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Dive into the research topics where Kristen S. Hill is active.

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Featured researches published by Kristen S. Hill.


PLOS ONE | 2012

Met Receptor Tyrosine Kinase Signaling Induces Secretion of the Angiogenic Chemokine Interleukin-8/CXCL8 in Pancreatic Cancer

Kristen S. Hill; Ivana Gaziova; Lindsay J. Harrigal; Yvette A. Guerra; Suimin Qiu; Sarita K. Sastry; Thiruvengadam Arumugam; Craig D. Logsdon; Lisa A. Elferink

At diagnosis, the majority of pancreatic cancer patients present with advanced disease when curative resection is no longer feasible and current therapeutic treatments are largely ineffective. An improved understanding of molecular targets for effective intervention of pancreatic cancer is thus urgent. The Met receptor tyrosine kinase is one candidate implicated in pancreatic cancer. Notably, Met is over expressed in up to 80% of invasive pancreatic cancers but not in normal ductal cells correlating with poor overall patient survival and increased recurrence rates following surgical resection. However the functional role of Met signaling in pancreatic cancer remains poorly understood. Here we used RNA interference to directly examine the pathobiological importance of increased Met signaling for pancreatic cancer. We show that Met knockdown in pancreatic tumor cells results in decreased cell survival, cell invasion, and migration on collagen I in vitro. Using an orthotopic model for pancreatic cancer, we provide in vivo evidence that Met knockdown reduced tumor burden correlating with decreased cell survival and tumor angiogenesis, with minimal effect on cell growth. Notably, we report that Met signaling regulates the secretion of the pro-angiogenic chemokine interleukin-8/CXCL8. Our data showing that the interleukin-8 receptors CXCR1 and CXCR2 are not expressed on pancreatic tumor cells, suggests a paracrine mechanism by which Met signaling regulates interleukin-8 secretion to remodel the tumor microenvironment, a novel finding that could have important clinical implications for improving the effectiveness of treatments for pancreatic cancer.


Methods of Molecular Biology | 2008

Analysis of Receptor Tyrosine Kinase Internalization Using Flow Cytometry

Ning Li; Kristen S. Hill; Lisa A. Elferink

The internalization of activated receptor tyrosine kinases (RTKs) by endocytosis and their subsequent down regulation in lysosomes plays a critical role in regulating the duration and intensity of downstream signaling events. Uncoupling of the RTK cMet from ligand-induced degradation was recently shown to correlate with sustained receptor signaling and increased cell tumorigenicity, suggesting that the corruption of these endocytic mechanisms could contribute to increased cMet signaling in metastatic cancers. To understand how cMet signaling for normal cell growth is controlled by endocytosis and how these mechanisms are dysregulated in metastatic cancers, we developed flow cytometry-based assays to examine cMet internalization.


Oral Oncology | 2014

Silencing Met receptor tyrosine kinase signaling decreased oral tumor growth and increased survival of nude mice

X. Tao; Kristen S. Hill; Ivana Gaziova; Sarita K. Sastry; S. Qui; Peter Szaniszlo; Susan M. Fennewald; Vicente A. Resto; Lisa A. Elferink

OBJECTIVES The hepatocyte growth factor receptor (Met) is frequently overexpressed in Head and Neck Squamous Cell Carcinoma (HNSCC), correlating positively with high-grade tumors and shortened patient survival. As such, Met may represent an important therapeutic target. The purpose of this study was to explore the role of Met signaling for HNSCC growth and locoregional dissemination. MATERIALS AND METHODS Using a lentiviral system for RNA interference, we knocked down Met in established HNSCC cell lines that express high levels of the endogenous receptor. The effect of Met silencing on in vitro proliferation, cell survival and migration was examined using western analysis, immunohistochemistry and live cell imaging. In vivo tumor growth, dissemination and mouse survival was assessed using an orthotopic tongue mouse model for HNSCC. RESULTS We show that Met knockdown (1) impaired activation of downstream MAPK signaling; (2) reduced cell viability and anchorage independent growth; (3) abrogated HGF-induced cell motility on laminin; (4) reduced in vivo tumor growth by increased cell apoptosis; (5) caused reduced incidence of tumor dissemination to regional lymph nodes and (6) increased the survival of nude mice with orthotopic xenografts. CONCLUSION Met signaling is important for HNSCC growth and locoregional dissemination in vivo and that targeting Met may be an important strategy for therapy.


Journal of Biological Chemistry | 2009

Met receptor tyrosine kinase degradation is altered in response to the leucine-rich repeat of the Listeria invasion protein internalin B.

Xiu Gao; Marta Lorinczi; Kristen S. Hill; Natasha C. Brooks; Hatem Dokainish; Keith Ireton; Lisa A. Elferink

Entry of the bacterial pathogen Listeria monocytogenes into host epithelial cells is critical for infection and virulence. One major pathway for Listeria entry involves binding of the bacterial protein Internalin B to the host receptor tyrosine kinase Met (hepatocyte growth factor receptor). Activation of Met and downstream signaling cascades is critical for Listeria entry. Internalin B is composed of several structural domains including an N-terminal leucine-rich repeat that is sufficient for binding Met and stimulating downstream signal transduction. Internalin B is monomeric, whereas the leucine-rich repeat is dimeric when expressed as an isolated fragment. The different quaternary states of Internalin B and the leucine-rich repeat suggest that these two Met ligands might cause distinct biological effects. Here we demonstrate that Internalin B and the leucine-rich repeat fragment exhibit agonist properties that differentially influence Met down-regulation in lysosomes. Specifically, Met stability is increased in response to the leucine-rich repeat fragment compared with Internalin B. Interestingly, Internalin B and the leucine-rich repeat stimulate equivalent rates of clathrin-mediated Met internalization. However, the leucine-rich repeat is defective in promoting lysosomal down-regulation of Met and instead enhances receptor recycling to the cell surface. In addition, the leucine-rich repeat causes prolonged Met activation (phosphorylation) and increased cell motility compared with Internalin B. Taken together, our findings indicate that individual domains of Internalin B differentially regulate Met trafficking. The ability of the leucine-rich repeat fragment to promote Met recycling could account for the increased cell motility induced by this ligand.


Cancer Research | 2018

Abstract 4364: R-Ras activation cooperates with BRAF mutation in melanoma tumorigenesis

Kristen S. Hill; Evan R. Roberts; Xue Wang; Young-Chul Kim; Jane L. Messina; Minjung Kim

The Ras family of small GTP binding proteins are tightly regulated through a complex network of proteins. In melanoma the Ras signaling pathway is frequently activated by mutations in NRAS (20%), KRAS (2%) and HRAS (1%); alternatively, Ras can also be activated by the inactivation of Ras GTPase activating proteins (RasGAPs) such as NF1, RASA1, and RASA2. Recently, we observed that inactivation of RASA1 (RAS p21 protein activator 1, also called p120RasGAP) suppressed melanoma via its RasGAP activity toward the R-Ras (related RAS viral (r-ras) oncogene homolog) isoform and that R-Ras was required to promote anchorage-independent growth driven by RASA1 inactivation. Moreover, a low level of RASA1 mRNA expression is associated with decreased overall survival in melanoma patients with BRAF mutations. Based on these observations, we hypothesized that, although not mutated, R-Ras is activated in melanoma by inactivation of RasGAPs and that BRAF activation cooperates with this RasGAP/R-Ras pathway activation in melanoma tumorigenesis. In this study, we addressed the importance of R-Ras, a previously less appreciated member of the Ras small GTPases family, in melanoma tumorigenesis. We observed frequent activation of R-Ras in BRAF mutant human melanoma cell lines and human melanoma specimens. In addition, RNAi-mediated knockdown of R-Ras suppressed anchorage-independent colony growth and tumor growth. Of the 3 major RAS effector pathways, specifically MEK/ERK, AKT and Ral-A, reduced R-Ras expression suppressed Ral-A activation, which may explain the mechanism of Ral-A activation in BRAF mutant melanoma. Interestingly, anchorage-independent growth driven by R-Ras activation downstream of RASA1 inactivation was suppressed by both genetic (siRNA targeting Ral-A) and pharmacological (Ral inhibitor BQU57) inhibition of Ral-A. To further investigate the impact of RASA1 loss, and thus R-Ras activation, on BRAF mutant melanoma development in vivo, we generated a Rasa1L/L; BRAFCA/CA; Tyr-CreERT2 mouse model in which treatment with 4OHT results in expression of constitutively activated mutant BRAF and deletion of Rasa1 in melanocytic lineage cells. Preliminary analysis shows hyperpigmentation of the ear, tail, and foot pad in Rasa1L/L BRAFCA/CA mice compared to Rasa1+/+ BRAFCA/CA littermates; as well as, the development of cutaneous melanoma in Rasa1 deficient mice. Tumors generated in this animal model will be analyzed to determine the extent of R-Ras and Ral-A activity in vivo. This study demonstrates the importance of the RASA1/R-Ras/Ral-A signaling pathway in BRAF mutant melanoma and supports the possible combinatorial treatment strategy targeting both the BRAF/MAPK and Ral signaling pathways. Citation Format: Kristen S. Hill, Evan R. Roberts, Xue Wang, Youngchul Kim, Jane Messina, Minjung Kim. R-Ras activation cooperates with BRAF mutation in melanoma tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4364.


Cancer Research | 2018

Abstract A04: Cross-species oncogenomics approach identifies PTPN11 as an oncogene and potential therapeutic target in melanoma

Kristen S. Hill; Xue Wang; Evan R. Roberts; Ellen Marin; Jamie K. Teer; Young-Chul Kim; Jane L. Messina; Jie Wu; Minjung Kim

Melanoma is a deadly disease carrying many genetic mutations. A major challenge to the development of effective targeted therapies in melanoma is the identification of true “driver” mutations among numerous “passenger” alterations. Several previous studies support using cross-species comparative oncogenomic approaches for cancer gene discovery. Specifically, it has been shown that mice and humans share several genetic events in the development of cancer and that these events that are conserved across different species may point to functionally important and evolutionary conserved alterations targeting “driver” genes. Recently, we analyzed melanoma genomes from a mouse model driven by the loss of PTEN and CDKN2A (INK4A/ARF), commonly observed alterations in human melanoma patients, by whole-exome sequencing. This study identified several conserved cross-species orthologous mutations in Kras , Erbb3 , and Ptpn11 . In this study, we addressed the functional roles of PTPN11 in melanoma tumorigenesis and tumor maintenance, its effect on RAS/RAF/MEK/ERK signaling pathway, and its activation status in human melanoma. Melanoma displays frequent activation of the RAS/RAF/MEK/ERK signaling pathway, which is intricately regulated by multiple proteins including PTPN11 (Tyrosine-Protein Phosphatase Non-Receptor Type 11, encoding SHP2). Although implicated as an oncogene in multiple cancer types, the oncogenic role of PTPN11 has not been fully established in melanoma. PTPN11 can be activated by receptor tyrosine kinases (RTKs) and/or by point mutations. Although the mutation rate is low (1~3%), we observed activating phosphorylation on Tyr 542 of PTPN11 in 40% (n=15/38) of melanoma specimens and the majority of human melanoma cell lines (n=14), indicating the potential frequent activation of PTPN11 in human melanoma. PTPN11 knock-down suppressed ERK activation in NRAS mutant (WM1361A, 1366, 1346) and BRAF/NRAS wt (WM3211, MeWo, CHL1) melanoma cells, but not in BRAF mutant (1205Lu, IGR1, 983C) cells. Moreover, we have shown that the expression of active PTPN11 E76K mutant drives soft-agar colony growth in vitro, tumor growth in nude mice, RAS/RAF/MEK/ERK activation, and resistance to MEK inhibition, whereas knock-down of Ptpn11 reduces colony growth and ERK activation. We generated a tet -inducible, melanocyte-specific, PTPN11 E76K transgenic mouse model in a Pten and Cdkn2a null background and observed melanoma formation. Implantation of melanoma cells derived from this model showed doxycycline-dependent tumor growth in nude mice; additionally, withdrawal of doxycycline and subsequent extinction of PTPN11 E76K caused regression of established tumors, supporting a tumor-maintenance role of PTPN11. These data support the oncogenic roles of PTPN11 in melanoma by regulating RAS/RAF/MAPK pathway activation and the value of PTPN11 as a novel and actionable therapeutic target. Citation Format: Kristen S. Hill, Xue Wang, Evan R. Roberts, Ellen M. Marin, Jamie K. Teer, Youngchul Kim, Jane Messina, Jie Wu, Minjung Kim. Cross-species oncogenomics approach identifies PTPN11 as an oncogene and potential therapeutic target in melanoma [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A04.


Cancer Research | 2017

Abstract B12: The importance of the RASA1/R-Ras/Ral-A signaling axis in melanoma tumorigenesis

Kristen S. Hill; Xue Wang; Evan R. Roberts; Young-Chul Kim; Jane L. Messina; Minjung Kim

The Ras family of small GTP-binding proteins is frequently activated by mutations, including NRAS (20%), KRAS (2%), and HRAS (1%), in melanoma. In addition to mutations, Ras isoforms can also be activated by the inactivation of Ras GTPase activating proteins (RasGAPs), such as NF1 , RASA1 , and RASA2 . In our recent study, we observed that the inactivation of RASA1 (RAS p21 protein activator 1, also called p120RasGAP) suppressed melanoma via its RasGAP activity toward the R-Ras (related RAS viral (r-ras) oncogene homolog) isoform. We hypothesized that, although not mutated, R-Ras is activated in melanoma through the inactivation of RasGAPs and that RasGAP/R-Ras pathway activation cooperates with BRAF activation in melanoma tumorigenesis. In this study, we addressed the importance of R-Ras, a previously less-appreciated member of the Ras family, in melanoma tumorigenesis and investigated the molecular mechanisms underlying R-Ras signaling in BRAF mutant melanoma. We observed frequent activation of R-Ras in BRAF mutant human melanoma cell lines. In addition, RNAi-mediated reduced expression of R-Ras suppressed anchorage-independent colony growth and tumor growth. Moreover, among the three major RAS effector pathways, reduced R-Ras expression suppressed Ral-A activation, which may explain the mechanism of Ral-A activation in BRAF mutant melanoma. Interestingly, anchorage-independent growth driven by RASA1 inactivation and subsequent R-Ras activation was suppressed by both genetic (siRNA targeting Ral-A) and pharmacologic (Ral inhibitor BQU57) inhibition of Ral-A. To further investigate the impact of RASA1 loss, and thus R-Ras activation, on BRAF mutant melanoma development in vivo, we generated a RASA1 L/L ; BRAF CA/CA ; Tyr-CreERT2 mouse model in which treatment with 4OHT results in the expression of constitutively activated mutant BRAF and the deletion of RASA1 in melanocytic lineage cells. Preliminary analysis shows hyperpigmentation of the ear, tail, and foot pad in RASA1 L/L BRAF CA/CA mice compared to RASA1 +/+ BRAF CA/CA littermates and the development of melanoma in RASA1 mutant mice. This study demonstrates the importance of the RASA1/R-Ras/Ral-A signaling pathway in BRAF mutant melanoma and supports the possible combinatorial treatment strategy targeting both the BRAF/MAPK and Ral signaling pathways. Citation Format: Kristen S. Hill, Xue Wang, Evan R. Roberts, Youngchul Kim, Jane Messina, Minjung Kim. The importance of the RASA1/R-Ras/Ral-A signaling axis in melanoma tumorigenesis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B12.


Cancer Research | 2016

Abstract 4164: Synergism between NEDD9 overexpression and loss of PTEN and INK4A/ARF in melanoma tumorigenesis

Kristen S. Hill; Xue Wang; Young-Chul Kim; Jane L. Messina; Minjung Kim

The fact that melanoma, the most aggressive form of skin cancer, is driven by multiple combinations of genetic lesions has supported the use of genetically engineered mouse (GEM) models in validating the etiological and biological roles of oncogenes and tumor suppressors. Most of the currently studied mouse melanoma models are driven by RAS/RAF/MAPK activation via activating RAS or RAF mutations in combination with loss of INK4A/ARF or PTEN; therefore, BRAF/NRAS wild-type melanoma remains less well characterized and the overall survival of patients with metastatic BRAF/NRAS wild-type melanoma remains poor. In this study, we investigated the hypothesis that NEDD9 could synergize with the loss of PTEN and INK4A/ARF in melanoma tumorigenesis. This hypothesis is based on our observation of an inverse correlation between PTEN expression and levels of NEDD9 gene expression in human melanoma samples. NEDD9 (neural precursor derived, developmentally downregulated gene 9) was previously identified by us as a target of a recurrent focal amplification, associated with acquisition of metastatic potential in the RAS-Ink/Arf model. We have shown that NEDD9 is up-regulated in 35∼50% of metastatic melanomas and enhances proliferation and invasion. First, we demonstrated that NEDD9 cooperated with PTEN loss in Ink4a/Arf-/- melanocytes to enhance cell proliferation, anchorage independent growth, and invasion in vitro. Additionally, when melanocytes were injected into nude mice either subcutaneously or intravenously, NEDD9 overexpression facilitated increased tumor growth and lung seeding, respectively. Further analysis showed that NEDD9 expression correlated with increased phosphorylation of ERK, SFKs (Src family kinases), AKT2, and STAT3. Of these pathways we have demonstrated through the use of small molecule inhibitors that both ERK and AKT2 signaling are required for the enhanced anchorage independent growth observed in NEDD9 overexpressing melanocytes. In addition, we generated a mouse model based on loss of PTEN and INK4A/ARF with or without NEDD9 upregulation. To do this, we generated a tet-inducible NEDD9 allele that carries a doxycycline-responsive, melanocyte-targeted NEDD9. These mice were crossed with a strain containing floxed PTEN and INK4A/ARF in combination with a melanocyte-targeted CreERT2. The development of cutaneous and ocular melanomas in these mice was enhanced by NEDD9 induction. This study will generate a body of knowledge for the in vivo roles of NEDD9 in melanoma tumorigenesis and identify signaling pathways that could be therapeutically targeted to treat patients with BRAF/NRAS wild-type melanoma Citation Format: Kristen S. Hill, Xue Wang, Youngchul Kim, Jane L. Messina, Minjung Kim. Synergism between NEDD9 overexpression and loss of PTEN and INK4A/ARF in melanoma tumorigenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4164.


Cancer Research | 2016

Abstract 1863: Inactivation of RASA1 promotes melanoma tumorigenesis via R-Ras activation

Kristen S. Hill; Hyeran Sung; Krishna L. Kanchi; Jane L. Messina; Ji-Hyun Lee; Young-Chul Kim; Li Ding; Richard Wilson; Jeffrey S. Weber; Minjung Kim

Hyperactivation of the Ras/Raf/Mitogen-activated protein kinase (MAPK) pathway has been commonly observed in melanoma via frequent activating mutations in NRAS and BRAF. Novel mutations in other components of this pathway such as MEK1, MEK2, MAP3K5, and MAP3K9 have been reported recently by high-throughput sequencing efforts. In addition, Ras GTPase activating proteins (RasGAPs) that negatively regulate Ras, such as NF1 (neurofibromatosis type 1) and RASA2, have been shown to be mutated or suppressed in melanoma. However, importance of other RasGAPs in melanoma has not been addressed. To obtain a comprehensive view of melanoma genomes, we conducted whole genome sequencing (WGS) of 15 metastatic melanomas and matched normal PBMC genomes from 13 melanoma patients. All melanoma genomes from these 13 patients contained at least one mutation in genes of Ras-Raf-MAPK pathway (MAPK1, MAP3K1, MAP4K2, MAP3K14, NRAS, and BRAF). In addition, we identified two novel, clustered somatic missense mutations (p.Tyr472His and p.Leu481Phe) in RASA1 (RAS p21 protein activator 1, p120RasGAP). In this study, we addressed functional roles of RASA1 in melanoma tumorigenesis. The RNAi-mediated down-regulation of RASA1 promoted, while ectopic expression of wild type RASA1 decreased, anchorage-independent colony formation, tumor growth, and RAS activation. Interestingly, RASA1 Y472H mutant enhanced soft agar colony formation and tumor growth, while RASA1 L481F mutant lost its tumor suppressive activity. Mechanistically, RASA1 required RasGAP activity to suppress colony formation and showed higher activity toward R-Ras (related RAS viral (r-ras) oncogene homolog) isoform among the Ras superfamily of small GTPases. Moreover, RASA1 consistently suppressed Ral-A among Ras downstream effectors. Reduced R-Ras or Ral-A expression via siRNAs suppressed anchorage-independent growth induced by RASA1 loss. Interestingly, RASA1 expression was frequently down-regulated in metastatic melanoma samples (11.4% (4/35) of lymph node metastasis and 3.4% (1/29) of distal metastases) compared to primary melanomas (33.3% (21/63)) and dysplastic nevi (44.1% (15/34)). We also observed significantly shorter overall survival of melanoma patients with BRAF mutations when RASA1 mRNA expression is low, which may be explained by possible cooperative interactions between activation of BRAF/MAPK/ERK and RASA1/R-Ras/Ral-A pathways. Taken together, these data support that RASA1 is a novel melanoma tumor suppressor that is inactivated by suppressed expression or by mutation. Citation Format: Kristen S. Hill, Hyeran Sung, Krishna L. Kanchi, Jane L. Messina, Ji-Hyun Lee, Youngchul Kim, Li Ding, Richard K. Wilson, Jeffrey S. Weber, Minjung Kim. Inactivation of RASA1 promotes melanoma tumorigenesis via R-Ras activation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1863.


Neoplasia | 2013

Regulation of HGF Expression by ΔEGFR-Mediated c-Met Activation in Glioblastoma Cells

Jeannine Garnett; Vaibhav Chumbalkar; Brian Vaillant; Anupama E. Gururaj; Kristen S. Hill; Khatri Latha; Jun Yao; Waldemar Priebe; Howard Colman; Lisa A. Elferink; Oliver Bögler

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Lisa A. Elferink

University of Texas Medical Branch

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Jane L. Messina

University of South Florida

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Young-Chul Kim

Chonnam National University

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Jamie K. Teer

University of South Florida

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Marta Lorinczi

University of Texas Medical Branch

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Anupama E. Gururaj

University of Texas MD Anderson Cancer Center

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Brian Vaillant

University of Texas MD Anderson Cancer Center

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Howard Colman

Huntsman Cancer Institute

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Ivana Gaziova

University of Texas Medical Branch

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