oncogene. Here we find that high HCK levels correlate with reduced survival of colorectal cancer patients. Likewise, increased Hck activity in mice promotes the growth of endogenous colonic malignancies and of human colorectal cancer cell xenografts. Furthermore, tumor-associated macrophages of the corresponding tumors show a pronounced alternatively activated endotype, which occurs independently of mature lymphocytes or of Stat6-dependent Th2 cytokine signaling. Accordingly, pharmacological inhibition or genetic reduction of Hck activity suppresses alternative activation of tumor-associated macrophages and the growth of colon cancer xenografts. Thus, Hck may serve as a promising therapeutic target for solid malignancies.

Published
2017

13. Loss of Bcl-G, a Bcl-2 family member, augments the development of inflammation-associated colorectal cancer

Author

Nguyen, Paul M., Dagley, Laura F., Preaudet, Adele, Lam, Nga, Giam, Maybelline, Fung, Ka Yee, Aizel, Kaheina, van Duijneveldt, Gemma, Tan, Chin Wee, Hirokawa, Yumiko, Yip, Hon Yan K., Love, Christopher G., Poh, Ashleigh R., Cruz, Akshay D’, Burstroem, Charlotte, Feltham, Rebecca, Abdirahman, Suad M., Meiselbach, Kristy, Low, Ronnie Ren Jie, Palmieri, Michelle, Ernst, Matthias, Webb, Andrew I., Burgess, Tony, Sieber, Oliver M., Bouillet, Philippe, and Putoczki, Tracy L.

Published
2020
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14. Data from Inhibition of the SRC Kinase HCK Impairs STAT3-Dependent Gastric Tumor Growth in Mice

Author

Poh, Ashleigh R., primary, Dwyer, Amy R., primary, Eissmann, Moritz F., primary, Chand, Ashwini L., primary, Baloyan, David, primary, Boon, Louis, primary, Murrey, Michael W., primary, Whitehead, Lachlan, primary, O'Brien, Megan, primary, Lowell, Clifford A., primary, Putoczki, Tracy L., primary, Pixley, Fiona J., primary, O'Donoghue, Robert J.J., primary, and Ernst, Matthias, primary

Published
2023
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15. Supplementary Table 1 from Inhibition of the SRC Kinase HCK Impairs STAT3-Dependent Gastric Tumor Growth in Mice

Author

Poh, Ashleigh R., primary, Dwyer, Amy R., primary, Eissmann, Moritz F., primary, Chand, Ashwini L., primary, Baloyan, David, primary, Boon, Louis, primary, Murrey, Michael W., primary, Whitehead, Lachlan, primary, O'Brien, Megan, primary, Lowell, Clifford A., primary, Putoczki, Tracy L., primary, Pixley, Fiona J., primary, O'Donoghue, Robert J.J., primary, and Ernst, Matthias, primary

Published
2023
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16. Figure S3 from Combined Treatment with a WNT Inhibitor and the NSAID Sulindac Reduces Colon Adenoma Burden in Mice with Truncated APC

Author

Faux, Maree C., primary, Weinstock, Janet, primary, Gogos, Sophia, primary, Prato, Emma, primary, Azimpour, Alexander I., primary, O'Keefe, Ryan, primary, Cathcart-King, Yasmin, primary, Garnham, Alexandra L., primary, Ernst, Matthias, primary, Preaudet, Adele, primary, Christie, Michael, primary, Putoczki, Tracy L., primary, Buchert, Michael, primary, and Burgess, Antony W., primary

Published
2023
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17. Data from Combined Treatment with a WNT Inhibitor and the NSAID Sulindac Reduces Colon Adenoma Burden in Mice with Truncated APC

Author

Faux, Maree C., primary, Weinstock, Janet, primary, Gogos, Sophia, primary, Prato, Emma, primary, Azimpour, Alexander I., primary, O'Keefe, Ryan, primary, Cathcart-King, Yasmin, primary, Garnham, Alexandra L., primary, Ernst, Matthias, primary, Preaudet, Adele, primary, Christie, Michael, primary, Putoczki, Tracy L., primary, Buchert, Michael, primary, and Burgess, Antony W., primary

Published
2023
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18. Supplementary Figure 2 from Inhibition of the SRC Kinase HCK Impairs STAT3-Dependent Gastric Tumor Growth in Mice

Author

Poh, Ashleigh R., primary, Dwyer, Amy R., primary, Eissmann, Moritz F., primary, Chand, Ashwini L., primary, Baloyan, David, primary, Boon, Louis, primary, Murrey, Michael W., primary, Whitehead, Lachlan, primary, O'Brien, Megan, primary, Lowell, Clifford A., primary, Putoczki, Tracy L., primary, Pixley, Fiona J., primary, O'Donoghue, Robert J.J., primary, and Ernst, Matthias, primary

Published
2023
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19. Supplementary Figure 1 from Inhibition of the SRC Kinase HCK Impairs STAT3-Dependent Gastric Tumor Growth in Mice

Author

Poh, Ashleigh R., primary, Dwyer, Amy R., primary, Eissmann, Moritz F., primary, Chand, Ashwini L., primary, Baloyan, David, primary, Boon, Louis, primary, Murrey, Michael W., primary, Whitehead, Lachlan, primary, O'Brien, Megan, primary, Lowell, Clifford A., primary, Putoczki, Tracy L., primary, Pixley, Fiona J., primary, O'Donoghue, Robert J.J., primary, and Ernst, Matthias, primary

Published
2023
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20. Supplementary Figure 4 from Inhibition of the SRC Kinase HCK Impairs STAT3-Dependent Gastric Tumor Growth in Mice

Author

Poh, Ashleigh R., primary, Dwyer, Amy R., primary, Eissmann, Moritz F., primary, Chand, Ashwini L., primary, Baloyan, David, primary, Boon, Louis, primary, Murrey, Michael W., primary, Whitehead, Lachlan, primary, O'Brien, Megan, primary, Lowell, Clifford A., primary, Putoczki, Tracy L., primary, Pixley, Fiona J., primary, O'Donoghue, Robert J.J., primary, and Ernst, Matthias, primary

Published
2023
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21. Supplementary Figure 3 from Inhibition of the SRC Kinase HCK Impairs STAT3-Dependent Gastric Tumor Growth in Mice

Author

Poh, Ashleigh R., primary, Dwyer, Amy R., primary, Eissmann, Moritz F., primary, Chand, Ashwini L., primary, Baloyan, David, primary, Boon, Louis, primary, Murrey, Michael W., primary, Whitehead, Lachlan, primary, O'Brien, Megan, primary, Lowell, Clifford A., primary, Putoczki, Tracy L., primary, Pixley, Fiona J., primary, O'Donoghue, Robert J.J., primary, and Ernst, Matthias, primary

Published
2023
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22. Supplementary Tables from MACROD2 Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors

Author

Sakthianandeswaren, Anuratha, primary, Parsons, Marie J., primary, Mouradov, Dmitri, primary, MacKinnon, Ruth N., primary, Catimel, Bruno, primary, Liu, Sheng, primary, Palmieri, Michelle, primary, Love, Christopher, primary, Jorissen, Robert N., primary, Li, Shan, primary, Whitehead, Lachlan, primary, Putoczki, Tracy L., primary, Preaudet, Adele, primary, Tsui, Cary, primary, Nowell, Cameron J., primary, Ward, Robyn L., primary, Hawkins, Nicholas J., primary, Desai, Jayesh, primary, Gibbs, Peter, primary, Ernst, Matthias, primary, Street, Ian, primary, Buchert, Michael, primary, and Sieber, Oliver M., primary

Published
2023
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23. Supplementary Data from MACROD2 Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors

Author

Sakthianandeswaren, Anuratha, primary, Parsons, Marie J., primary, Mouradov, Dmitri, primary, MacKinnon, Ruth N., primary, Catimel, Bruno, primary, Liu, Sheng, primary, Palmieri, Michelle, primary, Love, Christopher, primary, Jorissen, Robert N., primary, Li, Shan, primary, Whitehead, Lachlan, primary, Putoczki, Tracy L., primary, Preaudet, Adele, primary, Tsui, Cary, primary, Nowell, Cameron J., primary, Ward, Robyn L., primary, Hawkins, Nicholas J., primary, Desai, Jayesh, primary, Gibbs, Peter, primary, Ernst, Matthias, primary, Street, Ian, primary, Buchert, Michael, primary, and Sieber, Oliver M., primary

Published
2023
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24. Supplementary Table 1 from Interleukin 33 Signaling Restrains Sporadic Colon Cancer in an Interferon-γ–Dependent Manner

Author

Eissmann, Moritz F., primary, Dijkstra, Christine, primary, Wouters, Merridee A., primary, Baloyan, David, primary, Mouradov, Dmitri, primary, Nguyen, Paul M., primary, Davalos-Salas, Mercedes, primary, Putoczki, Tracy L., primary, Sieber, Oliver M., primary, Mariadason, John M., primary, Ernst, Matthias, primary, and Masson, Frederick, primary

Published
2023
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25. Data from Interleukin 33 Signaling Restrains Sporadic Colon Cancer in an Interferon-γ–Dependent Manner

Author

Eissmann, Moritz F., primary, Dijkstra, Christine, primary, Wouters, Merridee A., primary, Baloyan, David, primary, Mouradov, Dmitri, primary, Nguyen, Paul M., primary, Davalos-Salas, Mercedes, primary, Putoczki, Tracy L., primary, Sieber, Oliver M., primary, Mariadason, John M., primary, Ernst, Matthias, primary, and Masson, Frederick, primary

Published
2023
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26. Data from MACROD2 Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors

Author

Sakthianandeswaren, Anuratha, primary, Parsons, Marie J., primary, Mouradov, Dmitri, primary, MacKinnon, Ruth N., primary, Catimel, Bruno, primary, Liu, Sheng, primary, Palmieri, Michelle, primary, Love, Christopher, primary, Jorissen, Robert N., primary, Li, Shan, primary, Whitehead, Lachlan, primary, Putoczki, Tracy L., primary, Preaudet, Adele, primary, Tsui, Cary, primary, Nowell, Cameron J., primary, Ward, Robyn L., primary, Hawkins, Nicholas J., primary, Desai, Jayesh, primary, Gibbs, Peter, primary, Ernst, Matthias, primary, Street, Ian, primary, Buchert, Michael, primary, and Sieber, Oliver M., primary

Published
2023
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27. Supplementary Figure S4 from Interleukin 33 Signaling Restrains Sporadic Colon Cancer in an Interferon-γ–Dependent Manner

Author

Eissmann, Moritz F., primary, Dijkstra, Christine, primary, Wouters, Merridee A., primary, Baloyan, David, primary, Mouradov, Dmitri, primary, Nguyen, Paul M., primary, Davalos-Salas, Mercedes, primary, Putoczki, Tracy L., primary, Sieber, Oliver M., primary, Mariadason, John M., primary, Ernst, Matthias, primary, and Masson, Frederick, primary

Published
2023
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28. Supplementary Methods from MACROD2 Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors

Author

Sakthianandeswaren, Anuratha, primary, Parsons, Marie J., primary, Mouradov, Dmitri, primary, MacKinnon, Ruth N., primary, Catimel, Bruno, primary, Liu, Sheng, primary, Palmieri, Michelle, primary, Love, Christopher, primary, Jorissen, Robert N., primary, Li, Shan, primary, Whitehead, Lachlan, primary, Putoczki, Tracy L., primary, Preaudet, Adele, primary, Tsui, Cary, primary, Nowell, Cameron J., primary, Ward, Robyn L., primary, Hawkins, Nicholas J., primary, Desai, Jayesh, primary, Gibbs, Peter, primary, Ernst, Matthias, primary, Street, Ian, primary, Buchert, Michael, primary, and Sieber, Oliver M., primary

Published
2023
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29. Supplementary Figures from MACROD2 Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors

Author

Sakthianandeswaren, Anuratha, primary, Parsons, Marie J., primary, Mouradov, Dmitri, primary, MacKinnon, Ruth N., primary, Catimel, Bruno, primary, Liu, Sheng, primary, Palmieri, Michelle, primary, Love, Christopher, primary, Jorissen, Robert N., primary, Li, Shan, primary, Whitehead, Lachlan, primary, Putoczki, Tracy L., primary, Preaudet, Adele, primary, Tsui, Cary, primary, Nowell, Cameron J., primary, Ward, Robyn L., primary, Hawkins, Nicholas J., primary, Desai, Jayesh, primary, Gibbs, Peter, primary, Ernst, Matthias, primary, Street, Ian, primary, Buchert, Michael, primary, and Sieber, Oliver M., primary

Published
2023
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30. Supplementary Figure Legends from Stomach-Specific Activation of Oncogenic KRAS and STAT3-Dependent Inflammation Cooperatively Promote Gastric Tumorigenesis in a Preclinical Model

Author

Thiem, Stefan, primary, Eissmann, Moritz F., primary, Elzer, Joachim, primary, Jonas, Anna, primary, Putoczki, Tracy L., primary, Poh, Ashleigh, primary, Nguyen, Paul, primary, Preaudet, Adele, primary, Flanagan, Dustin, primary, Vincan, Elizabeth, primary, Waring, Paul, primary, Buchert, Michael, primary, Jarnicki, Andrew, primary, and Ernst, Matthias, primary

Published
2023
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31. Supplementary Figures 1 through 7 and Supplementary Table 1 from Stomach-Specific Activation of Oncogenic KRAS and STAT3-Dependent Inflammation Cooperatively Promote Gastric Tumorigenesis in a Preclinical Model

Author

Thiem, Stefan, primary, Eissmann, Moritz F., primary, Elzer, Joachim, primary, Jonas, Anna, primary, Putoczki, Tracy L., primary, Poh, Ashleigh, primary, Nguyen, Paul, primary, Preaudet, Adele, primary, Flanagan, Dustin, primary, Vincan, Elizabeth, primary, Waring, Paul, primary, Buchert, Michael, primary, Jarnicki, Andrew, primary, and Ernst, Matthias, primary

Published
2023
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32. Supplementary Methods from Stomach-Specific Activation of Oncogenic KRAS and STAT3-Dependent Inflammation Cooperatively Promote Gastric Tumorigenesis in a Preclinical Model

Author

Thiem, Stefan, primary, Eissmann, Moritz F., primary, Elzer, Joachim, primary, Jonas, Anna, primary, Putoczki, Tracy L., primary, Poh, Ashleigh, primary, Nguyen, Paul, primary, Preaudet, Adele, primary, Flanagan, Dustin, primary, Vincan, Elizabeth, primary, Waring, Paul, primary, Buchert, Michael, primary, Jarnicki, Andrew, primary, and Ernst, Matthias, primary

Published
2023
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33. Data from Stomach-Specific Activation of Oncogenic KRAS and STAT3-Dependent Inflammation Cooperatively Promote Gastric Tumorigenesis in a Preclinical Model

Author

Thiem, Stefan, primary, Eissmann, Moritz F., primary, Elzer, Joachim, primary, Jonas, Anna, primary, Putoczki, Tracy L., primary, Poh, Ashleigh, primary, Nguyen, Paul, primary, Preaudet, Adele, primary, Flanagan, Dustin, primary, Vincan, Elizabeth, primary, Waring, Paul, primary, Buchert, Michael, primary, Jarnicki, Andrew, primary, and Ernst, Matthias, primary

Published
2023
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34. The Interleukin-11/IL-11 Receptor Promotes Glioblastoma Survival and Invasion under Glucose-Starved Conditions through Enhanced Glutaminolysis

Author

Stuart, Sarah F., primary, Bezawork-Geleta, Ayenachew, additional, Areeb, Zammam, additional, Gomez, Juliana, additional, Tsui, Vanessa, additional, Zulkifli, Ahmad, additional, Paradiso, Lucia, additional, Jones, Jordan, additional, Nguyen, Hong P. T., additional, Putoczki, Tracy L., additional, Licciardi, Paul V., additional, Kannourakis, George, additional, Morokoff, Andrew P., additional, Achuthan, Adrian A., additional, and Luwor, Rodney B., additional

Published
2023
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36. NLRP1 restricts butyrate producing commensals to exacerbate inflammatory bowel disease

Author

Tye, Hazel, Yu, Chien-Hsiung, Simms, Lisa A., de Zoete, Marcel R., Kim, Man Lyang, Zakrzewski, Martha, Penington, Jocelyn S., Harapas, Cassandra R., Souza-Fonseca-Guimaraes, Fernando, Wockner, Leesa F., Preaudet, Adele, Mielke, Lisa A., Wilcox, Stephen A., Ogura, Yasunori, Corr, Sinead C., Kanojia, Komal, Kouremenos, Konstantinos A., De Souza, David P., McConville, Malcolm J., Flavell, Richard A., Gerlic, Motti, Kile, Benjamin T., Papenfuss, Anthony T., Putoczki, Tracy L., Radford-Smith, Graham L., and Masters, Seth L.

Published
2018
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37. Structures of the interleukin 11 signalling complex reveal dynamics of gp130 extracellular domains and the inhibitory mechanism of a cytokine variant

Author

Metcalfe, Riley D., primary, Hanssen, Eric, additional, Fung, Ka Yee, additional, Aizel, Kaheina, additional, Kosasih, Clara C., additional, Zlatic, Courtney O., additional, Doughty, Larissa, additional, Morton, Craig J., additional, Leis, Andrew P., additional, Parker, Michael W., additional, Gooley, Paul R., additional, Putoczki, Tracy L., additional, and Griffin, Michael D.W., additional

Published
2022
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38. Interleukin-11 Is the Dominant IL-6 Family Cytokine during Gastrointestinal Tumorigenesis and Can Be Targeted Therapeutically

Author

Putoczki, Tracy L., Thiem, Stefan, Loving, Andrea, Busuttil, Rita A., Wilson, Nicholas J., Ziegler, Paul K., Nguyen, Paul M., Preaudet, Adele, Farid, Ryan, Edwards, Kirsten M., Boglev, Yeliz, Luwor, Rodney B., Jarnicki, Andrew, Horst, David, Boussioutas, Alex, Heath, Joan K., Sieber, Oliver M., Pleines, Irina, Kile, Benjamin T., Nash, Andrew, Greten, Florian R., McKenzie, Brent S., and Ernst, Matthias

Published
2013
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39. TGF-beta1 induced S100 family protein expression is associated with epithelial to mesenchymal transition states and poor survival in pancreatic cancer

Author

Low, Ronnie Ren Jie, primary, Fung, Ka Yee, additional, Gao, Hugh, additional, Preaudet, Adele, additional, Dagley, Laura F., additional, Yousef, Jumana, additional, Lee, Belinda, additional, Larsen, Rune H., additional, Kershaw, Nadia J., additional, Burgess, Antony W, additional, Gibbs, Peter, additional, Hollande, Frederic, additional, Griffin, Michael D.W., additional, Grimmond, Sean M., additional, and Putoczki, Tracy L., additional

Published
2022
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40. Combined Treatment with a WNT Inhibitor and the NSAID Sulindac Reduces Colon Adenoma Burden in Mice with Truncated APC

Author

Faux, Maree C., primary, Weinstock, Janet, additional, Gogos, Sophia, additional, Prato, Emma, additional, Azimpour, Alexander I., additional, O'Keefe, Ryan, additional, Cathcart-King, Yasmin, additional, Garnham, Alexandra L., additional, Ernst, Matthias, additional, Preaudet, Adele, additional, Christie, Michael, additional, Putoczki, Tracy L., additional, Buchert, Michael, additional, and Burgess, Antony W., additional

Published
2022
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42. The minor spliceosome offers a therapeutically viable target for the treatment of a broad spectrum of cancers

Author

Doggett, Karen, primary, Morgan, Kimberly J, additional, Mieruszynski, Stephen, additional, Williams, Benjamin B, additional, Olthof, Anouk M, additional, Garnham, Alexandra L, additional, Milevskiy, Michael J G, additional, Whitehead, Lachlan, additional, Coates, Janine, additional, Buchert, Michael, additional, O’Donoghue, Robert JJ, additional, Hall, Thomas E, additional, Gong, Zhiyuan, additional, Putoczki, Tracy L, additional, Ernst, Matthias, additional, Sutherland, Kate D, additional, Kanadia, Rahul N, additional, and Heath, Joan K, additional

Published
2021
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47. mTORC1 inhibition restricts inflammation-associated gastrointestinal tumorigenesis in mice

Author

Thiem, Stefan, Pierce, Thomas P., Palmieri, Michelle, Putoczki, Tracy L., Buchert, Michael, Preaudet, Adele, Farid, Ryan O., Love, Chris, Catimel, Bruno, Lei, Zhengdeng, Rozen, Steve, Gopalakrishnan, Veena, Schaper, Fred, Hallek, Michael, Boussioutas, Alex, Tan, Patrick, Jarnicki, Andrew, and Ernst, Matthias

Subjects
Cytokines -- Health aspects -- Physiological aspects -- Research, Gastrointestinal tumors -- Risk factors -- Research -- Development and progression -- Genetic aspects, Health care industry
Abstract

Gastrointestinal cancers are frequently associated with chronic inflammation and excessive secretion of IL-6 family cytokines, which promote tumorigenesis through persistent activation of the GP130/JAK/STAT3 pathway. Although tumor progression can be prevented by genetic ablation of Stat3 in mice, this transcription factor remains a challenging therapeutic target with a paucity of clinically approved inhibitors. Here, we uncovered parallel and excessive activation of mTOR complex 1 (mTORC1) alongside STAT3 in human intestinal-type gastric cancers (IGCs). Furthermore, in a preclinical mouse model of IGC, GP130 ligand administration simultaneously activated mTORC1/S6 kinase and STAT3 signaling. We therefore investigated whether mTORC1 activation was required for inflammation-associated gastrointestinal tumorigenesis. Strikingly, the mTORC1-specific inhibitor RAD001 potently suppressed initiation and progression of both murine IGC and colitis-associated colon cancer. The therapeutic effect of RAD001 was associated with reduced tumor vascularization and cell proliferation but occurred independently of STAT3 activity. We analyzed the mechanism of GP130-mediated mTORC1 activation in cells and mice and revealed a requirement for JAK and PI3K activity but not for GP130 tyrosine phosphorylation or STAT3. Our results suggest that GP130-dependent activation of the druggable PI3K/mTORC1 pathway is required for inflammation-associated gastrointestinal tumorigenesis. These findings advocate clinical application of PI3K/mTORC1 inhibitors for the treatment of corresponding human malignancies., Introduction During the multistep process of tumor formation conditions within the tissue microenvironment can influence the fate of premalignant cells. In inflammation-associated cancers, tumor promotion is thought to be facilitated [...]

Published
2013
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48. Type 2 Innate Lymphoid Cells Protect against Colorectal Cancer Progression and Predict Improved Patient Survival

Author

Huang, Qiutong, primary, Jacquelot, Nicolas, additional, Preaudet, Adele, additional, Hediyeh-zadeh, Soroor, additional, Souza-Fonseca-Guimaraes, Fernando, additional, McKenzie, Andrew N. J., additional, Hansbro, Philip M., additional, Davis, Melissa J., additional, Mielke, Lisa A., additional, Putoczki, Tracy L., additional, and Belz, Gabrielle T., additional

Published
2021
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50. Necroptosis is dispensable for the development of inflammation-associated or sporadic colon cancer in mice

Author

Alvarez-Diaz, Silvia, primary, Preaudet, Adele, additional, Samson, Andre L., additional, Nguyen, Paul M., additional, Fung, Ka Yee, additional, Garnham, Alexandra L., additional, Alexander, Warren S., additional, Strasser, Andreas, additional, Ernst, Matthias, additional, Putoczki, Tracy L., additional, and Murphy, James M., additional

Published
2020
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