Vihas Vasu | Maharaja Sayajirao University of Baroda (original) (raw)
Papers by Vihas Vasu
Chronobiology International
American Journal of Respiratory Cell and Molecular Biology
The discovery of mutant tyrosine kinases as oncogenic drivers of lung adenocarcinomas has changed... more The discovery of mutant tyrosine kinases as oncogenic drivers of lung adenocarcinomas has changed the basic understanding of lung cancer development and therapy. Yet, expressed kinases (kinome) in lung cancer progenitor cells, as well as whether kinase expression and the overall kinome changes or is reprogrammed upon transformation, is incompletely understood. We hypothesized that the kinome differs between lung cancer progenitor cells, alveolar type II cells (ATII), and basal cells (BC) and that their respective kinomes undergo distinct lineage-specific reprogramming to adenocarcinomas and squamous cell carcinomas upon transformation. We performed RNA sequencing on freshly isolated human ATII, BC, and lung cancer cell lines to define the kinome in nontransformed cells and transformed cells. Our studies identified a unique kinome for ATII and BC and changes in their kinome upon transformation to their respective carcinomas.
The Faseb Journal, Mar 1, 2008
Nature communications, May 19, 2016
The precise molecular alterations driving castration-resistant prostate cancer (CRPC) are not cle... more The precise molecular alterations driving castration-resistant prostate cancer (CRPC) are not clearly understood. Using a novel network-based integrative approach, here, we show distinct alterations in the hexosamine biosynthetic pathway (HBP) to be critical for CRPC. Expression of HBP enzyme glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) is found to be significantly decreased in CRPC compared with localized prostate cancer (PCa). Genetic loss-of-function of GNPNAT1 in CRPC-like cells increases proliferation and aggressiveness, in vitro and in vivo. This is mediated by either activation of the PI3K-AKT pathway in cells expressing full-length androgen receptor (AR) or by specific protein 1 (SP1)-regulated expression of carbohydrate response element-binding protein (ChREBP) in cells containing AR-V7 variant. Strikingly, addition of the HBP metabolite UDP-N-acetylglucosamine (UDP-GlcNAc) to CRPC-like cells significantly decreases cell proliferation, both in-vitro and in animal s...
American journal of respiratory cell and molecular biology, Jun 24, 2015
The airway epithelium constitutes a protective barrier against inhaled insults such as viruses, b... more The airway epithelium constitutes a protective barrier against inhaled insults such as viruses, bacteria and toxic fumes including cigarette smoke (CS). Maintenance of bronchial epithelial integrity is central for airway health and defective epithelial barrier function contributes to the pathogenesis of CS-mediated diseases such as chronic obstructive pulmonary disease (COPD). While CS has been shown to increase epithelial permeability, current understanding of the mechanisms involved in CS-induced epithelial barrier disruption remains incomplete. We have previously identified that the receptor tyrosine kinase Human Epidermal Growth Factor 2 (HER2) is activated by the ligand neuregulin-1 (NRG-1) and increases epithelial permeability in models of inflammatory acute lung injury. We hypothesized that CS activates HER2 and that CS-mediated changes in barrier function would be HER2 dependent in airway epithelial cells. We determined that HER2 was activated in whole lung as well as isolat...
Journal of Thoracic Oncology, 2013
Introduction: KRAS mutations are poor prognostic markers for patients with non-small-cell lung ca... more Introduction: KRAS mutations are poor prognostic markers for patients with non-small-cell lung cancer (NSCLC). RALA and RALB GTPases lie downstream of RAS and are implicated in RASmediated tumorigenesis. However, their biological or prognostic role in the context of KRAS mutation in NSCLC is unclear. Methods: Using expression analysis of human tumors and a panel of cell lines coupled with functional in vivo and in vitro experiments, we evaluated the prognostic and functional importance of RAL in NSCLC and their relationship to KRAS expression and mutation. Results: Immunohistochemical (N = 189) and transcriptomic (N = 337) analyses of NSCLC patients revealed high RALA and RALB expression was associated with poor survival. In a panel of 14 human NSCLC cell lines, RALA and RALB had higher expression in KRAS mutant cell lines whereas RALA but not RALB activity was higher in KRAS mutant cell lines. Depletion of RAL paralogs identified cell lines that are dependent on RAL expression for proliferation and anchorage independent growth. Overall, growth of NSCLC cell lines that carry a glycine to cystine KRAS mutation were more sensitive to RAL depletion than those with wild-type KRAS. The use of gene expression and outcome data from 337 human tumors in RAL-KRAS interaction analysis revealed that KRAS and RAL paralog expression jointly impact patient prognosis. Conclusion: RAL GTPase expression carries important additional prognostic information to KRAS status in NSCLC patients. Simultaneously targeting RAL may provide a novel therapeutic approach in NSCLC patients harboring glycine to cystine KRAS mutations.
Free Radical Research, 2007
α-tocopherol (α-T) may affect biological processes by modulating mRNA concentrations. This study ... more α-tocopherol (α-T) may affect biological processes by modulating mRNA concentrations. This study screened the responses of ~15,000 lung mRNAs to dietary α-T in mice. The lung was chosen as the target organ because it is subjected to cyclical variations in oxidant and inflammatory stressors and α-T has been implicated in their modulations. The analysis identified ~400 mRNAs sensitive to α-T status of lungs determined by dietary α-T. The female lung transcriptome appears to be more sensitive to the α-T status than that of the male lungs. Here, we focus on the induction of 13 cytoskeleton genes by dietary α-T because they were similarly induced in the male and the female lungs. Their inductions were confirmed by quantitative-real-time-polymerase chain reaction (qRT-PCR). Immunohistochemical analyses of three of the encoded proteins suggest that they are expressed in lung vasculature and alveolar regions. The data suggest that the lung α-T status may modulate cytoarchitecture of lungs.
Free Radical Biology and Medicine, 2013
High dietary α-tocopherol levels reportedly result in osteopenia in growing rats, whereas α-tocop... more High dietary α-tocopherol levels reportedly result in osteopenia in growing rats, whereas α-tocopherol deficiency in α-tocopherol transfer protein-knockout (α-TTP-KO) mice results in increased cancellous bone mass. Because osteoporosis is a disease associated primarily with aging, we hypothesized that age-related bone loss would be attenuated in α-TTP-KO mice. Cancellous and cortical bone mass and microarchitecture were assessed using dual-energy X-ray absorptiometry and micro-computed tomography in 2-year-old α-TTP-KO and wild-type (WT) male and female mice fed dl-α-tocopherol acetate. In contrast to our expectations, differences in cancellous bone were not detected between WT and α-TTP-KO mice of either gender, and α-TTP-KO males had lower (p<0.05) cortical bone mass than WT males. We therefore evaluated bone mass, density, and microarchitecture in proximal femur of skeletally mature (8.5-month-old) male Sprague-Dawley rats fed diets containing low (15 IU/kg diet), adequate (75 IU/kg diet), or high (500 IU/kg diet) dl-α-tocopherol acetate for 13 weeks. Low dietary α-tocopherol did not increase bone mass. Furthermore, no reductions in cancellous or cortical bone mass were detected with high dietary α-tocopherol. Failure to detect increased bone mass in aged α-TTP-KO mice or bone changes in skeletally mature rats fed either low or high levels of α-tocopherol does not support the hypothesis that α-tocopherol has a negative impact on bone mass, density, or microarchitecture in rodents.
α-tocopherol (α-T) may affect biological processes by modulating mRNA concentrations. This study ... more α-tocopherol (α-T) may affect biological processes by modulating mRNA concentrations. This study screened the responses of ~15,000 lung mRNAs to dietary α-T in mice. The lung was chosen as the target organ because it is subjected to cyclical variations in oxidant and inflammatory stressors and α-T has been implicated in their modulations. The analysis identified ~400 mRNAs sensitive to α-T status of lungs determined by dietary α-T. The female lung transcriptome appears to be more sensitive to the α-T status than that of the male lungs. Here, we focus on the induction of 13 cytoskeleton genes by dietary α-T because they were similarly induced in the male and the female lungs. Their inductions were confirmed by quantitative-real-time-polymerase chain reaction (qRT-PCR). Immunohistochemical analyses of three of the encoded proteins suggest that they are expressed in lung vasculature and alveolar regions. The data suggest that the lung α-T status may modulate cytoarchitecture of lungs.
American Journal of Physiology - Lung Cellular and Molecular Physiology, 2014
The receptor tyrosine kinase HER2 is known to regulate pulmonary epithelial barrier function, 35 ... more The receptor tyrosine kinase HER2 is known to regulate pulmonary epithelial barrier function, 35 however, the mechanisms behind this effect remain unidentified. We hypothesized that HER2 36 signaling alters the epithelial barrier through an interaction with the adherens junction (AJ) 37 protein β-catenin leading to dissolution of the AJ. In quiescent pulmonary epithelial cells, HER2 38 and β-catenin co-localized along the lateral inter-cellular junction. HER2 activation by the ligand 39 neuregulin-1 was associated with tyrosine phosphorylation of β-catenin, dissociation of β-40 catenin from E-cadherin and decreased E-cadherin mediated cell adhesion. All effects were 41 blocked with the HER2 inhibitor lapatinib. β-catenin knock-down using shRNA significantly 42 attenuated NRG-1 induced decreases in pulmonary epithelial resistance in vitro. Our data 43 indicate that HER2 interacts with β-catenin leading to dissolution of the AJ, decreased cell-cell 44 adhesion and disruption of the pulmonary epithelial barrier.
Chronobiology International
American Journal of Respiratory Cell and Molecular Biology
The discovery of mutant tyrosine kinases as oncogenic drivers of lung adenocarcinomas has changed... more The discovery of mutant tyrosine kinases as oncogenic drivers of lung adenocarcinomas has changed the basic understanding of lung cancer development and therapy. Yet, expressed kinases (kinome) in lung cancer progenitor cells, as well as whether kinase expression and the overall kinome changes or is reprogrammed upon transformation, is incompletely understood. We hypothesized that the kinome differs between lung cancer progenitor cells, alveolar type II cells (ATII), and basal cells (BC) and that their respective kinomes undergo distinct lineage-specific reprogramming to adenocarcinomas and squamous cell carcinomas upon transformation. We performed RNA sequencing on freshly isolated human ATII, BC, and lung cancer cell lines to define the kinome in nontransformed cells and transformed cells. Our studies identified a unique kinome for ATII and BC and changes in their kinome upon transformation to their respective carcinomas.
The Faseb Journal, Mar 1, 2008
Nature communications, May 19, 2016
The precise molecular alterations driving castration-resistant prostate cancer (CRPC) are not cle... more The precise molecular alterations driving castration-resistant prostate cancer (CRPC) are not clearly understood. Using a novel network-based integrative approach, here, we show distinct alterations in the hexosamine biosynthetic pathway (HBP) to be critical for CRPC. Expression of HBP enzyme glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1) is found to be significantly decreased in CRPC compared with localized prostate cancer (PCa). Genetic loss-of-function of GNPNAT1 in CRPC-like cells increases proliferation and aggressiveness, in vitro and in vivo. This is mediated by either activation of the PI3K-AKT pathway in cells expressing full-length androgen receptor (AR) or by specific protein 1 (SP1)-regulated expression of carbohydrate response element-binding protein (ChREBP) in cells containing AR-V7 variant. Strikingly, addition of the HBP metabolite UDP-N-acetylglucosamine (UDP-GlcNAc) to CRPC-like cells significantly decreases cell proliferation, both in-vitro and in animal s...
American journal of respiratory cell and molecular biology, Jun 24, 2015
The airway epithelium constitutes a protective barrier against inhaled insults such as viruses, b... more The airway epithelium constitutes a protective barrier against inhaled insults such as viruses, bacteria and toxic fumes including cigarette smoke (CS). Maintenance of bronchial epithelial integrity is central for airway health and defective epithelial barrier function contributes to the pathogenesis of CS-mediated diseases such as chronic obstructive pulmonary disease (COPD). While CS has been shown to increase epithelial permeability, current understanding of the mechanisms involved in CS-induced epithelial barrier disruption remains incomplete. We have previously identified that the receptor tyrosine kinase Human Epidermal Growth Factor 2 (HER2) is activated by the ligand neuregulin-1 (NRG-1) and increases epithelial permeability in models of inflammatory acute lung injury. We hypothesized that CS activates HER2 and that CS-mediated changes in barrier function would be HER2 dependent in airway epithelial cells. We determined that HER2 was activated in whole lung as well as isolat...
Journal of Thoracic Oncology, 2013
Introduction: KRAS mutations are poor prognostic markers for patients with non-small-cell lung ca... more Introduction: KRAS mutations are poor prognostic markers for patients with non-small-cell lung cancer (NSCLC). RALA and RALB GTPases lie downstream of RAS and are implicated in RASmediated tumorigenesis. However, their biological or prognostic role in the context of KRAS mutation in NSCLC is unclear. Methods: Using expression analysis of human tumors and a panel of cell lines coupled with functional in vivo and in vitro experiments, we evaluated the prognostic and functional importance of RAL in NSCLC and their relationship to KRAS expression and mutation. Results: Immunohistochemical (N = 189) and transcriptomic (N = 337) analyses of NSCLC patients revealed high RALA and RALB expression was associated with poor survival. In a panel of 14 human NSCLC cell lines, RALA and RALB had higher expression in KRAS mutant cell lines whereas RALA but not RALB activity was higher in KRAS mutant cell lines. Depletion of RAL paralogs identified cell lines that are dependent on RAL expression for proliferation and anchorage independent growth. Overall, growth of NSCLC cell lines that carry a glycine to cystine KRAS mutation were more sensitive to RAL depletion than those with wild-type KRAS. The use of gene expression and outcome data from 337 human tumors in RAL-KRAS interaction analysis revealed that KRAS and RAL paralog expression jointly impact patient prognosis. Conclusion: RAL GTPase expression carries important additional prognostic information to KRAS status in NSCLC patients. Simultaneously targeting RAL may provide a novel therapeutic approach in NSCLC patients harboring glycine to cystine KRAS mutations.
Free Radical Research, 2007
α-tocopherol (α-T) may affect biological processes by modulating mRNA concentrations. This study ... more α-tocopherol (α-T) may affect biological processes by modulating mRNA concentrations. This study screened the responses of ~15,000 lung mRNAs to dietary α-T in mice. The lung was chosen as the target organ because it is subjected to cyclical variations in oxidant and inflammatory stressors and α-T has been implicated in their modulations. The analysis identified ~400 mRNAs sensitive to α-T status of lungs determined by dietary α-T. The female lung transcriptome appears to be more sensitive to the α-T status than that of the male lungs. Here, we focus on the induction of 13 cytoskeleton genes by dietary α-T because they were similarly induced in the male and the female lungs. Their inductions were confirmed by quantitative-real-time-polymerase chain reaction (qRT-PCR). Immunohistochemical analyses of three of the encoded proteins suggest that they are expressed in lung vasculature and alveolar regions. The data suggest that the lung α-T status may modulate cytoarchitecture of lungs.
Free Radical Biology and Medicine, 2013
High dietary α-tocopherol levels reportedly result in osteopenia in growing rats, whereas α-tocop... more High dietary α-tocopherol levels reportedly result in osteopenia in growing rats, whereas α-tocopherol deficiency in α-tocopherol transfer protein-knockout (α-TTP-KO) mice results in increased cancellous bone mass. Because osteoporosis is a disease associated primarily with aging, we hypothesized that age-related bone loss would be attenuated in α-TTP-KO mice. Cancellous and cortical bone mass and microarchitecture were assessed using dual-energy X-ray absorptiometry and micro-computed tomography in 2-year-old α-TTP-KO and wild-type (WT) male and female mice fed dl-α-tocopherol acetate. In contrast to our expectations, differences in cancellous bone were not detected between WT and α-TTP-KO mice of either gender, and α-TTP-KO males had lower (p<0.05) cortical bone mass than WT males. We therefore evaluated bone mass, density, and microarchitecture in proximal femur of skeletally mature (8.5-month-old) male Sprague-Dawley rats fed diets containing low (15 IU/kg diet), adequate (75 IU/kg diet), or high (500 IU/kg diet) dl-α-tocopherol acetate for 13 weeks. Low dietary α-tocopherol did not increase bone mass. Furthermore, no reductions in cancellous or cortical bone mass were detected with high dietary α-tocopherol. Failure to detect increased bone mass in aged α-TTP-KO mice or bone changes in skeletally mature rats fed either low or high levels of α-tocopherol does not support the hypothesis that α-tocopherol has a negative impact on bone mass, density, or microarchitecture in rodents.
α-tocopherol (α-T) may affect biological processes by modulating mRNA concentrations. This study ... more α-tocopherol (α-T) may affect biological processes by modulating mRNA concentrations. This study screened the responses of ~15,000 lung mRNAs to dietary α-T in mice. The lung was chosen as the target organ because it is subjected to cyclical variations in oxidant and inflammatory stressors and α-T has been implicated in their modulations. The analysis identified ~400 mRNAs sensitive to α-T status of lungs determined by dietary α-T. The female lung transcriptome appears to be more sensitive to the α-T status than that of the male lungs. Here, we focus on the induction of 13 cytoskeleton genes by dietary α-T because they were similarly induced in the male and the female lungs. Their inductions were confirmed by quantitative-real-time-polymerase chain reaction (qRT-PCR). Immunohistochemical analyses of three of the encoded proteins suggest that they are expressed in lung vasculature and alveolar regions. The data suggest that the lung α-T status may modulate cytoarchitecture of lungs.
American Journal of Physiology - Lung Cellular and Molecular Physiology, 2014
The receptor tyrosine kinase HER2 is known to regulate pulmonary epithelial barrier function, 35 ... more The receptor tyrosine kinase HER2 is known to regulate pulmonary epithelial barrier function, 35 however, the mechanisms behind this effect remain unidentified. We hypothesized that HER2 36 signaling alters the epithelial barrier through an interaction with the adherens junction (AJ) 37 protein β-catenin leading to dissolution of the AJ. In quiescent pulmonary epithelial cells, HER2 38 and β-catenin co-localized along the lateral inter-cellular junction. HER2 activation by the ligand 39 neuregulin-1 was associated with tyrosine phosphorylation of β-catenin, dissociation of β-40 catenin from E-cadherin and decreased E-cadherin mediated cell adhesion. All effects were 41 blocked with the HER2 inhibitor lapatinib. β-catenin knock-down using shRNA significantly 42 attenuated NRG-1 induced decreases in pulmonary epithelial resistance in vitro. Our data 43 indicate that HER2 interacts with β-catenin leading to dissolution of the AJ, decreased cell-cell 44 adhesion and disruption of the pulmonary epithelial barrier.