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Start Over Author "Dosch A" Publisher american association for cancer research (aacr)
196 results on '"Dosch A"'

1. Supplementary Figure S6 from Tumor Cell–Intrinsic p38 MAPK Signaling Promotes IL1α-Mediated Stromal Inflammation and Therapeutic Resistance in Pancreatic Cancer

Author

Singh, Samara P., primary, Dosch, Austin R., primary, Mehra, Siddharth, primary, De Castro Silva, Iago, primary, Bianchi, Anna, primary, Garrido, Vanessa T., primary, Zhou, Zhiqun, primary, Adams, Andrew, primary, Amirian, Haleh, primary, Box, Edmond W., primary, Sun, Xiaodian, primary, Ban, Yuguang, primary, Datta, Jashodeep, primary, Nagathihalli, Nagaraj S., primary, and Merchant, Nipun B., primary

Published
2024
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2. Supplementary Data from Tumor Cell–Intrinsic p38 MAPK Signaling Promotes IL1α-Mediated Stromal Inflammation and Therapeutic Resistance in Pancreatic Cancer

Author

Singh, Samara P., primary, Dosch, Austin R., primary, Mehra, Siddharth, primary, De Castro Silva, Iago, primary, Bianchi, Anna, primary, Garrido, Vanessa T., primary, Zhou, Zhiqun, primary, Adams, Andrew, primary, Amirian, Haleh, primary, Box, Edmond W., primary, Sun, Xiaodian, primary, Ban, Yuguang, primary, Datta, Jashodeep, primary, Nagathihalli, Nagaraj S., primary, and Merchant, Nipun B., primary

Published
2024
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3. Supplementary Materials and Methods from Tumor Cell–Intrinsic p38 MAPK Signaling Promotes IL1α-Mediated Stromal Inflammation and Therapeutic Resistance in Pancreatic Cancer

Author

Singh, Samara P., primary, Dosch, Austin R., primary, Mehra, Siddharth, primary, De Castro Silva, Iago, primary, Bianchi, Anna, primary, Garrido, Vanessa T., primary, Zhou, Zhiqun, primary, Adams, Andrew, primary, Amirian, Haleh, primary, Box, Edmond W., primary, Sun, Xiaodian, primary, Ban, Yuguang, primary, Datta, Jashodeep, primary, Nagathihalli, Nagaraj S., primary, and Merchant, Nipun B., primary

Published
2024
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4. Supplementary Figure Legends from Tumor Cell–Intrinsic p38 MAPK Signaling Promotes IL1α-Mediated Stromal Inflammation and Therapeutic Resistance in Pancreatic Cancer

Author

Singh, Samara P., primary, Dosch, Austin R., primary, Mehra, Siddharth, primary, De Castro Silva, Iago, primary, Bianchi, Anna, primary, Garrido, Vanessa T., primary, Zhou, Zhiqun, primary, Adams, Andrew, primary, Amirian, Haleh, primary, Box, Edmond W., primary, Sun, Xiaodian, primary, Ban, Yuguang, primary, Datta, Jashodeep, primary, Nagathihalli, Nagaraj S., primary, and Merchant, Nipun B., primary

Published
2024
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5. Data from Tumor Cell–Intrinsic p38 MAPK Signaling Promotes IL1α-Mediated Stromal Inflammation and Therapeutic Resistance in Pancreatic Cancer

Author

Singh, Samara P., primary, Dosch, Austin R., primary, Mehra, Siddharth, primary, De Castro Silva, Iago, primary, Bianchi, Anna, primary, Garrido, Vanessa T., primary, Zhou, Zhiqun, primary, Adams, Andrew, primary, Amirian, Haleh, primary, Box, Edmond W., primary, Sun, Xiaodian, primary, Ban, Yuguang, primary, Datta, Jashodeep, primary, Nagathihalli, Nagaraj S., primary, and Merchant, Nipun B., primary

Published
2024
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6. Abstract B093: Alcoholic chronic inflammation driven CREB mediates acinar-to-ductal reprogramming and promote neoplastic progression

Author

Mehra, Siddharth, primary, Srinivasan, Supriya, additional, Bianchi, Anna, additional, Dosch, Austin, additional, Singh, Samara, additional, Garrido, Vanessa, additional, De Castro Silva, Iago, additional, Krishnamoorthy, Varunkumar, additional, Jinka, Sudhakar, additional, Datta, Jashodeep, additional, Merchant, Nipun B., additional, and Nagathihalli, Nagaraj, additional

Published
2024
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7. Abstract C025: Fibroblast-specific IL1R1-p38 MAPK signaling sustains stromal inflammation and contributes to therapeutic resistance in pancreatic cancer

Author

Singh, Samara P., primary, Dosch, Austin R., additional, Mehra, Siddharth, additional, de Castro Silva, Iago, additional, Garrido, Vanessa Tonin, additional, Bianchi, Anna, additional, Amirian, Haleh, additional, Box, Edmond W., additional, Datta, Jashodeep, additional, Nagathihalli, Nagaraj S., additional, and Merchant, Nipun B., additional

Published
2024
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8. Cell-Autonomous Cxcl1 Sustains Tolerogenic Circuitries and Stromal Inflammation via Neutrophil-Derived TNF in Pancreatic Cancer

Author

Anna Bianchi, Iago De Castro Silva, Nilesh U. Deshpande, Samara Singh, Siddharth Mehra, Vanessa T. Garrido, Xinyu Guo, Luis A. Nivelo, Despina S. Kolonias, Shannon J. Saigh, Eric Wieder, Christine I. Rafie, Austin R. Dosch, Zhiqun Zhou, Oliver Umland, Haleh Amirian, Ifeanyichukwu C. Ogobuiro, Jian Zhang, Yuguang Ban, Carina Shiau, Nagaraj S. Nagathihalli, Elizabeth A. Montgomery, William L. Hwang, Roberta Brambilla, Krishna Komanduri, Alejandro V. Villarino, Eneda Toska, Ben Z. Stanger, Dmitry I. Gabrilovich, Nipun B. Merchant, and Jashodeep Datta

Subjects
Oncology
Abstract

We have shown that KRAS–TP53 genomic coalteration is associated with immune-excluded microenvironments, chemoresistance, and poor survival in pancreatic ductal adenocarcinoma (PDAC) patients. By treating KRAS–TP53 cooperativity as a model for high-risk biology, we now identify cell-autonomous Cxcl1 as a key mediator of spatial T-cell restriction via interactions with CXCR2+ neutrophilic myeloid-derived suppressor cells in human PDAC using imaging mass cytometry. Silencing of cell-intrinsic Cxcl1 in LSL-KrasG12D/+;Trp53R172H/+;Pdx-1Cre/+(KPC) cells reprograms the trafficking and functional dynamics of neutrophils to overcome T-cell exclusion and controls tumor growth in a T cell–dependent manner. Mechanistically, neutrophil-derived TNF is a central regulator of this immunologic rewiring, instigating feed-forward Cxcl1 overproduction from tumor cells and cancer-associated fibroblasts (CAF), T-cell dysfunction, and inflammatory CAF polarization via transmembrane TNF–TNFR2 interactions. TNFR2 inhibition disrupts this circuitry and improves sensitivity to chemotherapy in vivo. Our results uncover cancer cell–neutrophil cross-talk in which context-dependent TNF signaling amplifies stromal inflammation and immune tolerance to promote therapeutic resistance in PDAC. Significance: By decoding connections between high-risk tumor genotypes, cell-autonomous inflammatory programs, and myeloid-enriched/T cell–excluded contexts, we identify a novel role for neutrophil-derived TNF in sustaining immunosuppression and stromal inflammation in pancreatic tumor microenvironments. This work offers a conceptual framework by which targeting context-dependent TNF signaling may overcome hallmarks of chemoresistance in pancreatic cancer.

Published
2023
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9. Remodeling of Stromal Immune Microenvironment by Urolithin A Improves Survival with Immune Checkpoint Blockade in Pancreatic Cancer

Author

Mehra, Siddharth, primary, Garrido, Vanessa T., additional, Dosch, Austin R., additional, Lamichhane, Purushottam, additional, Srinivasan, Supriya, additional, Singh, Samara P., additional, Zhou, Zhiqun, additional, De Castro Silva, Iago, additional, Joshi, Chandrashekar, additional, Ban, Yuguang, additional, Datta, Jashodeep, additional, Gilboa, Eli, additional, Merchant, Nipun B., additional, and Nagathihalli, Nagaraj S., additional

Published
2023
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10. Data from Remodeling of Stromal Immune Microenvironment by Urolithin A Improves Survival with Immune Checkpoint Blockade in Pancreatic Cancer

Author

Mehra, Siddharth, primary, Garrido, Vanessa T., primary, Dosch, Austin R., primary, Lamichhane, Purushottam, primary, Srinivasan, Supriya, primary, Singh, Samara P., primary, Zhou, Zhiqun, primary, De Castro Silva, Iago, primary, Joshi, Chandrashekar, primary, Ban, Yuguang, primary, Datta, Jashodeep, primary, Gilboa, Eli, primary, Merchant, Nipun B., primary, and Nagathihalli, Nagaraj S., primary

Published
2023
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11. Figure S5 from Remodeling of Stromal Immune Microenvironment by Urolithin A Improves Survival with Immune Checkpoint Blockade in Pancreatic Cancer

Author

Mehra, Siddharth, primary, Garrido, Vanessa T., primary, Dosch, Austin R, primary, Lamichhane, Purushottam, primary, Srinivasan, Supriya, primary, Singh, Samara P, primary, Zhou, Zhiqun, primary, De Castro Silva, Iago, primary, Joshi, Chandrashekar, primary, Ban, Yuguang, primary, Datta, Jashodeep, primary, Gilboa, Eli, primary, Merchant, Nipun B, primary, and Nagathihalli, Nagaraj S, primary

Published
2023
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12. Supplementary Tables S1-S2 from Remodeling of Stromal Immune Microenvironment by Urolithin A Improves Survival with Immune Checkpoint Blockade in Pancreatic Cancer

Author

Mehra, Siddharth, primary, Garrido, Vanessa T., primary, Dosch, Austin R, primary, Lamichhane, Purushottam, primary, Srinivasan, Supriya, primary, Singh, Samara P, primary, Zhou, Zhiqun, primary, De Castro Silva, Iago, primary, Joshi, Chandrashekar, primary, Ban, Yuguang, primary, Datta, Jashodeep, primary, Gilboa, Eli, primary, Merchant, Nipun B, primary, and Nagathihalli, Nagaraj S, primary

Published
2023
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13. Supplementary Materials from Cell-Autonomous Cxcl1 Sustains Tolerogenic Circuitries and Stromal Inflammation via Neutrophil-Derived TNF in Pancreatic Cancer

Author

Bianchi, Anna, primary, De Castro Silva, Iago, primary, Deshpande, Nilesh U., primary, Singh, Samara, primary, Mehra, Siddharth, primary, Garrido, Vanessa T., primary, Guo, Xinyu, primary, Nivelo, Luis A., primary, Kolonias, Despina S., primary, Saigh, Shannon J., primary, Wieder, Eric, primary, Rafie, Christine I., primary, Dosch, Austin R., primary, Zhou, Zhiqun, primary, Umland, Oliver, primary, Amirian, Haleh, primary, Ogobuiro, Ifeanyichukwu C., primary, Zhang, Jian, primary, Ban, Yuguang, primary, Shiau, Carina, primary, Nagathihalli, Nagaraj S., primary, Montgomery, Elizabeth A., primary, Hwang, William L., primary, Brambilla, Roberta, primary, Komanduri, Krishna, primary, Villarino, Alejandro V., primary, Toska, Eneda, primary, Stanger, Ben Z., primary, Gabrilovich, Dmitry I., primary, Merchant, Nipun B., primary, and Datta, Jashodeep, primary

Published
2023
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14. Supplementary Table S1 from Cell-Autonomous Cxcl1 Sustains Tolerogenic Circuitries and Stromal Inflammation via Neutrophil-Derived TNF in Pancreatic Cancer

Author

Bianchi, Anna, primary, De Castro Silva, Iago, primary, Deshpande, Nilesh U., primary, Singh, Samara, primary, Mehra, Siddharth, primary, Garrido, Vanessa T., primary, Guo, Xinyu, primary, Nivelo, Luis A., primary, Kolonias, Despina S., primary, Saigh, Shannon J., primary, Wieder, Eric, primary, Rafie, Christine I., primary, Dosch, Austin R., primary, Zhou, Zhiqun, primary, Umland, Oliver, primary, Amirian, Haleh, primary, Ogobuiro, Ifeanyichukwu C., primary, Zhang, Jian, primary, Ban, Yuguang, primary, Shiau, Carina, primary, Nagathihalli, Nagaraj S., primary, Montgomery, Elizabeth A., primary, Hwang, William L., primary, Brambilla, Roberta, primary, Komanduri, Krishna, primary, Villarino, Alejandro V., primary, Toska, Eneda, primary, Stanger, Ben Z., primary, Gabrilovich, Dmitry I., primary, Merchant, Nipun B., primary, and Datta, Jashodeep, primary

Published
2023
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15. Data from Cell-Autonomous Cxcl1 Sustains Tolerogenic Circuitries and Stromal Inflammation via Neutrophil-Derived TNF in Pancreatic Cancer

Author

Bianchi, Anna, primary, De Castro Silva, Iago, primary, Deshpande, Nilesh U., primary, Singh, Samara, primary, Mehra, Siddharth, primary, Garrido, Vanessa T., primary, Guo, Xinyu, primary, Nivelo, Luis A., primary, Kolonias, Despina S., primary, Saigh, Shannon J., primary, Wieder, Eric, primary, Rafie, Christine I., primary, Dosch, Austin R., primary, Zhou, Zhiqun, primary, Umland, Oliver, primary, Amirian, Haleh, primary, Ogobuiro, Ifeanyichukwu C., primary, Zhang, Jian, primary, Ban, Yuguang, primary, Shiau, Carina, primary, Nagathihalli, Nagaraj S., primary, Montgomery, Elizabeth A., primary, Hwang, William L., primary, Brambilla, Roberta, primary, Komanduri, Krishna, primary, Villarino, Alejandro V., primary, Toska, Eneda, primary, Stanger, Ben Z., primary, Gabrilovich, Dmitry I., primary, Merchant, Nipun B., primary, and Datta, Jashodeep, primary

Published
2023
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16. Abstract 3627: Inhibition of tumor cell-autonomous p38 MAPK suppresses IL1α-mediated inflammatory tumor-stromal crosstalk in pancreatic adenocarcinoma

Author

Singh, Samara, primary, Dosch, Austin R., additional, Mehra, Siddharth, additional, Silva, Iago de Castro, additional, Bianchi, Anna, additional, Garrido, Vanessa Tonin, additional, Zhou, Zhiqun, additional, Amirian, Haleh, additional, Box, Edmond W., additional, Datta, Jashodeep, additional, Nagathihalli, Nagaraj, additional, and Merchant, Nipun B., additional

Published
2023
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17. Supplementary Tables S1-S3 from Urolithin A, a Novel Natural Compound to Target PI3K/AKT/mTOR Pathway in Pancreatic Cancer

Author

Totiger, Tulasigeri M., primary, Srinivasan, Supriya, primary, Jala, Venkatakrishna R., primary, Lamichhane, Purushottam, primary, Dosch, Austin R., primary, Gaidarski, Alexander A., primary, Joshi, Chandrashekhar, primary, Rangappa, Shobith, primary, Castellanos, Jason, primary, Vemula, Praveen Kumar, primary, Chen, Xi, primary, Kwon, Deukwoo, primary, Kashikar, Nilesh, primary, VanSaun, Michael, primary, Merchant, Nipun B., primary, and Nagathihalli, Nagaraj S., primary

Published
2023
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19. Supplementary Figure S2 from Combined Src/EGFR Inhibition Targets STAT3 Signaling and Induces Stromal Remodeling to Improve Survival in Pancreatic Cancer

Author

Dosch, Austin R., primary, Dai, Xizi, primary, Reyzer, Michelle L., primary, Mehra, Siddharth, primary, Srinivasan, Supriya, primary, Willobee, Brent A., primary, Kwon, Deukwoo, primary, Kashikar, Nilesh, primary, Caprioli, Richard, primary, Merchant, Nipun B., primary, and Nagathihalli, Nagaraj S., primary

Published
2023
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20. Supplementary Figure Legends from Combined Src/EGFR Inhibition Targets STAT3 Signaling and Induces Stromal Remodeling to Improve Survival in Pancreatic Cancer

Author

Dosch, Austin R., primary, Dai, Xizi, primary, Reyzer, Michelle L., primary, Mehra, Siddharth, primary, Srinivasan, Supriya, primary, Willobee, Brent A., primary, Kwon, Deukwoo, primary, Kashikar, Nilesh, primary, Caprioli, Richard, primary, Merchant, Nipun B., primary, and Nagathihalli, Nagaraj S., primary

Published
2023
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21. Supplementary Tables from Combined Blockade of MEK and CDK4/6 Pathways Induces Senescence to Improve Survival in Pancreatic Ductal Adenocarcinoma

Author

Willobee, Brent A., primary, Gaidarski, Alexander A., primary, Dosch, Austin R., primary, Castellanos, Jason A., primary, Dai, Xizi, primary, Mehra, Siddharth, primary, Messaggio, Fanuel, primary, Srinivasan, Supriya, primary, VanSaun, Michael N., primary, Nagathihalli, Nagaraj S., primary, and Merchant, Nipun B., primary

Published
2023
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22. Supplementary Table S1 from Combined Src/EGFR Inhibition Targets STAT3 Signaling and Induces Stromal Remodeling to Improve Survival in Pancreatic Cancer

Author

Dosch, Austin R., primary, Dai, Xizi, primary, Reyzer, Michelle L., primary, Mehra, Siddharth, primary, Srinivasan, Supriya, primary, Willobee, Brent A., primary, Kwon, Deukwoo, primary, Kashikar, Nilesh, primary, Caprioli, Richard, primary, Merchant, Nipun B., primary, and Nagathihalli, Nagaraj S., primary

Published
2023
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23. Data from Urolithin A, a Novel Natural Compound to Target PI3K/AKT/mTOR Pathway in Pancreatic Cancer

Author

Totiger, Tulasigeri M., primary, Srinivasan, Supriya, primary, Jala, Venkatakrishna R., primary, Lamichhane, Purushottam, primary, Dosch, Austin R., primary, Gaidarski, Alexander A., primary, Joshi, Chandrashekhar, primary, Rangappa, Shobith, primary, Castellanos, Jason, primary, Vemula, Praveen Kumar, primary, Chen, Xi, primary, Kwon, Deukwoo, primary, Kashikar, Nilesh, primary, VanSaun, Michael, primary, Merchant, Nipun B., primary, and Nagathihalli, Nagaraj S., primary

Published
2023
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24. Supplementary Figures & Legends from Targeting Tumor–Stromal IL6/STAT3 Signaling through IL1 Receptor Inhibition in Pancreatic Cancer

Author

Dosch, Austin R., primary, Singh, Samara, primary, Dai, Xizi, primary, Mehra, Siddharth, primary, Silva, Iago De Castro, primary, Bianchi, Anna, primary, Srinivasan, Supriya, primary, Gao, Zhen, primary, Ban, Yuguang, primary, Chen, Xi, primary, Banerjee, Sulagna, primary, Nagathihalli, Nagaraj S., primary, Datta, Jashodeep, primary, and Merchant, Nipun B., primary

Published
2023
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25. Supplementary Materials and Methods from Urolithin A, a Novel Natural Compound to Target PI3K/AKT/mTOR Pathway in Pancreatic Cancer

Author

Totiger, Tulasigeri M., primary, Srinivasan, Supriya, primary, Jala, Venkatakrishna R., primary, Lamichhane, Purushottam, primary, Dosch, Austin R., primary, Gaidarski, Alexander A., primary, Joshi, Chandrashekhar, primary, Rangappa, Shobith, primary, Castellanos, Jason, primary, Vemula, Praveen Kumar, primary, Chen, Xi, primary, Kwon, Deukwoo, primary, Kashikar, Nilesh, primary, VanSaun, Michael, primary, Merchant, Nipun B., primary, and Nagathihalli, Nagaraj S., primary

Published
2023
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26. Supplementary Data from Combined Blockade of MEK and CDK4/6 Pathways Induces Senescence to Improve Survival in Pancreatic Ductal Adenocarcinoma

Author

Willobee, Brent A., primary, Gaidarski, Alexander A., primary, Dosch, Austin R., primary, Castellanos, Jason A., primary, Dai, Xizi, primary, Mehra, Siddharth, primary, Messaggio, Fanuel, primary, Srinivasan, Supriya, primary, VanSaun, Michael N., primary, Nagathihalli, Nagaraj S., primary, and Merchant, Nipun B., primary

Published
2023
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27. Supplementary Figure S1 from Urolithin A, a Novel Natural Compound to Target PI3K/AKT/mTOR Pathway in Pancreatic Cancer

Author

Totiger, Tulasigeri M., primary, Srinivasan, Supriya, primary, Jala, Venkatakrishna R., primary, Lamichhane, Purushottam, primary, Dosch, Austin R., primary, Gaidarski, Alexander A., primary, Joshi, Chandrashekhar, primary, Rangappa, Shobith, primary, Castellanos, Jason, primary, Vemula, Praveen Kumar, primary, Chen, Xi, primary, Kwon, Deukwoo, primary, Kashikar, Nilesh, primary, VanSaun, Michael, primary, Merchant, Nipun B., primary, and Nagathihalli, Nagaraj S., primary

Published
2023
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28. Supplementary Tables from Targeting Tumor–Stromal IL6/STAT3 Signaling through IL1 Receptor Inhibition in Pancreatic Cancer

Author

Dosch, Austin R., primary, Singh, Samara, primary, Dai, Xizi, primary, Mehra, Siddharth, primary, Silva, Iago De Castro, primary, Bianchi, Anna, primary, Srinivasan, Supriya, primary, Gao, Zhen, primary, Ban, Yuguang, primary, Chen, Xi, primary, Banerjee, Sulagna, primary, Nagathihalli, Nagaraj S., primary, Datta, Jashodeep, primary, and Merchant, Nipun B., primary

Published
2023
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29. Data from Cell-Autonomous Cxcl1 Sustains Tolerogenic Circuitries and Stromal Inflammation via Neutrophil-Derived TNF in Pancreatic Cancer

Author

Jashodeep Datta, Nipun B. Merchant, Dmitry I. Gabrilovich, Ben Z. Stanger, Eneda Toska, Alejandro V. Villarino, Krishna Komanduri, Roberta Brambilla, William L. Hwang, Elizabeth A. Montgomery, Nagaraj S. Nagathihalli, Carina Shiau, Yuguang Ban, Jian Zhang, Ifeanyichukwu C. Ogobuiro, Haleh Amirian, Oliver Umland, Zhiqun Zhou, Austin R. Dosch, Christine I. Rafie, Eric Wieder, Shannon J. Saigh, Despina S. Kolonias, Luis A. Nivelo, Xinyu Guo, Vanessa T. Garrido, Siddharth Mehra, Samara Singh, Nilesh U. Deshpande, Iago De Castro Silva, and Anna Bianchi

Abstract

We have shown that KRAS–TP53 genomic coalteration is associated with immune-excluded microenvironments, chemoresistance, and poor survival in pancreatic ductal adenocarcinoma (PDAC) patients. By treating KRAS–TP53 cooperativity as a model for high-risk biology, we now identify cell-autonomous Cxcl1 as a key mediator of spatial T-cell restriction via interactions with CXCR2+ neutrophilic myeloid-derived suppressor cells in human PDAC using imaging mass cytometry. Silencing of cell-intrinsic Cxcl1 in LSL-KrasG12D/+;Trp53R172H/+;Pdx-1Cre/+(KPC) cells reprograms the trafficking and functional dynamics of neutrophils to overcome T-cell exclusion and controls tumor growth in a T cell–dependent manner. Mechanistically, neutrophil-derived TNF is a central regulator of this immunologic rewiring, instigating feed-forward Cxcl1 overproduction from tumor cells and cancer-associated fibroblasts (CAF), T-cell dysfunction, and inflammatory CAF polarization via transmembrane TNF–TNFR2 interactions. TNFR2 inhibition disrupts this circuitry and improves sensitivity to chemotherapy in vivo. Our results uncover cancer cell–neutrophil cross-talk in which context-dependent TNF signaling amplifies stromal inflammation and immune tolerance to promote therapeutic resistance in PDAC.Significance:By decoding connections between high-risk tumor genotypes, cell-autonomous inflammatory programs, and myeloid-enriched/T cell–excluded contexts, we identify a novel role for neutrophil-derived TNF in sustaining immunosuppression and stromal inflammation in pancreatic tumor microenvironments. This work offers a conceptual framework by which targeting context-dependent TNF signaling may overcome hallmarks of chemoresistance in pancreatic cancer.

Published
2023
Full Text
View/download PDF

30. Supplementary Table S1 from Cell-Autonomous Cxcl1 Sustains Tolerogenic Circuitries and Stromal Inflammation via Neutrophil-Derived TNF in Pancreatic Cancer

Author

Jashodeep Datta, Nipun B. Merchant, Dmitry I. Gabrilovich, Ben Z. Stanger, Eneda Toska, Alejandro V. Villarino, Krishna Komanduri, Roberta Brambilla, William L. Hwang, Elizabeth A. Montgomery, Nagaraj S. Nagathihalli, Carina Shiau, Yuguang Ban, Jian Zhang, Ifeanyichukwu C. Ogobuiro, Haleh Amirian, Oliver Umland, Zhiqun Zhou, Austin R. Dosch, Christine I. Rafie, Eric Wieder, Shannon J. Saigh, Despina S. Kolonias, Luis A. Nivelo, Xinyu Guo, Vanessa T. Garrido, Siddharth Mehra, Samara Singh, Nilesh U. Deshpande, Iago De Castro Silva, and Anna Bianchi

Abstract

Differentially expressed pathways comparing transcriptomes in KRAS-TP53 co-altered (n=23) and KRAS-altered/TP53WT (n=5) derived from Cancer Cell Line Encyclopedia

Published
2023
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31. Supplementary Figure S1 from Combined Src/EGFR Inhibition Targets STAT3 Signaling and Induces Stromal Remodeling to Improve Survival in Pancreatic Cancer

Author

Nagaraj S. Nagathihalli, Nipun B. Merchant, Richard Caprioli, Nilesh Kashikar, Deukwoo Kwon, Brent A. Willobee, Supriya Srinivasan, Siddharth Mehra, Michelle L. Reyzer, Xizi Dai, and Austin R. Dosch

Abstract

Combined Src and EGFR inhibition decreases collagen I content in PANC1 orthotopic xenograft models of PDAC.

Published
2023
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32. Data from Urolithin A, a Novel Natural Compound to Target PI3K/AKT/mTOR Pathway in Pancreatic Cancer

Author

Nagaraj S. Nagathihalli, Nipun B. Merchant, Michael VanSaun, Nilesh Kashikar, Deukwoo Kwon, Xi Chen, Praveen Kumar Vemula, Jason Castellanos, Shobith Rangappa, Chandrashekhar Joshi, Alexander A. Gaidarski, Austin R. Dosch, Purushottam Lamichhane, Venkatakrishna R. Jala, Supriya Srinivasan, and Tulasigeri M. Totiger

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy and is highly resistant to standard treatment regimens. Targeted therapies against KRAS, a mutation present in an overwhelming majority of PDAC cases, have been largely ineffective. However, inhibition of downstream components in the KRAS signaling cascade provides promising therapeutic targets in the management of PDAC and warrants further exploration. Here, we investigated Urolithin A (Uro A), a novel natural compound derived from pomegranates, which targets numerous kinases downstream of KRAS, in particular the PI3K/AKT/mTOR signaling pathways. We showed that treatment of PDAC cells with Uro A blocked the phosphorylation of AKT and p70S6K in vitro, successfully inhibited the growth of tumor xenografts, and increased overall survival of Ptf1aCre/+;LSL-KrasG12D/+;Tgfbr2flox/flox (PKT) mice compared with vehicle or gemcitabine therapy alone. Histologic evaluation of these Uro A–treated tumor samples confirmed mechanistic actions of Uro A via decreased phosphorylation of AKT and p70S6K, reduced proliferation, and increased cellular apoptosis in both xenograft and PKT mouse models. In addition, Uro A treatment reprogrammed the tumor microenvironment, as evidenced by reduced levels of infiltrating immunosuppressive cell populations such as myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Overall, this work provides convincing preclinical evidence for the utility of Uro A as a therapeutic agent in PDAC through suppression of the PI3K/AKT/mTOR pathway.

Published
2023
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33. Data from Combined Blockade of MEK and CDK4/6 Pathways Induces Senescence to Improve Survival in Pancreatic Ductal Adenocarcinoma

Author

Nipun B. Merchant, Nagaraj S. Nagathihalli, Michael N. VanSaun, Supriya Srinivasan, Fanuel Messaggio, Siddharth Mehra, Xizi Dai, Jason A. Castellanos, Austin R. Dosch, Alexander A. Gaidarski, and Brent A. Willobee

Abstract

Activating KRAS mutations, a defining feature of pancreatic ductal adenocarcinoma (PDAC), promote tumor growth in part through the activation of cyclin-dependent kinases (CDK) that induce cell-cycle progression. p16INK4a (p16), encoded by the gene CDKN2A, is a potent inhibitor of CDK4/6 and serves as a critical checkpoint of cell proliferation. Mutations in and subsequent loss of the p16 gene occur in PDAC at a rate higher than that reported in any other tumor type and results in Rb inactivation and unrestricted cellular growth. Therefore, strategies targeting downstream RAS pathway effectors combined with CDK4/6 inhibition (CDK4/6i) may have the potential to improve outcomes in this disease. Herein, we show that expression of p16 is markedly reduced in PDAC tumors compared with normal pancreatic or pre-neoplastic tissues. Combined MEK inhibition (MEKi) and CDK4/6i results in sustained downregulation of both ERK and Rb phosphorylation and a significant reduction in cell proliferation compared with monotherapy in human PDAC cells. MEKi with CDK4/6i reduces tumor cell proliferation by promoting senescence-mediated growth arrest, independent of apoptosis in vitro. We show that combined MEKi and CDK4/6i treatment attenuates tumor growth in xenograft models of PDAC and improves overall survival over 200% compared with treatment with vehicle or individual agents alone in Ptf1acre/+;LSL-KRASG12D/+;Tgfbr2flox/flox (PKT) mice. Histologic analysis of PKT tumor lysates reveal a significant decrease in markers of cell proliferation and an increase in senescence-associated markers without any significant change in apoptosis. These results demonstrate that combined targeting of both MEK and CDK4/6 represents a novel therapeutic strategy to synergistically reduce tumor growth through induction of cellular senescence in PDAC.

Published
2023
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35. Supplementary Figure S6 from Urolithin A, a Novel Natural Compound to Target PI3K/AKT/mTOR Pathway in Pancreatic Cancer

Author

Nagaraj S. Nagathihalli, Nipun B. Merchant, Michael VanSaun, Nilesh Kashikar, Deukwoo Kwon, Xi Chen, Praveen Kumar Vemula, Jason Castellanos, Shobith Rangappa, Chandrashekhar Joshi, Alexander A. Gaidarski, Austin R. Dosch, Purushottam Lamichhane, Venkatakrishna R. Jala, Supriya Srinivasan, and Tulasigeri M. Totiger

Abstract

Supplementary Figure S6 shows body weight of PKT mice and xenograft mice.

Published
2023
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39. Supplementary Materials and Methods from Urolithin A, a Novel Natural Compound to Target PI3K/AKT/mTOR Pathway in Pancreatic Cancer

Author

Nagaraj S. Nagathihalli, Nipun B. Merchant, Michael VanSaun, Nilesh Kashikar, Deukwoo Kwon, Xi Chen, Praveen Kumar Vemula, Jason Castellanos, Shobith Rangappa, Chandrashekhar Joshi, Alexander A. Gaidarski, Austin R. Dosch, Purushottam Lamichhane, Venkatakrishna R. Jala, Supriya Srinivasan, and Tulasigeri M. Totiger

Abstract

Supplementary Materials and Methods

Published
2023
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41. Supplementary Tables S1-S3 from Urolithin A, a Novel Natural Compound to Target PI3K/AKT/mTOR Pathway in Pancreatic Cancer

Author

Nagaraj S. Nagathihalli, Nipun B. Merchant, Michael VanSaun, Nilesh Kashikar, Deukwoo Kwon, Xi Chen, Praveen Kumar Vemula, Jason Castellanos, Shobith Rangappa, Chandrashekhar Joshi, Alexander A. Gaidarski, Austin R. Dosch, Purushottam Lamichhane, Venkatakrishna R. Jala, Supriya Srinivasan, and Tulasigeri M. Totiger

Abstract

Supplementary Tables shows primary antibodies used for Western blot, IHC, Flow Cytometry and IC50 values for Uro A.

Published
2023
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43. Data from Targeting Tumor–Stromal IL6/STAT3 Signaling through IL1 Receptor Inhibition in Pancreatic Cancer

Author

Nipun B. Merchant, Jashodeep Datta, Nagaraj S. Nagathihalli, Sulagna Banerjee, Xi Chen, Yuguang Ban, Zhen Gao, Supriya Srinivasan, Anna Bianchi, Iago De Castro Silva, Siddharth Mehra, Xizi Dai, Samara Singh, and Austin R. Dosch

Abstract

A hallmark of pancreatic ductal adenocarcinoma (PDAC) is the presence of a dense, desmoplastic stroma and the consequent altered interactions between cancer cells and their surrounding tumor microenvironment (TME) that promote disease progression, metastasis, and chemoresistance. We have previously shown that IL6 secreted from pancreatic stellate cells (PSC) stimulates the activation of STAT3 signaling in tumor cells, an established mechanism of therapeutic resistance in PDAC. We have now identified the tumor cell–derived cytokine IL1α as an upstream mediator of IL6 release from PSCs that is involved in STAT3 activation within the TME. Herein, we show that IL1α is overexpressed in both murine and human PDAC tumors and engages with its cognate receptor IL1R1, which is strongly expressed on stromal cells. Further, we show that IL1R1 inhibition using anakinra (recombinant IL1 receptor antagonist) significantly reduces stromal-derived IL6, thereby suppressing IL6-dependent STAT3 activation in human PDAC cell lines. Anakinra treatment results in significant reduction in IL6 and activated STAT3 levels in pancreatic tumors from Ptf1aCre/+;LSL-KrasG12D/+; Tgfbr2flox/flox (PKT) mice. Additionally, the combination of anakinra with cytotoxic chemotherapy significantly extends overall survival compared with vehicle treatment or anakinra monotherapy in this aggressive genetic mouse model of PDAC. These data highlight the importance of IL1 in mediating tumor–stromal IL6/STAT3 cross-talk in the TME and provide a preclinical rationale for targeting IL1 signaling as a therapeutic strategy in PDAC.

Published
2023
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46. Supplementary Tables from Tobacco Carcinogen–Induced Production of GM-CSF Activates CREB to Promote Pancreatic Cancer

Author

Nagaraj S. Nagathihalli, Michael VanSaun, Nipun B. Merchant, Yuguang Ban, Kumaraswamy Honnenahally, Nilesh Kashikar, Fanuel Messaggio, Austin R. Dosch, Purushottam Lamichhane, Jason Castellanos, Chanjuan Shi, Tulasigeri Totiger, and Supriya Srinivasan

Abstract

Supplementary Tables show all the primary antibodies, primer sequences, antibodies used in the flow cytometry assay, up- and down-regulated gene list and CREB signature gene list.

Published
2023
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47. Supplementary Table 1 from Sensitivity of KRAS-Mutant Colorectal Cancers to Combination Therapy That Cotargets MEK and CDK4/6

Author

Judith S. Sebolt-Leopold, Karin M. Hardiman, Theodore H. Welling, Ananda Sen, Amrith Shettigar, Joel D. Maust, Joseph S. Dosch, and Elizabeth K. Ziemke

Abstract

Clinical and Pathological Features of 18 CRC PDX Models Established from Patients Undergoing Surgical Resection or Hepatic Metastasectomy at the University of Michigan

Published
2023
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48. Data from Tobacco Carcinogen–Induced Production of GM-CSF Activates CREB to Promote Pancreatic Cancer

Author

Nagaraj S. Nagathihalli, Michael VanSaun, Nipun B. Merchant, Yuguang Ban, Kumaraswamy Honnenahally, Nilesh Kashikar, Fanuel Messaggio, Austin R. Dosch, Purushottam Lamichhane, Jason Castellanos, Chanjuan Shi, Tulasigeri Totiger, and Supriya Srinivasan

Abstract

Although smoking is a significant risk factor for pancreatic ductal adenocarcinoma (PDAC), the molecular mechanisms underlying PDAC development and progression in smokers are still unclear. Here, we show the role of cyclic AMP response element-binding protein (CREB) in the pathogenesis of smoking-induced PDAC. Smokers had significantly higher levels of activated CREB when compared with nonsmokers. Cell lines derived from normal pancreas and pancreatic intraepithelial neoplasm (PanIN) exhibited low baseline pCREB levels compared with PDAC cell lines. Furthermore, elevated CREB expression correlated with reduced survival in patients with PDAC. Depletion of CREB significantly reduced tumor burden after tobacco-specific nitrosamine 4-(methyl nitrosamino)-1-(3-pyridyl)-1-butanone (NNK) treatment, suggesting a CREB-dependent contribution to PDAC growth and progression in smokers. Conversely, NNK accelerated PanIN lesion and PDAC formation via GM-CSF–mediated activation of CREB in a PDAC mouse model. CREB inhibition (CREBi) in mice more effectively reduced primary tumor burden compared with control or GM-CSF blockade alone following NNK exposure. GM-CSF played a role in the recruitment of tumor-associated macrophages (TAM) and regulatory T cell (Treg) expansion and promotion, whereas CREBi significantly reduced TAM and Treg populations in NNK-exposed mice. Overall, these results suggest that NNK exposure leads to activation of CREB through GM-CSF, promoting inflammatory and Akt pathways. Direct inhibition of CREB, but not GM-CSF, effectively abrogates these effects and inhibits tumor progression, offering a viable therapeutic strategy for patients with PDAC.Significance: These findings identify GM-CSF-induced CREB as a driver of pancreatic cancer in smokers and demonstrate the therapeutic potential of targeting CREB to reduce PDAC tumor growth.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/21/6146/F1.large.jpg. Cancer Res; 78(21); 6146–58. ©2018 AACR.

Published
2023
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49. Supplementary Figure 1 from Sensitivity of KRAS-Mutant Colorectal Cancers to Combination Therapy That Cotargets MEK and CDK4/6

Author

Judith S. Sebolt-Leopold, Karin M. Hardiman, Theodore H. Welling, Ananda Sen, Amrith Shettigar, Joel D. Maust, Joseph S. Dosch, and Elizabeth K. Ziemke

Abstract

Body Weight Change in Mice Treated with Trametinib and/or Palbociclib. Toxicity assessment of single agent and combination therapy with trametinib and palbociclib.

Published
2023
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