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1. The NOGO receptor NgR2, a novel αVβ3 integrin effector, induces neuroendocrine differentiation in prostate cancer

Author

Quaglia, Fabio, Krishn, Shiv Ram, Sossey-Alaoui, Khalid, Rana, Priyanka Shailendra, Pluskota, Elzbieta, Park, Pyung Hun, Shields, Christopher D., Lin, Stephen, McCue, Peter, Kossenkov, Andrew V., Wang, Yanqing, Goodrich, David W., Ku, Sheng-Yu, Beltran, Himisha, Kelly, William K., Corey, Eva, Klose, Maja, Bandtlow, Christine, Liu, Qin, Altieri, Dario C., Plow, Edward F., and Languino, Lucia R.

Published
2022
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3. Supplementary Data from BCA101 Is a Tumor-Targeted Bifunctional Fusion Antibody That Simultaneously Inhibits EGFR and TGFβ Signaling to Durably Suppress Tumor Growth

Author

Boreddy, Srinivas Reddy, primary, Nair, Reshmi, primary, Pandey, Prashant Kumar, primary, Kuriakose, Anshu, primary, Marigowda, Shivakumar Bhadravathi, primary, Dey, Chaitali, primary, Banerjee, Arindam, primary, Kulkarni, Hanumant, primary, Sagar, Milind, primary, Krishn, Shiv Ram, primary, Rao, Shruthi, primary, AR, Madhukara, primary, Tiwari, Vinita, primary, Alke, Bhavna, primary, MV, Prashantha Kumar, primary, Shri, Meena, primary, Dhamne, Chaitrali, primary, Patel, Sonal, primary, Sharma, Pinky, primary, Periyasamy, Sankar, primary, Bhatnagar, Jaya, primary, Kuriakose, Moni Abraham, primary, Reddy, Ram Bhupal, primary, Suresh, Amritha, primary, Sreenivas, Suma, primary, Govindappa, Nagaraja, primary, Moole, Praveen Reddy, primary, Bughani, Usha, primary, Tan, Seng-Lai, primary, and Nair, Pradip, primary

Published
2023
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4. Data from BCA101 Is a Tumor-Targeted Bifunctional Fusion Antibody That Simultaneously Inhibits EGFR and TGFβ Signaling to Durably Suppress Tumor Growth

Author

Boreddy, Srinivas Reddy, primary, Nair, Reshmi, primary, Pandey, Prashant Kumar, primary, Kuriakose, Anshu, primary, Marigowda, Shivakumar Bhadravathi, primary, Dey, Chaitali, primary, Banerjee, Arindam, primary, Kulkarni, Hanumant, primary, Sagar, Milind, primary, Krishn, Shiv Ram, primary, Rao, Shruthi, primary, AR, Madhukara, primary, Tiwari, Vinita, primary, Alke, Bhavna, primary, MV, Prashantha Kumar, primary, Shri, Meena, primary, Dhamne, Chaitrali, primary, Patel, Sonal, primary, Sharma, Pinky, primary, Periyasamy, Sankar, primary, Bhatnagar, Jaya, primary, Kuriakose, Moni Abraham, primary, Reddy, Ram Bhupal, primary, Suresh, Amritha, primary, Sreenivas, Suma, primary, Govindappa, Nagaraja, primary, Moole, Praveen Reddy, primary, Bughani, Usha, primary, Tan, Seng-Lai, primary, and Nair, Pradip, primary

Published
2023
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6. Abstract 6677: Preliminary immune correlatives from BCA101 trial show favorable modulation of tumor immune microenvironment

Author

Lizotte, Patrick H., primary, Paik, Paul, additional, Niculescu, Liviu, additional, Tan, Seng-Lai H., additional, Bohr, David, additional, Gharakhani, Elham, additional, Reiners, Ralf, additional, Salazar, Rachel, additional, Varshney, Avanish, additional, Krishn, Shiv Ram, additional, Nair, Pradip, additional, and Paweletz, Cloud, additional

Published
2023
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7. Supplementary Information from MUC4-Mediated Regulation of Acute Phase Protein Lipocalin 2 through HER2/AKT/NF-κB Signaling in Pancreatic Cancer

Author

Kaur, Sukhwinder, primary, Sharma, Neil, primary, Krishn, Shiv Ram, primary, Lakshmanan, Imay, primary, Rachagani, Satyanarayana, primary, Baine, Michael J., primary, Smith, Lynette M., primary, Lele, Subodh M., primary, Sasson, Aaron R., primary, Guha, Sushovan, primary, Mallya, Kavita, primary, Anderson, Judy M., primary, Hollingsworth, Michael A., primary, and Batra, Surinder K., primary

Published
2023
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8. Supplementary Fig. 2 from MUC4-Mediated Regulation of Acute Phase Protein Lipocalin 2 through HER2/AKT/NF-κB Signaling in Pancreatic Cancer

Author

Kaur, Sukhwinder, primary, Sharma, Neil, primary, Krishn, Shiv Ram, primary, Lakshmanan, Imay, primary, Rachagani, Satyanarayana, primary, Baine, Michael J., primary, Smith, Lynette M., primary, Lele, Subodh M., primary, Sasson, Aaron R., primary, Guha, Sushovan, primary, Mallya, Kavita, primary, Anderson, Judy M., primary, Hollingsworth, Michael A., primary, and Batra, Surinder K., primary

Published
2023
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9. Supplementary Fig. 3 from MUC4-Mediated Regulation of Acute Phase Protein Lipocalin 2 through HER2/AKT/NF-κB Signaling in Pancreatic Cancer

Author

Kaur, Sukhwinder, primary, Sharma, Neil, primary, Krishn, Shiv Ram, primary, Lakshmanan, Imay, primary, Rachagani, Satyanarayana, primary, Baine, Michael J., primary, Smith, Lynette M., primary, Lele, Subodh M., primary, Sasson, Aaron R., primary, Guha, Sushovan, primary, Mallya, Kavita, primary, Anderson, Judy M., primary, Hollingsworth, Michael A., primary, and Batra, Surinder K., primary

Published
2023
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10. Supplementary Fig. 1 from MUC4-Mediated Regulation of Acute Phase Protein Lipocalin 2 through HER2/AKT/NF-κB Signaling in Pancreatic Cancer

Author

Kaur, Sukhwinder, primary, Sharma, Neil, primary, Krishn, Shiv Ram, primary, Lakshmanan, Imay, primary, Rachagani, Satyanarayana, primary, Baine, Michael J., primary, Smith, Lynette M., primary, Lele, Subodh M., primary, Sasson, Aaron R., primary, Guha, Sushovan, primary, Mallya, Kavita, primary, Anderson, Judy M., primary, Hollingsworth, Michael A., primary, and Batra, Surinder K., primary

Published
2023
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13. Small extracellular vesicle-mediated ITGB6 siRNA delivery downregulates the αVβ6 integrin and inhibits adhesion and migration of recipient prostate cancer cells

Author

Krishn, Shiv Ram, primary, Garcia, Vaughn, additional, Naranjo, Nicole M., additional, Quaglia, Fabio, additional, Shields, Christopher D., additional, Harris, Maisha A., additional, Kossenkov, Andrew V., additional, Liu, Qin, additional, Corey, Eva, additional, Altieri, Dario C., additional, and Languino, Lucia R., additional

Published
2022
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14. Differential expression of αVβ3 and αVβ6 integrins in prostate cancer progression

Author

Quaglia, Fabio, Krishn, Shiv Ram, Wang, Yanqing, Goodrich, David W., McCue, Peter, Kossenkov, Andrew V., Mandigo, Amy C., Knudsen, Karen E., Weinreb, Paul H., Corey, Eva, Kelly, William K., and Languino, Lucia R.

Subjects
Male, Integrins, Retinoblastoma Protein, Lung and Intrathoracic Tumors, Metastasis, Mice, Basic Cancer Research, Medicine and Health Sciences, Prostate Cancer, Genetically Modified Organisms, Prostate Diseases, Prostate, Animal Models, Extracellular Matrix, Gene Expression Regulation, Neoplastic, Oncology, Experimental Organism Systems, Disease Progression, Engineering and Technology, Medicine, Cellular Structures and Organelles, Anatomy, Genetic Engineering, Research Article, Biotechnology, Urology, Science, Synaptophysin, Mice, Nude, Mouse Models, Bioengineering, Mice, Transgenic, Adenocarcinoma, Research and Analysis Methods, Model Organisms, Exocrine Glands, Antigens, Neoplasm, Cell Line, Tumor, Cell Adhesion, Animals, Humans, Genetically Modified Animals, Biology and Life Sciences, Cancers and Neoplasms, Prostatic Neoplasms, Cell Biology, Integrin alphaVbeta3, Genitourinary Tract Tumors, Disease Models, Animal, Animal Studies, Prostate Gland, Tumor Suppressor Protein p53, Neoplasm Transplantation
Abstract

Neuroendocrine prostate cancer (NEPrCa) arises de novo or after accumulation of genomic alterations in pre-existing adenocarcinoma tumors in response to androgen deprivation therapies. We have provided evidence that small extracellular vesicles released by PrCa cells and containing the αVβ3 integrin promote neuroendocrine differentiation of PrCa in vivo and in vitro. Here, we examined αVβ3 integrin expression in three murine models carrying a deletion of PTEN (SKO), PTEN and RB1 (DKO), or PTEN, RB1 and TRP53 (TKO) genes in the prostatic epithelium; of these three models, the DKO and TKO tumors develop NEPrCa with a gene signature comparable to those of human NEPrCa. Immunostaining analysis of SKO, DKO and TKO tumors shows that αVβ3 integrin expression is increased in DKO and TKO primary tumors and metastatic lesions, but absent in SKO primary tumors. On the other hand, SKO tumors show higher levels of a different αV integrin, αVβ6, as compared to DKO and TKO tumors. These results are confirmed by RNA-sequencing analysis. Moreover, TRAMP mice, which carry NEPrCa and adenocarcinoma of the prostate, also have increased levels of αVβ3 in their NEPrCa primary tumors. In contrast, the αVβ6 integrin is only detectable in the adenocarcinoma areas. Finally, analysis of 42 LuCaP patient-derived xenografts and primary adenocarcinoma samples shows a positive correlation between αVβ3, but not αVβ6, and the neuronal marker synaptophysin; it also demonstrates that αVβ3 is absent in prostatic adenocarcinomas. In summary, we demonstrate that αVβ3 integrin is upregulated in NEPrCa primary and metastatic lesions; in contrast, the αVβ6 integrin is confined to adenocarcinoma of the prostate. Our findings suggest that the αVβ3 integrin, but not αVβ6, may promote a shift in lineage plasticity towards a NE phenotype and might serve as an informative biomarker for the early detection of NE differentiation in prostate cancer.

Published
2021

15. Small extracellular vesicle-mediated ITGB6siRNA delivery downregulates the αVβ6 integrin and inhibits adhesion and migration of recipient prostate cancer cells

Author

Krishn, Shiv Ram, Garcia, Vaughn, Naranjo, Nicole M., Quaglia, Fabio, Shields, Christopher D., Harris, Maisha A., Kossenkov, Andrew V., Liu, Qin, Corey, Eva, Altieri, Dario C., and Languino, Lucia R.

Abstract

ABSTRACTThe αVβ6 integrin, an epithelial-specific cell surface receptor absent in normal prostate and expressed during prostate cancer (PrCa) progression, is a therapeutic target in many cancers. Here, we report that transcript levels of ITGB6(encoding the β6 integrin subunit) are significantly increased in metastatic castrate-resistant androgen receptor-negative prostate tumors compared to androgen receptor-positive prostate tumors. In addition, the αVβ6 integrin protein levels are significantly elevated in androgen receptor-negative PrCa patient derived xenografts (PDXs) compared to androgen receptor-positive PDXs. In vitro, the androgen receptor-negative PrCa cells express high levels of the αVβ6 integrin compared to androgen receptor-positive PrCa cells. Additionally, expression of androgen receptor (wild type or variant 7) in androgen receptor-negative PrCa cells downregulates the expression of the β6 but not αV subunit compared to control cells. We demonstrate an efficient strategy to therapeutically target the αVβ6 integrin during PrCa progression by using short interfering RNA (siRNA) loaded into PrCa cell-derived small extracellular vesicles (sEVs). We first demonstrate that fluorescently-labeled siRNAs can be efficiently loaded into PrCa cell-derived sEVs by electroporation. By confocal microscopy, we show efficient internalization of these siRNA-loaded sEVs into PrCa cells. We show that sEV-mediated delivery of ITGB6-targeting siRNAs into PC3 cells specifically downregulates expression of the β6 subunit. Furthermore, treatment with sEVs encapsulating ITGB6siRNA significantly reduces cell adhesion and migration of PrCa cells on an αVβ6-specific substrate, LAP-TGFβ1. Our results demonstrate an approach for specific targeting of the αVβ6 integrin in PrCa cells using sEVs encapsulating ITGB6-specific siRNAs.

Published
2022
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16. The αvβ6 integrin in cancer cell-derived small extracellular vesicles enhances angiogenesis

Author

Krishn, Shiv Ram, Salem, Israa, Quaglia, Fabio, Naranjo, Nicole M., Agarwal, Ekta, Liu, Qin, Sarker, Srawasti, Kopenhaver, Jessica, McCue, Peter A., Weinreb, Paul H., Violette, Shelia M., Altieri, Dario C., and Languino, Lucia R.

Subjects
lcsh:Cytology, integrin, viruses, endothelial cell, virus diseases, Angiogenesis, extracellular vesicle, lcsh:QH573-671, respiratory system, survivin, urologic and male genital diseases, prostate cancer, Research Article
Abstract

Prostate cancer (PrCa) cells crosstalk with the tumour microenvironment by releasing small extracellular vesicles (sEVs). sEVs, as well as large extracellular vesicles (LEVs), isolated via iodixanol density gradients from PrCa cell culture media, express the epithelial-specific αvβ6 integrin, which is known to be induced in cancer. In this study, we show sEV-mediated protein transfer of αvβ6 integrin to microvascular endothelial cells (human microvascular endothelial cells 1 – HMEC1) and demonstrate that de novo αvβ6 integrin expression is not caused by increased mRNA levels. Incubation of HMEC1 with sEVs isolated from PrCa PC3 cells that express the αvβ6 integrin results in a highly significant increase in the number of nodes, junctions and tubules. In contrast, incubation of HMEC1 with sEVs isolated from β6 negative PC3 cells, generated by shRNA against β6, results in a reduction in the number of nodes, junctions and tubules, a decrease in survivin levels and an increase in a negative regulator of angiogenesis, pSTAT1. Furthermore, treatment of HMEC1 with sEVs generated by CRISPR/Cas9-mediated down-regulation of β6, causes up-regulation of pSTAT1. Overall, our findings suggest that αvβ6 integrin in cancer sEVs regulates angiogenesis during PrCa progression.

Published
2020

17. Secretory Mucin 5AC Promotes Neoplastic Progression by Augmenting KLF4-Mediated Pancreatic Cancer Cell Stemness

Author

Ganguly, Koelina, primary, Krishn, Shiv Ram, additional, Rachagani, Satyanarayana, additional, Jahan, Rahat, additional, Shah, Ashu, additional, Nallasamy, Palanisamy, additional, Rauth, Sanchita, additional, Atri, Pranita, additional, Cox, Jesse L., additional, Pothuraju, Ramesh, additional, Smith, Lynette M., additional, Ayala, Sudhua, additional, Evans, Christopher, additional, Ponnusamy, Moorthy P., additional, Kumar, Sushil, additional, Kaur, Sukhwinder, additional, and Batra, Surinder K., additional

Published
2021
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19. Small extracellular vesicles modulated by αVβ3 integrin induce neuroendocrine differentiation in recipient cancer cells

Author

Quaglia, Fabio, primary, Krishn, Shiv Ram, additional, Daaboul, George G., additional, Sarker, Srawasti, additional, Pippa, Raffaella, additional, Domingo‐Domenech, Josep, additional, Kumar, Gaurav, additional, Fortina, Paolo, additional, McCue, Peter, additional, Kelly, William K., additional, Beltran, Himisha, additional, Liu, Qin, additional, and Languino, Lucia R., additional

Published
2020
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21. Methods for extracellular vesicle isolation from cancer cells

Author

Salem, Israa, primary, Naranjo, Nicole M., additional, Singh, Amrita, additional, DeRita, Rachel, additional, Krishn, Shiv Ram, additional, Sirman, Luca S., additional, Quaglia, Fabio, additional, Duffy, Alexander, additional, Bowler, Nicholas, additional, Sayeed, Aejaz, additional, and Languino, Lucia R., additional

Published
2020
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22. Acinar transformed ductal cells exhibit differential mucin expression in a tamoxifen-induced pancreatic ductal adenocarcinoma mouse model

Author

Mallya, Kavita, primary, Haridas, Dhanya, additional, Seshacharyulu, Parthasarathy, additional, Pothuraju, Ramesh, additional, Junker, Wade M., additional, Krishn, Shiv Ram, additional, Muniyan, Sakthivel, additional, Vengoji, Raghupathy, additional, Batra, Surinder K., additional, and Rachagani, Satyanarayana, additional

Published
2020
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23. Myc-mediated transcriptional regulation of the mitochondrial chaperone TRAP1 controls primary and metastatic tumor growth.

Author

Agarwal, Ekta, Altman, Brian J., Seo, Jae Ho, Ghosh, Jagadish C., Kossenkov, Andrew V, Tang, Hsin-Yao, Krishn, Shiv Ram, Languino, Lucia R., Gabrilovich, Dmitry I., Speicher, David W., Dang, Chi V., Altieri, Dario C., Agarwal, Ekta, Altman, Brian J., Seo, Jae Ho, Ghosh, Jagadish C., Kossenkov, Andrew V, Tang, Hsin-Yao, Krishn, Shiv Ram, Languino, Lucia R., Gabrilovich, Dmitry I., Speicher, David W., Dang, Chi V., and Altieri, Dario C.

Abstract

The role of mitochondria in cancer continues to be debated, and whether exploitation of mitochondrial functions is a general hallmark of malignancy or a tumor- or context-specific response is still unknown. Using a variety of cancer cell lines and several technical approaches, including siRNA-mediated gene silencing, ChIP assays, global metabolomics and focused metabolite analyses, bioenergetics, and cell viability assays, we show that two oncogenic Myc proteins, c-Myc and N-Myc, transcriptionally control the expression of the mitochondrial chaperone TNFR-associated protein- 1 (TRAP1) in cancer. In turn, this Myc-mediated regulation preserved the folding and function of mitochondrial oxidative phosphorylation (OXPHOS) complex II and IV subunits, dampened reactive oxygen species production, and enabled oxidative bioenergetics in tumor cells. Of note, we found that genetic or pharmacological targeting of this pathway shuts off tumor cell motility and invasion, kills Myc-expressing cells in a TRAP1-dependent manner, and suppresses primary and metastatic tumor growth in vivo. We conclude that exploitation of mitochondrial functions is a general trait of tumorigenesis and that this reliance of cancer cells on mitochondrialOXPHOSpathways could offer an actionable therapeutic target in the clinic.

Published
2019

25. Myc-mediated transcriptional regulation of the mitochondrial chaperone TRAP1 controls primary and metastatic tumor growth

Author

Agarwal, Ekta, primary, Altman, Brian J., additional, Seo, Jae Ho, additional, Ghosh, Jagadish C., additional, Kossenkov, Andrew V., additional, Tang, Hsin-Yao, additional, Krishn, Shiv Ram, additional, Languino, Lucia R., additional, Gabrilovich, Dmitry I., additional, Speicher, David W., additional, Dang, Chi V., additional, and Altieri, Dario C., additional

Published
2019
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26. Prostate cancer sheds the αvβ3 integrin in vivo through exosomes

Author

Krishn, Shiv Ram, primary, Singh, Amrita, additional, Bowler, Nicholas, additional, Duffy, Alexander N., additional, Friedman, Andrea, additional, Fedele, Carmine, additional, Kurtoglu, Senem, additional, Tripathi, Sushil K., additional, Wang, Kerith, additional, Hawkins, Adam, additional, Sayeed, Aejaz, additional, Goswami, Chirayu P., additional, Thakur, Madhukar L., additional, Iozzo, Renato V., additional, Peiper, Stephen C., additional, Kelly, William K., additional, and Languino, Lucia R., additional

Published
2019
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27. Exosomal αvβ6 integrin is required for monocyte M2 polarization in prostate cancer

Author

Lu, Huimin, primary, Bowler, Nicholas, additional, Harshyne, Larry A., additional, Craig Hooper, D., additional, Krishn, Shiv Ram, additional, Kurtoglu, Senem, additional, Fedele, Carmine, additional, Liu, Qin, additional, Tang, Hsin-Yao, additional, Kossenkov, Andrew V., additional, Kelly, William K., additional, Wang, Kerith, additional, Kean, Rhonda B., additional, Weinreb, Paul H., additional, Yu, Lei, additional, Dutta, Anindita, additional, Fortina, Paolo, additional, Ertel, Adam, additional, Stanczak, Maria, additional, Forsberg, Flemming, additional, Gabrilovich, Dmitry I., additional, Speicher, David W., additional, Altieri, Dario C., additional, and Languino, Lucia R., additional

Published
2018
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29. A Combination of MUC5AC and CA19-9 Improves the Diagnosis of Pancreatic Cancer: A Multicenter Study

Author

Kaur, Sukhwinder, primary, Smith, Lynette M, additional, Patel, Asish, additional, Menning, Melanie, additional, Watley, Duncan C, additional, Malik, Saad S, additional, Krishn, Shiv Ram, additional, Mallya, Kavita, additional, Aithal, Abhijit, additional, Sasson, Aaron R, additional, Johansson, Sonny L, additional, Jain, Maneesh, additional, Singh, Shailender, additional, Guha, Sushovan, additional, Are, Chandrakanth, additional, Raimondo, Massimo, additional, Hollingsworth, Michael A, additional, Brand, Randall E, additional, and Batra, Surinder K, additional

Published
2017
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30. Mucins and associated glycan signatures in colon adenoma-carcinoma sequence:Prospective pathological implication(s) for early diagnosis of colon cancer

Author

Krishn, Shiv Ram, Kaur, Sukhwinder, Smith, Lynette M, Johansson, Sonny L, Jain, Maneesh, Patel, Asish, Gautam, Shailendra K, Hollingsworth, Michael A, Mandel, Ulla, Clausen, Henrik, Lo, Wing-Cheong, Fan, Wai-Tong Louis, Manne, Upender, Batra, Surinder K, Krishn, Shiv Ram, Kaur, Sukhwinder, Smith, Lynette M, Johansson, Sonny L, Jain, Maneesh, Patel, Asish, Gautam, Shailendra K, Hollingsworth, Michael A, Mandel, Ulla, Clausen, Henrik, Lo, Wing-Cheong, Fan, Wai-Tong Louis, Manne, Upender, and Batra, Surinder K

Abstract

Development of biomarkers that detect early stage resectable premalignant lesions of colon can provide critical aid in the prevention of colorectal cancer. Recent lines of evidence suggest the utility of mucin expression to predict malignant transformation of colon pre-neoplastic lesions. In this study, we investigated the combined expression of multiple mucins and mucin-associated glycans during the adenoma-carcinoma sequence of colon cancer progression. Further, we evaluated their applicability as markers for differentiating adenomas/adenocarcinomas from hyperplastic polyps. Immunohistochemical analyses performed on colon disease tissue microarrays revealed downregulation of MUC2 and MUC4 expression (p < 0.0001) while MUC1 and MUC5AC expressions were upregulated (p = 0.01) during adenoma-adenocarcinoma progression. Expression of MUC17 was downregulated in inflamed tissues compared to normal tissues, but its increased expression differentiated adenomas (p = 0.0028) and adenocarcinomas (p = 0.025) from inflammation. Glycan epitope-Tn/STn on MUC1 showed higher expression in hyperplastic polyps (p = 0.023), adenomas (p = 0.042) and adenocarcinomas (p = 0.0096) compared to normal tissues. Multivariate regression analyses indicated that a combination of MUC2, MUC5AC, and MUC17 could effectively discriminate adenoma-adenocarcinoma from hyperplastic polyps. Altogether, a combined analysis of altered mucins and mucin-associated glycans is a useful approach to distinguish premalignant/malignant lesions of colon from benign polyps.

Published
2016

31. Mucins and associated O-glycans based immunoprofile for stratification of colorectal polyps: clinical implication for improved colon surveillance

Author

Krishn, Shiv Ram, primary, Kaur, Sukhwinder, additional, Sheinin, Yuri M., additional, Smith, Lynette M., additional, Gautam, Shailendra K., additional, Patel, Asish, additional, Jain, Maneesh, additional, Juvvigunta, Vasthala, additional, Pai, Priya, additional, Lazenby, Audrey J., additional, Roy, Hemant K., additional, and Batra, Surinder K., additional

Published
2016
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33. MUC4-Mediated Regulation of Acute Phase Protein Lipocalin 2 through HER2/AKT/NF-κB Signaling in Pancreatic Cancer

Author

Kaur, Sukhwinder, primary, Sharma, Neil, additional, Krishn, Shiv Ram, additional, Lakshmanan, Imay, additional, Rachagani, Satyanarayana, additional, Baine, Michael J., additional, Smith, Lynette M., additional, Lele, Subodh M., additional, Sasson, Aaron R., additional, Guha, Sushovan, additional, Mallya, Kavita, additional, Anderson, Judy M., additional, Hollingsworth, Michael A., additional, and Batra, Surinder K., additional

Published
2014
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34. BCA101 Is a Tumor-Targeted Bifunctional Fusion Antibody That Simultaneously Inhibits EGFR and TGFβ Signaling to Durably Suppress Tumor Growth.

Author

Boreddy SR, Nair R, Pandey PK, Kuriakose A, Marigowda SB, Dey C, Banerjee A, Kulkarni H, Sagar M, Krishn SR, Rao S, Ar M, Tiwari V, Alke B, Mv PK, Shri M, Dhamne C, Patel S, Sharma P, Periyasamy S, Bhatnagar J, Kuriakose MA, Reddy RB, Suresh A, Sreenivas S, Govindappa N, Moole PR, Bughani U, Tan SL, and Nair P

Subjects
Animals, Humans, Mice, Cell Line, Tumor, Cetuximab pharmacology, Cetuximab therapeutic use, ErbB Receptors metabolism, Transforming Growth Factor beta, Tumor Microenvironment, Xenograft Model Antitumor Assays, Antibodies, Monoclonal, Humanized therapeutic use, Carcinoma, Squamous Cell therapy, Head and Neck Neoplasms therapy, Neoplasms therapy
Abstract

The EGFR and TGFβ signaling pathways are important mediators of tumorigenesis, and cross-talk between them contributes to cancer progression and drug resistance. Therapies capable of simultaneously targeting EGFR and TGFβ could help improve patient outcomes across various cancer types. Here, we developed BCA101, an anti-EGFR IgG1 mAb linked to an extracellular domain of human TGFβRII. The TGFβ "trap" fused to the light chain in BCA101 did not sterically interfere with its ability to bind EGFR, inhibit cell proliferation, or mediate antibody-dependent cellular cytotoxicity. Functional neutralization of TGFβ by BCA101 was demonstrated by several in vitro assays. BCA101 increased production of proinflammatory cytokines and key markers associated with T-cell and natural killer-cell activation, while suppressing VEGF secretion. In addition, BCA101 inhibited differentiation of naïve CD4+ T cells to inducible regulatory T cells (iTreg) more strongly than the anti-EGFR antibody cetuximab. BCA101 localized to tumor tissues in xenograft mouse models with comparable kinetics to cetuximab, both having better tumor tissue retention over TGFβ "trap." TGFβ in tumors was neutralized by approximately 90% in animals dosed with 10 mg/kg of BCA101 compared with 54% in animals dosed with equimolar TGFβRII-Fc. In patient-derived xenograft mouse models of head and neck squamous cell carcinoma, BCA101 showed durable response after dose cessation. The combination of BCA101 and anti-PD1 antibody improved tumor inhibition in both B16-hEGFR-expressing syngeneic mouse models and in humanized HuNOG-EXL mice bearing human PC-3 xenografts. Together, these results support the clinical development of BCA101 as a monotherapy and in combination with immune checkpoint therapy., Significance: The bifunctional mAb fusion design of BCA101 targets it to the tumor microenvironment where it inhibits EGFR and neutralizes TGFβ to induce immune activation and to suppress tumor growth., (©2023 The Authors; Published by the American Association for Cancer Research.)

Published
2023
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35. Mucins and associated O-glycans based immunoprofile for stratification of colorectal polyps: clinical implication for improved colon surveillance.

Author

Krishn SR, Kaur S, Sheinin YM, Smith LM, Gautam SK, Patel A, Jain M, Juvvigunta V, Pai P, Lazenby AJ, Roy HK, and Batra SK

Subjects
Adult, Aged, Aged, 80 and over, Diagnosis, Differential, Female, Humans, Male, Middle Aged, Antigens, Tumor-Associated, Carbohydrate metabolism, Colonic Polyps immunology, Mucins metabolism
Abstract

Sessile serrated adenoma/polyps (SSA/P) are premalignant lesions of colorectal cancer that are difficult to distinguish histologically from hyperplastic polyps (HP) of minimal to no malignant potential. Specific markers for differentiating SSA/P from HP can aid clinicians for optimizing colon surveillance intervals. The present study investigates the potential of mucins and associated O-glycans to distinguish SSA/P from HP. Expression of colonic mucins (MUC1, MUC4, MUC17, MUC2, and MUC5AC) and O-glycans [Sialyl LewisA (CA19-9) and Tn/Sialyl-Tn on MUC1] were analyzed in HP (n=33), SSA/P (n=39), and tubular adenoma (TA) (n=36) samples by immunohistochemistry. A significantly reduced expression of MUC4 (p=0.0066), elevated expression of MUC17 (p=0.0002), and MUC5AC (p<0.0001) was observed in SSA/P cases in comparison to HP cases. Interestingly, significantly higher number of SSA/P cases (p<0.0001) exhibited MUC5AC expression in the goblet cells as well as filled the crypt lumen compared to only goblet cells in majority of the HP cases. Improved diagnostic potential was revealed by multivariate logistic regression analysis where combinatorial panel of MUC5AC/MUC17 discriminated SSA/P from HP (SN/SP=85/82%). Finally, the decision tree model based marker panel (CA19-9/MUC17/MUC5AC) predicted HP, SSA/P and TA with SN/SP of 58%/95%, 79%/90% and 97%/83%, respectively. Overall, the mucin and associated O-glycan based panel defined in the present study could aid in discriminating SSA/P from HP to devise better colon surveillance strategies.

Published
2017
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37. MicroRNAs (miRNAs) as biomarker(s) for prognosis and diagnosis of gastrointestinal (GI) cancers.

Author

Macha MA, Seshacharyulu P, Krishn SR, Pai P, Rachagani S, Jain M, and Batra SK

Subjects
Biomarkers, Tumor metabolism, Gastrointestinal Neoplasms metabolism, Humans, MicroRNAs metabolism, Prognosis, Biomarkers, Tumor genetics, Gastrointestinal Neoplasms diagnosis, Gastrointestinal Neoplasms genetics, MicroRNAs genetics
Abstract

Gastrointestinal (GI) cancers remain one of the most common malignancies and are the second common cause of cancer deaths worldwide. The limited effectiveness of therapy for patients with advanced stage and recurrent disease is a reflection of an incomplete understanding of the molecular basis of GI carcinogenesis. Major advancements have improved our understanding of pathology and pathogenesis of GI cancers, but high mortality rates, unfavorable prognosis and lack of clinical predictive biomarkers provide an impetus to investigate new sensitive and specific diagnostic and prognostic markers for GI cancers. MicroRNAs (miRNAs) are short (19-24 nucleotides) noncoding RNA molecules that regulate gene expression at the posttranscriptional level thus playing an important role in modulating various biological processes including, but not limited to developmental processes, proliferation, apoptosis, metabolism, differentiation, epithelial-mechenchymal transition and are involved in the initiation and progression of various human cancers. Unique miRNA expression profiles have been observed in various cancer types at different stages, suggesting their potential as diagnostic and prognostic biomarkers. Due to their tumor-specific and tissue-specific expression profiles, stability, robust clinical assays for detection in serum as well as in formalin-fixed tissue samples, miRNAs have emerged as attractive candidates for diagnostic and prognostic applications. This review summarizes recent research supporting the utility of miRNAs as novel diagnostic and prognostic tools for GI cancers.

Published
2014
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