Steven M Frisch

West Virginia University, Morgantown, West Virginia, United States

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Publications (37)370.96 Total impact

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    Benjamin Cieply · Colton Koontz · Steven M. Frisch ·
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    ABSTRACT: The detachment of normal epithelial cells from matrix triggers an apoptotic response known as anoikis, during homeostatic turnover. Metastatic tumor cells evade anoikis, by mechanisms that are only partly characterized. In particular, the epithelial-mesenchymal transition (EMT) in a subset of invasive tumor cells confers anoikis-resistance. In some cases, EMT up-regulates the cancer stem cell marker CD44S and the enzyme hyaluronic acid synthase-2 (HAS2). CD44S is the major receptor for hyaluronan in the extracellular matrix. Herein, we demonstrate that CD44S, unlike the CD44E isoform expressed in normal epithelial cells, contributes to the protection against anoikis. This protection requires the interaction of CD44S with hyaluronan (HA). CD44S-HA interaction is proposed to play an important role in in tumor metastasis through enhanced cell survival under detached conditions. Copyright © 2015. Published by Elsevier B.V.
    Matrix biology: journal of the International Society for Matrix Biology 04/2015; 124. DOI:10.1016/j.matbio.2015.04.010 · 5.07 Impact Factor
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    Steven M Frisch · Michael D Schaller ·
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    ABSTRACT: In this issue of Cancer Cell, Li and colleagues demonstrate that the hematopoietic transcription factor Aiolos (named after the Wind God of Greek mythology) confers anoikis resistance in lung tumor cells through repression of cell adhesion-related genes including the mechanosensor p66Shc.
    Cancer cell 05/2014; 25(5):551-2. DOI:10.1016/j.ccr.2014.04.022 · 23.52 Impact Factor
  • Benjamin Cieply · Joshua Farris · James Denvir · Heide L. Ford · Steven M Frisch ·
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    ABSTRACT: The oncogenic Epithelial-Mesenchymal Transition (EMT) enhances malignant progression by promoting invasion and survival of tumor cells. EMT is induced by microenvironmental factors including TGF-β and Wnt agonists, and transcription factors including the E-box binding factors Twist, Snail and ZEB. Previously, we reported that a member of the mammalian Grainyhead family of wound healing-regulatory transcription factors, Grainyhead-like-2 (GRHL2), suppresses EMT and restores sensitivity to anoikis by repressing ZEB1 expression and inhibiting TGF-β signaling. Here, we elucidate the functional relationship between GRHL2 and ZEB1 in EMT/MET and tumor biology. At least three homeodomain proteins, Six1, LBX1, and HoxA5, transactivated the ZEB1 promoter; for Six1, this occurred through direct protein-promoter interaction. GRHL2 altered the Six1-DNA complex, inhibiting this transactivation. Correspondingly, GRHL2 expression prevented tumor initiation in xenograft assays, sensitized breast cancer cells to paclitaxel, and suppressed the emergence of CD44highCD24low cells in a cell line where this marker set correlates with cancer stem cell phenotype. GRHL2 was down-regulated in recurrent mouse tumors that had evolved to an oncogene-independent, EMT-like state, supporting a role for GRHL2 down-regulation in this tumor phenotype transition modeling disease recurrence. The combination of TGF-β and Wnt activation repressed GRHL2 expression through direct interaction of ZEB1 with the GRHL2 promoter, inducing EMT. These observations indicate that a reciprocal feedback loop between GRHL2 and ZEB1 controls epithelial vs. mesenchymal phenotypes and EMT-driven tumor progression.
    Cancer Research 08/2013; 73(19 Supplement). DOI:10.1158/0008-5472.CAN-12-4082 · 9.33 Impact Factor
  • Sun Hee Park · Philip Riley · Steven M Frisch ·
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    ABSTRACT: Anoikis-resistance of tumor cells is critical for anchorage-independent growth and metastasis. The inflammatory-response transcription factor NF-κB contributes to anoikis-resistance and tumor progression through mechanisms that are understood incompletely. Deleted in breast cancer-1 (DBC1) protein (KIAA1967) is over-expressed in several tumor types, and correlates with a poorer prognosis in some cases. We report here that DBC1 suppressed anoikis in normal epithelial and breast cancer cell lines. DBC1 interacted with IKK-β, stimulating its kinase activity, promoting NF-κB transcriptional activity through the phosphorylation of relA serine-536 and enhancing the expression of the NF-κB target genes, c-FLIP and bcl-xl. Our results indicate that DBC1 is an important co-factor for the control of the IKK-β-NF-κB signaling pathway that regulates anoikis.
    Apoptosis 04/2013; 18(8). DOI:10.1007/s10495-013-0847-1 · 3.69 Impact Factor
  • Steven M Frisch · Michael Schaller · Benjamin Cieply ·
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    ABSTRACT: The oncogenic epithelial-mesenchymal transition (EMT) contributes to tumor progression in various context-dependent ways, including increased metastatic potential, expansion of cancer stem cell subpopulations, chemo-resistance and disease recurrence. One of the hallmarks of EMT is resistance of tumor cells to anoikis. This resistance contributes to metastasis and is a defining property not only of EMT but also of cancer stem cells. Here, we review the mechanistic coupling between EMT and resistance to anoikis. The discussion focuses on several key aspects. First, we provide an update on new pathways that lead from the loss of E-cadherin to anoikis resistance. We then discuss the relevance of transcription factors that are crucial in wound healing in the context of oncogenic EMT. Next, we explore the consequences of the breakdown of cell-polarity complexes upon anoikis sensitivity, through the Hippo, Wnt and transforming growth factor β (TGF-β) pathways, emphasizing points of crossregulation. Finally, we summarize the direct regulation of cell survival genes through EMT-inducing transcription factors, and the roles of the tyrosine kinases focal adhesion kinase (FAK) and TrkB neurotrophin receptor in EMT-related regulation of anoikis. Emerging from these studies are unifying principles that will lead to improvements in cancer therapy by reprogramming sensitivity of anoikis.
    Journal of Cell Science 03/2013; 126(Pt 1):21-9. DOI:10.1242/jcs.120907 · 5.43 Impact Factor

  • Cancer Research 06/2012; 72(8 Supplement):3436-3436. DOI:10.1158/1538-7445.AM2012-3436 · 9.33 Impact Factor
  • Sun Park · Philip A. Riley · Benjamin Cieply · Steven M. Frisch ·

    Cancer Research 04/2012; 72(8 Supplement):4956-4956. DOI:10.1158/1538-7445.AM2012-4956 · 9.33 Impact Factor
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    ABSTRACT: Grainyhead genes are involved in wound healing and developmental neural tube closure. In light of the high degree of similarity between the epithelial-mesenchymal transitions (EMT) occurring in wound-healing processes and the cancer stem cell-like compartment of tumors, including TGF-β dependence, we investigated the role of the Grainyhead gene, Grainyhead-like-2 (GRHL2) in oncogenic EMT. GRHL2 was downregulated specifically in the claudin-low subclass breast tumors and in basal-B subclass breast cancer cell lines. GRHL2 suppressed TGF-β-induced, Twist-induced or spontaneous EMT, enhanced anoikis sensitivity, and suppressed mammosphere generation in mammary epithelial cells. These effects were mediated in part by suppression of ZEB1 expression via direct repression of the ZEB1 promoter. GRHL2 also inhibited Smad-mediated transcription and it upregulated mir-200b/c as well as the TGF-β receptor antagonist, BMP2. Finally, ectopic expression of GRHL2 in MDA-MB-231 breast cancer cells triggered an MET and restored sensitivity to anoikis. Taken together, our findings define a major role for GRHL2 in the suppression of oncogenic EMT in breast cancer cells.
    Cancer Research 03/2012; 72(9):2440-53. DOI:10.1158/0008-5472.CAN-11-4038 · 9.33 Impact Factor
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    ABSTRACT: Detachment of epithelial cells from matrix or attachment to an inappropriate matrix engages an apoptotic response known as anoikis, which prevents metastasis. Cellular sensitivity to anoikis is compromised during the oncogenic epithelial-to-mesenchymal transition (EMT), through unknown mechanisms. We report here a pathway through which EMT confers anoikis resistance. NRAGE (neurotrophin receptor-interacting melanoma antigen) interacted with a component of the E-cadherin complex, ankyrin-G, maintaining NRAGE in the cytoplasm. Oncogenic EMT downregulated ankyrin-G, enhancing the nuclear localization of NRAGE. The oncogenic transcriptional repressor protein TBX2 interacted with NRAGE, repressing the tumor suppressor gene p14ARF. P14ARF sensitized cells to anoikis; conversely, the TBX2/NRAGE complex protected cells against anoikis by downregulating this gene. This represents a novel pathway for the regulation of anoikis by EMT and E-cadherin.
    Molecular and Cellular Biology 07/2011; 31(19):4036-51. DOI:10.1128/MCB.01342-10 · 4.78 Impact Factor
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    Michael D Schaller · Steven M Frisch ·
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    ABSTRACT: Commentary to:PND-1186 FAK inhibitor selectively promotes tumor cell apoptosis in three-dimensional environmentsIsabelle Tanjoni, Colin Walsh, Sean Uryu, Alok Tomar, Ju-Ock Nam, Ainhoa Mielgo, Ssang-Taek Lim, Congxin Liang, Marcel Koenig, Neela Patel, Cheni Kwok, Gerald McMahon, Dwayne G. Stupack and David D. Schlaepfer
    Cancer biology & therapy 05/2010; 9(10):791-3. DOI:10.4161/cbt.11729 · 3.07 Impact Factor
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    Steven M Frisch ·
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    ABSTRACT: Recent studies have revealed that procaspase-8 has an important function in cell adhesion and motility. Src phosphorylation controls this function by preventing the conversion of procaspase-8, which is an adhesion/migration factor, to mature caspase-8, which is an apoptosis-inducing factor. This provides a mechanism to switch these opposing functions. In its migratory role, procaspase-8 interacts with the phosphatidylinositol-3-OH kinase regulatory subunit p85alpha and c-src to modulate signaling by Rac and extracellular signal-regulated kinase, and promote calpain activation. Here, I survey the findings of these studies and discuss potential mechanisms and ramifications for cancer prognosis and therapy.
    Cancer Research 07/2008; 68(12):4491-3. DOI:10.1158/0008-5472.CAN-08-0952 · 9.33 Impact Factor
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    Jamie Senft · Brooke Helfer · Steven M Frisch ·
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    ABSTRACT: Cell migration plays an important role in tumor cell invasion and metastasis. Previously, we reported that caspase-8 contributes to cell migration and adhesion, a novel nonapoptotic function of an established apoptotic factor. Herein, we report that pro-caspase-8 is capable of restoring cell migration/adhesion to caspase-8-null cells, establishing the first biological function of a pro-caspase. The catalytic activity of caspase-8 was not required for cell motility. Stimulation of motility with epidermal growth factor induced the phosphorylation of caspase-8 on tyrosine-380 and the interaction of caspase-8 with the p85 alpha subunit of phosphatidylinositol 3-kinase. Tyrosine-380 was required for the restoration of cell motility and cell adhesion in caspase-8-null cells, demonstrating the importance of the caspase-8-p85 interaction for these nonapoptotic functions. These results suggest that caspase-8 phosphorylation converts it from a proapoptotic factor to a cell motility factor that, through tyrosine-380, interacts with p85, an established cell migration component.
    Cancer Research 01/2008; 67(24):11505-9. DOI:10.1158/0008-5472.CAN-07-5755 · 9.33 Impact Factor
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    ABSTRACT: Tumor necrosis factor-alpha (TNF) activates caspase-8 to cleave effector caspases or Bid, resulting in type-1 or type-2 apoptosis, respectively. We show here that TNF also induces caspase-8-dependent C-terminal cleavage of the retinoblastoma protein (Rb). Interestingly, fibroblasts from Rb(MI/MI) mice, in which the C-terminal caspase cleavage site is mutated, exhibit a defect in Bid cleavage despite caspase-8 activation. Recent results suggest that TNF receptor endocytosis is required for the activation of caspase-8. Consistent with this notion, inhibition of V-ATPase, which plays an essential role in acidification and degradation of endosomes, specifically restores Bid cleavage in Rb(MI/MI) cells. Inhibition of V-ATPase sensitizes Rb(MI/MI) but not wild-type fibroblasts to TNF-induced apoptosis and stimulates inflammation-associated colonic apoptosis in Rb(MI/MI) but not wild-type mice. These results suggest that Rb cleavage is required for Bid cleavage in TNF-induced type-2 apoptosis, and this requirement can be supplanted by the inhibition of V-ATPase.
    Journal of Biological Chemistry 11/2007; 282(40):29401-13. DOI:10.1074/jbc.M702261200 · 4.57 Impact Factor
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    ABSTRACT: Significant caspase-8 activity has been found in normal and certain tumor cells, suggesting that caspase-8 possesses an alternative, nonapoptotic function that may contribute to tumor progression. In this article, we report that caspase-8 promotes cell motility. In particular, caspase-8 is required for the optimal activation of calpains, Rac, and lamellipodial assembly. This represents a novel nonapoptotic function of caspase-8 acting at the intersection of the caspase-8 and calpain proteolytic pathways to coordinate cell death versus cell motility signaling.
    Cancer Research 05/2006; 66(8):4273-8. DOI:10.1158/0008-5472.CAN-05-4183 · 9.33 Impact Factor
  • Steven M Frisch ·

    Clinical Cancer Research 06/2004; 10(9):2905-7. · 8.72 Impact Factor
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    S. M. Frisch ·

    Clinical Cancer Research 05/2004; 10(9):2905-2907. DOI:10.1158/1078-0432.CCR-04-0644 · 8.72 Impact Factor
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    ABSTRACT: Genetic knockout of the transcriptional corepressor CtBP in mouse embryo fibroblasts upregulates several genes involved in apoptosis. We predicted, therefore, that a propensity toward apoptosis might be regulated through changes in cellular CtBP. To identify pathways involved in this regulation, we screened a mouse embryo cDNA library with an E1A-CtBP complex and identified the homeodomain interacting protein kinase 2 (HIPK2), which had previously been linked to UV-directed apoptosis through its ability to phosphorylate p53. Expression of HIPK2 or exposure to UV irradiation reduced CtBP levels via a proteosome-mediated pathway. The UV effect was prevented by coexpression of kinase-inactive HIPK2 or reduction in HIPK2 levels via siRNA. Mutation of the residue phosphorylated by HIPK2 prevented UV- and HIPK2-directed CtBP clearance. Finally, reduction in CtBP levels, either by genetic knockout or siRNA, promoted apoptosis in p53-deficient cells. These findings provide a pathway for UV-induced apoptosis in cells lacking p53.
    Cell 10/2003; 115(2):177-86. DOI:10.1016/S0092-8674(03)00802-X · 32.24 Impact Factor
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    Steven M. Frisch ·
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    ABSTRACT: This project is investigating the role of microtubule alterations in anoikis, with a view toward re-examining the mechanism of microtubule-targeting drugs such as taxol. During the past year, we have uncovered a new mechanism by which cell adhesion controls apoptosis. The death receptor adaptor protein FADD (FAS-associated death domain protein) is critical for anoikis as well as death ligand (e.g., FASL) induced apoptosis. Recently, we discovered that FADD is primarily in the nucleus of attached cells, where it is unavailable for apoptosis induction. Detachment of mammary epithelial cells form extracellular matrix, however, provokes the export of FADD form the nucleus, thus promoting apoptosis. Our preliminary work suggests that microtubule drugs can promote FADD export, suggesting a new mechanism by which the can promote apoptosis. This is expected to have major ramifications for optimizing the use of taxol or other microtubule drugs in connection with other agents that may promote apoptosis. During the latter year of the project, we found that a protein kinase known as Glycogen Synthase Kinase-3 (GSK-3) phosphorylates FADD and that this phosphorylation is required for both the transport of FADD into and out of the nucleus. In that GSD-3 is a microtubule-regulatory kinase, this represents a new link between microtubules and apoptosis.
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    ABSTRACT: Fas-associated death domain protein (FADD) is an adaptor protein bridging death receptors with initiator caspases. Thus, its function and localization are assumed to be cytoplasmic, although the localization of endogenous FADD has not been reported. Surprisingly, the data presented here demonstrate that FADD is mainly nuclear in several adherent cell lines. Its accumulation in the nucleus and export to the cytoplasm required the phosphorylation site Ser-194, which was also required for its interaction with the nucleocytoplasmic shuttling protein exportin-5. Within the nucleus, FADD interacted with the methyl-CpG binding domain protein 4 (MBD4), which excises thymine from GT mismatches in methylated regions of chromatin. The MBD4-interacting mismatch repair factor MLH1 was also found in a complex with FADD. The FADD-MBD4 interaction involved the death effector domain of FADD and a region of MBD4 adjacent to the glycosylase domain. The FADD-binding region of MBD4 was downstream of a frameshift mutation that occurs in a significant fraction of human colorectal carcinomas. Consistent with the idea that MBD4 can signal to an apoptotic effector, MBD4 regulated DNA damage-, Fas ligand-, and cell detachment-induced apoptosis. The nuclear localization of FADD and its interaction with a genome surveillance/DNA repair protein that can regulate apoptosis suggests a novel function of FADD distinct from direct participation in death receptor signaling complexes.
    Proceedings of the National Academy of Sciences 05/2003; 100(9):5211-6. DOI:10.1073/pnas.0431215100 · 9.67 Impact Factor
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    ABSTRACT: The genesis of carcinoma cells often involves epithelial-to-mesenchymal transitions and the acquisition of apoptosis resistance, but it is unclear whether these alterations are controlled coordinately or independently. Our previously reported effects of adenovirus E1a in human tumor cells raised the possibility that the E1a-interacting corepressor protein C-terminal-binding protein (CtBP) might selectively repress epithelial cell adhesion and proapoptotic genes. Here, we report that CtBP-knockout cells were hypersensitive to apoptosis. Correspondingly, microarray analysis of CtBP-knockout vs. CtBP-rescued mouse embryo fibroblasts revealed that many epithelial-specific and proapoptotic genes were indeed regulated by CtBP. Neither the apoptosis nor the repression activities of CtBP required histidine-315, suggesting that the proposed dehydrogenase activity is not essential for CtBP function. The results presented herein establish two functional roles of CtBP: to corepress epithelial genes, thus permitting epithelial-to-mesenchymal transitions, and to modulate the cellular threshold for apoptotic responses.
    Proceedings of the National Academy of Sciences 05/2003; 100(8):4568-73. DOI:10.1073/pnas.0830998100 · 9.67 Impact Factor

Publication Stats

7k Citations
370.96 Total Impact Points


  • 2006-2014
    • West Virginia University
      • Department of Biochemistry
      Morgantown, West Virginia, United States
  • 2003
    • Oregon Health and Science University
      Portland, Oregon, United States
  • 1997-2003
    • Sanford-Burnham Medical Research Institute
      La Jolla, California, United States
  • 2002
    • The University of Western Ontario
      • Department of Microbiology and Immunology
      London, Ontario, Canada