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Start Over Author "D'Silva NJ" Journal nature communications
3 results on '"D'Silva NJ"'

2. Galanin modulates the neural niche to favour perineural invasion in head and neck cancer.

Author

Scanlon CS, Banerjee R, Inglehart RC, Liu M, Russo N, Hariharan A, van Tubergen EA, Corson SL, Asangani IA, Mistretta CM, Chinnaiyan AM, and D'Silva NJ

Subjects
Animals, Cell Line, Tumor, Chick Embryo, Cyclooxygenase 2 metabolism, Disease Progression, Humans, Mice, NFATC Transcription Factors metabolism, Neoplasm Invasiveness, Random Allocation, Rats, Receptor, Galanin, Type 2 metabolism, Galanin metabolism, Head and Neck Neoplasms metabolism, Neurites metabolism
Abstract

Perineural invasion (PNI) is an indicator of poor survival in multiple cancers. Unfortunately, there is no targeted treatment for PNI since the molecular mechanisms are largely unknown. PNI is an active process, suggesting that cancer cells communicate with nerves. However, nerve-tumour crosstalk is understudied due to the lack of in vivo models to investigate the mechanisms. Here we developed an in vivo model of PNI to characterize this interaction. We show that the neuropeptide galanin (GAL) initiates nerve-tumour crosstalk via activation of its G protein-coupled receptor, GALR2. Our data reveal a novel mechanism by which GAL from nerves stimulates GALR2 on cancer cells to induce NFATC2-mediated transcription of cyclooxygenase-2 and GAL. Prostaglandin E2 promotes cancer invasion, and in a feedback mechanism, GAL released by cancer induces neuritogenesis, facilitating PNI. This study describes a novel in vivo model for PNI and reveals the dynamic interaction between nerve and cancer.

Published
2015
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3. TRIP13 promotes error-prone nonhomologous end joining and induces chemoresistance in head and neck cancer.

Author

Banerjee R, Russo N, Liu M, Basrur V, Bellile E, Palanisamy N, Scanlon CS, van Tubergen E, Inglehart RC, Metwally T, Mani RS, Yocum A, Nyati MK, Castilho RM, Varambally S, Chinnaiyan AM, and D'Silva NJ

Subjects
ATPases Associated with Diverse Cellular Activities, Animals, Antineoplastic Agents pharmacology, Carcinoma, Squamous Cell drug therapy, Carcinoma, Squamous Cell metabolism, Carcinoma, Squamous Cell pathology, Carrier Proteins antagonists & inhibitors, Carrier Proteins metabolism, Cell Cycle Proteins, Cell Line, Transformed, Cell Line, Tumor, Cell Movement, Cell Transformation, Neoplastic genetics, Cell Transformation, Neoplastic metabolism, Cell Transformation, Neoplastic pathology, Chick Embryo, Chorioallantoic Membrane blood supply, Chorioallantoic Membrane drug effects, Chorioallantoic Membrane metabolism, DNA Breaks, Double-Stranded, DNA-Activated Protein Kinase antagonists & inhibitors, DNA-Activated Protein Kinase metabolism, Drug Resistance, Neoplasm genetics, Head and Neck Neoplasms drug therapy, Head and Neck Neoplasms metabolism, Head and Neck Neoplasms pathology, Humans, Injections, Subcutaneous, Keratinocytes drug effects, Keratinocytes metabolism, Keratinocytes pathology, Mice, Mice, Nude, NIH 3T3 Cells, Nuclear Proteins antagonists & inhibitors, Nuclear Proteins metabolism, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Signal Transduction, Squamous Cell Carcinoma of Head and Neck, Xenograft Model Antitumor Assays, Carcinoma, Squamous Cell genetics, Carrier Proteins genetics, DNA End-Joining Repair, DNA-Activated Protein Kinase genetics, Gene Expression Regulation, Neoplastic, Head and Neck Neoplasms genetics, Nuclear Proteins genetics
Abstract

Squamous cell carcinoma of the head and neck (SCCHN) is a common, aggressive, treatment-resistant cancer with a high recurrence rate and mortality, but the mechanism of treatment resistance remains unclear. Here we describe a mechanism where the AAA-ATPase TRIP13 promotes treatment resistance. Overexpression of TRIP13 in non-malignant cells results in malignant transformation. High expression of TRIP13 in SCCHN leads to aggressive, treatment-resistant tumors and enhanced repair of DNA damage. Using mass spectrometry, we identify DNA-PKcs complex proteins that mediate nonhomologous end joining (NHEJ), as TRIP13-binding partners. Using repair-deficient reporter systems, we show that TRIP13 promotes NHEJ, even when homologous recombination is intact. Importantly, overexpression of TRIP13 sensitizes SCCHN to an inhibitor of DNA-PKcs. Thus, this study defines a new mechanism of treatment resistance in SCCHN and underscores the importance of targeting NHEJ to overcome treatment failure in SCCHN and potentially in other cancers that overexpress TRIP13.

Published
2014
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