Publications by authors named "Deepika Neelakantan"

9 Publications

  • Page 1 of 1

VEGF-C mediates tumor growth and metastasis through promoting EMT-epithelial breast cancer cell crosstalk.

Oncogene 2021 Feb 9;40(5):964-979. Epub 2020 Dec 9.

Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

It is well established that a subset of cells within primary breast cancers can undergo an epithelial-to-mesenchymal transition (EMT), although the role of EMT in metastasis remains controversial. We previously demonstrated that breast cancer cells that had undergone an oncogenic EMT could increase metastasis of neighboring cancer cells via non-canonical paracrine-mediated activation of GLI activity that is dependent on SIX1 expression in the EMT cancer cells. However, the mechanism by which these SIX1-expressing EMT cells activate GLI signaling remained unclear. In this study, we demonstrate a novel mechanism for activation of GLI-mediated signaling in epithelial breast tumor cells via EMT cell-induced production and secretion of VEGF-C. We show that VEGF-C, secreted by breast cancer cells that have undergone an EMT, promotes paracrine-mediated increases in proliferation, migration, and invasion of epithelial breast cancer cells, via non-canonical activation of GLI-signaling. We further show that the aggressive phenotypes, including metastasis, imparted by EMT cells on adjacent epithelial cancer cells can be disrupted by either inhibiting VEGF-C in EMT cells or by knocking down NRP2, a receptor which interacts with VEGF-C, in neighboring epithelial cancer cells. Interrogation of TCGA and GEO public datasets supports the relevance of this pathway in human breast cancer, demonstrating that VEGF-C strongly correlates with activation of Hedgehog signaling and EMT in the human disease. Our study suggests that the VEGF-C/NRP2/GLI axis is a novel and conserved paracrine means by which EMT cells enhance metastasis, and provides potential targets for therapeutic intervention in this heterogeneous disease.
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http://dx.doi.org/10.1038/s41388-020-01539-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867573PMC
February 2021

Identification of signature genes associated with therapeutic resistance to anti-VEGF therapy.

Oncotarget 2020 Jan 7;11(1):99-114. Epub 2020 Jan 7.

Department of Pharmaceutical Sciences, College of Pharmacy, the University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.

VEGF-mediated tumor angiogenesis is a validated clinical target in many cancers, but modest efficacy and rapid development of resistance are major challenges of VEGF-targeted therapies. To establish a molecular signature of this resistance in ovarian cancer, we developed preclinical tumor models of adaptive resistance to chronic anti-VEGF treatment. We performed RNA-seq analysis and reverse-phase protein array to compare changes in gene and protein expressions in stroma and cancer cells from resistant and responsive tumors. We identified a unique set of stromal-specific genes that were strongly correlated with resistance phenotypes against two different anti-VEGF treatments, and selected the apelin/APJ signaling pathway for further validation. Using various functional assays, we showed that activation of apelin/APJ signaling reduces the efficacy of a VEGF inhibitor in endothelial cells. In patients with ovarian cancer treated with bevacizumab, increased expression of apelin was associated with significantly decreased disease-free survival. These findings link signature gene expressions with anti-VEGF response, and may thus provide novel targetable mechanisms of clinical resistance to anti-VEGF therapies.
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http://dx.doi.org/10.18632/oncotarget.27307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6967771PMC
January 2020

Multifunctional APJ Pathway Promotes Ovarian Cancer Progression and Metastasis.

Mol Cancer Res 2019 06 11;17(6):1378-1390. Epub 2019 Mar 11.

Department of Pharmaceutical Sciences, College of Pharmacy, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.

High mortality rates in ovarian cancer are due to late-stage diagnosis when extensive metastases are present, coupled with the eventual development of resistance to standard chemotherapy. There is, thus, an urgent need to identify targetable pathways to curtail this deadly disease. In this study, we show that the apelin receptor, APJ, is a viable target that promotes tumor progression of high-grade serous ovarian cancer (HGSOC). APJ is specifically overexpressed in tumor tissue, and is elevated in metastatic tissues compared with primary tumors. Importantly, increased APJ expression significantly correlates with decreased median overall survival (OS) by 14.7 months in patients with HGSOC. Using various ovarian cancer model systems, we demonstrate that APJ expression in cancer cells is both necessary and sufficient to increase prometastatic phenotypes , including proliferation, cell adhesion to various molecules of the extracellular matrix (ECM), anoikis resistance, migration, and invasion; and these phenotypes are efficiently inhibited by the APJ inhibitor, ML221. Overexpression of APJ also increases metastasis of ovarian cancer cells . Mechanistically, the prometastatic STAT3 pathway is activated downstream of APJ, and in addition to the ERK and AKT pathways, contributes to its aggressive phenotypes. Our findings suggest that the APJ pathway is a novel and viable target, with potential to curb ovarian cancer progression and metastasis. IMPLICATIONS: The APJ pathway is a viable target in HGSOC.
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http://dx.doi.org/10.1158/1541-7786.MCR-18-0989DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548659PMC
June 2019

Publisher Correction: EMT cells increase breast cancer metastasis via paracrine GLI activation in neighbouring tumour cells.

Nat Commun 2018 11 12;9(1):4720. Epub 2018 Nov 12.

Department of Pharmacology, University of Colorado-Denver, 12800 East 19th Avenue, Room P18-6115, Aurora, Colorado, 80045, USA.

This Article contains an error in Figure 2. In panel a, the second lane of the western blot should have been labelled 'siNT'. A correct version of Figure 2a appears in the Author Correction associated with this Article; the error has not been fixed in the original Article.
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http://dx.doi.org/10.1038/s41467-018-07168-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6232083PMC
November 2018

EMT cells increase breast cancer metastasis via paracrine GLI activation in neighbouring tumour cells.

Nat Commun 2017 06 12;8:15773. Epub 2017 Jun 12.

Department of Pharmacology, University of Colorado-Denver, 12800 East 19th Avenue, Room P18-6115, Aurora, Colorado 80045, USA.

Recent fate-mapping studies concluded that EMT is not required for metastasis of carcinomas. Here we challenge this conclusion by showing that these studies failed to account for possible crosstalk between EMT and non-EMT cells that promotes dissemination of non-EMT cells. In breast cancer models, EMT cells induce increased metastasis of weakly metastatic, non-EMT tumour cells in a paracrine manner, in part by non-cell autonomous activation of the GLI transcription factor. Treatment with GANT61, a GLI1/2 inhibitor, but not with IPI 926, a Smoothened inhibitor, blocks this effect and inhibits growth in PDX models. In human breast tumours, the EMT-transcription factors strongly correlate with activated Hedgehog/GLI signalling but not with the Hh ligands. Our findings indicate that EMT contributes to metastasis via non-cell autonomous effects that activate the Hh pathway. Although all Hh inhibitors may act against tumours with canonical Hh/GLI signalling, only GLI inhibitors would act against non-canonical EMT-induced GLI activation.
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http://dx.doi.org/10.1038/ncomms15773DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5472791PMC
June 2017

CD147: a small molecule transporter ancillary protein at the crossroad of multiple hallmarks of cancer and metabolic reprogramming.

Oncotarget 2017 Jan;8(4):6742-6762

Department of Biochemistry and Molecular Genetics, School of Medicine, University of Colorado Denver, CO, USA.

Increased expression of CD147 in pancreatic cancer has been proposed to play a critical role in cancer progression via CD147 chaperone function for lactate monocarboxylate transporters (MCTs). Here, we show for the first time that CD147 interacts with membrane transporters beyond MCTs and exhibits a protective role for several of its interacting partners. CD147 prevents its interacting partner's proteasome-dependent degradation and incorrect plasma membrane localization through the CD147 transmembrane (TM) region. The interactions with transmembrane small molecule and ion transporters identified here indicate a central role of CD147 in pancreatic cancer metabolic reprogramming, particularly with respect to amino acid anabolism and calcium signaling. Importantly, CD147 genetic ablation prevents pancreatic cancer cell proliferation and tumor growth in vitro and in vivo in conjunction with metabolic rewiring towards amino acid anabolism, thus paving the way for future combined pharmacological treatments.
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http://dx.doi.org/10.18632/oncotarget.14272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5341751PMC
January 2017

Clonal cooperativity in heterogenous cancers.

Semin Cell Dev Biol 2017 04 28;64:79-89. Epub 2016 Aug 28.

Program in Cancer Biology, University of Colorado School of Medicine, 12800 East 19th Avenue, Aurora, CO 80045, United States; Program in Molecular Biology, University of Colorado School of Medicine, 12800 East 19th Avenue, Aurora, CO 80045, United States; Department of Pharmacology, University of Colorado School of Medicine, 12800 East 19th Avenue, Aurora, CO 80045, United States. Electronic address:

Tumor heterogeneity is a major obstacle to the development of effective therapies and is thus an important focus of cancer research. Genetic and epigenetic alterations, as well as altered tumor microenvironments, result in tumors made up of diverse subclones with different genetic and phenotypic characteristics. Intratumor heterogeneity enables competition, but also supports clonal cooperation via cell-cell contact or secretion of factors, resulting in enhanced tumor progression. Here, we summarize recent findings related to interclonal interactions within a tumor and the therapeutic implications of such interactions, with an emphasis on how different subclones collaborate with each other to promote proliferation, metastasis and therapy-resistance. Furthermore, we propose that disruption of clonal cooperation by targeting key factors (such as Wnt and Hedgehog, amongst others) can be an alternative approach to improving clinical outcomes.
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http://dx.doi.org/10.1016/j.semcdb.2016.08.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5330947PMC
April 2017

TWIST1-Induced miR-424 Reversibly Drives Mesenchymal Programming while Inhibiting Tumor Initiation.

Cancer Res 2015 May 25;75(9):1908-21. Epub 2015 Feb 25.

Program in Molecular Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, Colorado. Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, Colorado.

Epithelial-to-mesenchymal transition (EMT) is a dynamic process that relies on cellular plasticity. Recently, the process of an oncogenic EMT, followed by a reverse mesenchymal-to-epithelial transition (MET), has been implicated as critical in the metastatic colonization of carcinomas. Unlike governance of epithelial programming, regulation of mesenchymal programming is not well understood in EMT. Here, we describe and characterize the first microRNA that enhances exclusively mesenchymal programming. We demonstrate that miR-424 is upregulated early during a TWIST1 or SNAI1-induced EMT, and that it causes cells to express mesenchymal genes without affecting epithelial genes, resulting in a mixed/intermediate EMT. Furthermore, miR-424 increases motility, decreases adhesion, and induces a growth arrest, changes associated with a complete EMT that can be reversed when miR-424 expression is lowered, concomitant with an MET-like process. Breast cancer patient miR-424 levels positively associate with TWIST1/2 and EMT-like gene signatures, and miR-424 is increased in primary tumors versus matched normal breast. However, miR-424 is downregulated in patient metastases versus matched primary tumors. Correspondingly, miR-424 decreases tumor initiation and is posttranscriptionally downregulated in macrometastases in mice, suggesting the need for biphasic expression of miR-424 to transit the EMT-MET axis. Next-generation RNA sequencing revealed miR-424 regulates numerous EMT and cancer stemness-associated genes, including TGFBR3, whose downregulation promotes mesenchymal phenotypes, but not tumor-initiating phenotypes. Instead, we demonstrate that increased MAPK-ERK signaling is critical for miR-424-mediated decreases in tumor-initiating phenotypes. These findings suggest miR-424 plays distinct roles in tumor progression, potentially facilitating earlier, but repressing later, stages of metastasis by regulating an EMT-MET axis.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-2394DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4417413PMC
May 2015

Intratumoral heterogeneity: Clonal cooperation in epithelial-to-mesenchymal transition and metastasis.

Cell Adh Migr 2015 16;9(4):265-76. Epub 2014 Oct 16.

a Department of Pharmacology ; University of Colorado; School of Medicine ; Aurora, CO USA.

Although phenotypic intratumoral heterogeneity was first described many decades ago, the advent of next-generation sequencing has provided conclusive evidence that in addition to phenotypic diversity, significant genotypic diversity exists within tumors. Tumor heterogeneity likely arises both from clonal expansions, as well as from differentiation hierarchies existent in the tumor, such as that established by cancer stem cells (CSCs) and non-CSCs. These differentiation hierarchies may arise due to genetic mutations, epigenetic alterations, or microenvironmental influences. An additional differentiation hierarchy within epithelial tumors may arise when only a few tumor cells trans-differentiate into mesenchymal-like cells, a process known as epithelial-to-mesenchymal transition (EMT). Again, this process can be influenced by both genetic and non-genetic factors. In this review we discuss the evidence for clonal interaction and cooperation for tumor maintenance and progression, particularly with respect to EMT, and further address the far-reaching effects that tumor heterogeneity may have on cancer therapy.
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http://dx.doi.org/10.4161/19336918.2014.972761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4594578PMC
May 2016