Dhanya Nambiar

Bio: Dhanya Nambiar is an academic researcher from Stanford University. The author has contributed to research in topics: Silibinin & Medicine. The author has an hindex of 18, co-authored 36 publications receiving 844 citations. Previous affiliations of Dhanya Nambiar include Burnet Institute & University of Colorado Hospital.

The Immune Subtypes and Landscape of Squamous Cell Carcinoma

Abstract: Purpose: To identify immune subtypes and investigate the immune landscape of squamous cell carcinomas (SCC), which share common etiology and histologic features. Experimental Design: Based on the immune gene expression profiles of 1,368 patients with SCC in the Cancer Genome Atlas (TCGA), we used consensus clustering to identify robust clusters of patients and assessed their reproducibility in an independent pan-SCC cohort of 938 patients. We further applied graph structure learning-based dimensionality reduction to the immune profiles to visualize the distribution of individual patients. Results: We identified and independently validated six reproducible immune subtypes associated with distinct molecular characteristics and clinical outcomes. An immune-cold subtype had the least amount of lymphocyte infiltration and a high level of aneuploidy, and these patients had the worst prognosis. By contrast, an immune-hot subtype demonstrated the highest infiltration of CD8+ T cells, activated NK cells, and elevated IFNγ response. Accordingly, these patients had the best prognosis. A third subtype was dominated by M2-polarized macrophages with potent immune-suppressive factors such as TGFβ signaling and reactive stroma, and these patients had relatively inferior prognosis. Other subtypes showed more diverse immunologic features with intermediate prognoses. Finally, our analysis revealed a complex immune landscape consisting of both discrete clusters and continuous spectrum. Conclusions: This study provides a conceptual framework to understand the tumor immune microenvironment of SCCs. Future work is needed to evaluate its relevance in the design of combination treatment strategies and guiding optimal selection of patients for immunotherapy.

Hypoxia induces triglycerides accumulation in prostate cancer cells and extracellular vesicles supporting growth and invasiveness following reoxygenation

Abstract: // Isabel R. Schlaepfer 1,* , Dhanya K. Nambiar 2,3,* , Anand Ramteke 2,4,* , Rahul Kumar 2 , Deepanshi Dhar 2 , Chapla Agarwal 2,5 , Bryan Bergman 6 , Michael Graner 7 , Paul Maroni 8 , Rana P. Singh 3 , Rajesh Agarwal 2,5 and Gagan Deep 2,5 1 Division of Medical Oncology, Department of Medicine, University of Colorado Denver, Aurora, Colorado, USA 2 Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Denver, Aurora, Colorado, USA 3 Cancer Biology Laboratory, School of Life Sciences, Jawaharlal Nehru University, New Delhi, India 4 Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur, India 5 University of Colorado Cancer Center, University of Colorado Denver, Aurora, Colorado, USA 6 Division of Endocrinology, Metabolism and Diabetes, University of Colorado Denver, Aurora, Colorado, USA 7 Department of Neurosurgery, University of Colorado Denver, Aurora, Colorado, USA 8 Department of Surgery, University of Colorado Denver, Aurora, Colorado, USA * These authors have contributed equally to this work Correspondence to: Gagan Deep, email: // Rajesh Agarwal, email: // Keywords : hypoxia, extracellular vesicle, prostate cancer, lipids, β-oxidation Received : January 30, 2015 Accepted : May 22, 2015 Published : June15 ,2015 Abstract Hypoxia is an independent prognostic indicator of poor outcome in several malignancies. However, precise mechanism through which hypoxia promotes disease aggressiveness is still unclear. Here, we report that under hypoxia (1% O 2 ), human prostate cancer (PCA) cells, and extracellular vesicles (EVs) released by these cells, are significantly enriched in triglycerides due to the activation of lipogenesis-related enzymes and signaling molecules. This is likely a survival response to hypoxic stress as accumulated lipids could support growth following reoxygenation. Consistent with this, significantly higher proliferation was observed in hypoxic PCA cells following reoxygenation associated with rapid use of accumulated lipids. Importantly, lipid utilization inhibition by CPT1 inhibitor etomoxir and shRNA-mediated CPT1-knockdown significantly compromised hypoxic PCA cell proliferation following reoxygenation. Furthermore, COX2 inhibitor celecoxib strongly reduced growth and invasiveness following hypoxic PCA cells reoxygenation, and inhibited invasiveness induced by hypoxic PCA EVs. This establishes a role for COX2 enzymatic products in the enhanced PCA growth and invasiveness. Importantly, concentration and loading of EVs secreted by PCA cells were significantly compromised under delipidized serum condition and by lipogenesis inhibitors (fatostatin and silibinin). Overall, present study highlights the biological significance of lipid accumulation in hypoxic PCA cells and its therapeutic relevance in PCA.

Effects of phytochemicals on ionization radiation-mediated carcinogenesis and cancer therapy.

Abstract: Ionizing radiation (IR)-induced cellular damage is implicated in carcinogenesis as well as therapy of cancer. Advances in radiation therapy have led to the decrease in dosage and localizing the effects to the tumor; however, the development of radioresistance in cancer cells and radiation toxicity to normal tissues are still the major concerns. The development of radioresistance involves several mechanisms, including the activation of mitogenic and survival signaling, induction of DNA repair, and changes in redox signaling and epigenetic regulation. The current strategy of combining radiation with standard cytotoxic chemotherapeutic agents can potentially lead to unwanted side effects due to both agents. Thus agents are needed that could improve the efficacy of radiation killing of cancer cells and prevent the damage to normal cells and tissues caused by the direct and bystander effects of radiation, without have its own systemic toxicity. Chemopreventive phytochemicals, usually non-toxic agents with both cancer preventive and therapeutic activities, could rightly fit in this approach. In this regard, naturally occurring compounds, including curcumin, parthenolide, genistein, gossypol, ellagic acid, withaferin, plumbagin and resveratrol, have shown considerable potential. These agents suppress the radiation-induced activation of receptor tyrosine kinases and nuclear factor-κB signaling, can modify cell survival and DNA repair efficacy, and may potentiate ceramide signaling. These radiosensitizing and counter radioresistance mechanisms of phytochemicals in cancer cells are also associated with changes in epigenetic gene regulation. Because radioresistance involves multiple mechanisms, more studies are needed to discover novel phytochemicals having multiple mechanisms of radiosensitization and to overcome radioresistance of cancer cells. Pre-clinical studies are needed to address the appropriate dosage, timing, and duration of the application of phytochemicals with radiation to justify clinical trials. Nonetheless, some phytochemicals in combination with IR may play a significant role in enhancing the therapeutic index of cancer treatment.

Fisetin inhibits various attributes of angiogenesis in vitro and in vivo—implications for angioprevention

Abstract: Studies have shown that fisetin, a small phytochemical molecule, has antitumor activity; however, its antiangiogenic activity has not yet been examined. Accordingly, herein, we investigated the antiangiogenic efficacy and associated mechanisms of fisetin in human umbilical vein endothelial cells (HUVECs). Fisetin (10-50 μM) strongly inhibited the regular serum plus growth supplement- and vascular endothelial growth factor (VEGF)-induced growth (up to 92%, P < 0.001) and survival (up to 16%, P < 0.001) of HUVEC in a dose- and time-dependent manner. Fisetin also caused cell cycle arrest at G(1) (strong) and G(2)/M (moderate) phases together with a decrease in cyclin D1 and an increase in p53 levels. Fisetin-caused cell death was accompanied by decreased expression of survivin and an increase in cleaved levels of caspases-3 and -7 and poly-(ADP-ribose) polymerase along with an increased ratio of Bax to Bcl-2. Furthermore, fisetin inhibited capillary-like tube formation on Matrigel (up to 85%, P < 0.001) as well as migration (up to 66%, P < 0.001), which were associated with decreased expression of endothelial nitric oxide synthase (eNOS) and VEGF in HUVEC. It also decreased the expression of eNOS, VEGF, inducible nitric oxide synthase, matrix metalloproteinase-2 and -9 in A549 and DU145 human cancer cells. In vivo matrigel plug assay in mice showed significant decrease in size (up to 43%, P < 0.001), vascularization and hemoglobin content (up to 94%, P < 0.001) in the plugs from fisetin-treated, compared with control mice. Overall, these results suggest that fisetin inhibits various attributes of angiogenesis, which might contribute to its reported antitumor effects, and therefore, fisetin warrants further investigation for its angiopreventive potential toward cancer control.

Galectin-1–driven T cell exclusion in the tumor endothelium promotes immunotherapy resistance

Abstract: Immune checkpoint inhibitors (ICIs), although promising, have variable benefit in head and neck cancer (HNC). We noted that tumor galectin-1 (Gal1) levels were inversely correlated with treatment response and survival in patients with HNC who were treated with ICIs. Using multiple HNC mouse models, we show that tumor-secreted Gal1 mediates immune evasion by preventing T cell migration into the tumor. Mechanistically, Gal1 reprograms the tumor endothelium to upregulate cell-surface programmed death ligand 1 (PD-L1) and galectin-9. Using genetic and pharmacological approaches, we show that Gal1 blockade increases intratumoral T cell infiltration, leading to a better response to anti-PD1 therapy with or without radiotherapy. Our study reveals the function of Gal1 in transforming the tumor endothelium into an immune-suppressive barrier and that its inhibition synergizes with ICIs.

Cancer metabolism: a therapeutic perspective

Abstract: Awareness that the metabolic phenotype of cells within tumours is heterogeneous - and distinct from that of their normal counterparts - is growing. In general, tumour cells metabolize glucose, lactate, pyruvate, hydroxybutyrate, acetate, glutamine, and fatty acids at much higher rates than their nontumour equivalents; however, the metabolic ecology of tumours is complex because they contain multiple metabolic compartments, which are linked by the transfer of these catabolites. This metabolic variability and flexibility enables tumour cells to generate ATP as an energy source, while maintaining the reduction-oxidation (redox) balance and committing resources to biosynthesis - processes that are essential for cell survival, growth, and proliferation. Importantly, experimental evidence indicates that metabolic coupling between cell populations with different, complementary metabolic profiles can induce cancer progression. Thus, targeting the metabolic differences between tumour and normal cells holds promise as a novel anticancer strategy. In this Review, we discuss how cancer cells reprogramme their metabolism and that of other cells within the tumour microenvironment in order to survive and propagate, thus driving disease progression; in particular, we highlight potential metabolic vulnerabilities that might be targeted therapeutically.

The biology and role of CD44 in cancer progression: Therapeutic implications

Abstract: CD44, a non-kinase transmembrane glycoprotein, is overexpressed in several cell types including cancer stem cells and frequently shows alternative spliced variants that are thought to play a role in cancer development and progression. Hyaluronan, the main ligand for CD44, binds to and activates CD44 resulting in activation of cell signaling pathways that induces cell proliferation, increases cell survival, modulates cytoskeletal changes, and enhances cellular motility. The different functional roles of CD44 standard (CD44s) and specific CD44 variant (CD44v) isoforms are not fully understood. CD44v contain additional peptide motifs that can interact with and sequester growth factors and cytokines at the cell surface thereby functioning as coreceptors to facilitate cell signaling. Moreover, CD44v were expressed in metastasized tumors, whereas switching between CD44v and CD44s may play a role in regulating epithelial to mesenchymal transition (EMT) and in the adaptive plasticity of cancer cells. Here, we review current data on the structural and functional properties of CD44, the known roles for CD44 in tumorigencity, the regulation of CD44 expression, and the potential for targeting CD44 for cancer therapy.