Volume 20, Issue 6, Pages (December 2011)

Slides:



Advertisements
Similar presentations
Tumor-Induced Sentinel Lymph Node Lymphangiogenesis and Increased Lymph Flow Precede Melanoma Metastasis  Maria I. Harrell, Brian M. Iritani, Alanna Ruddell 
Advertisements

Volume 22, Issue 6, Pages (December 2012)
Matrix Metalloproteinase-9 Is Required for Tumor Vasculogenesis but Not for Angiogenesis: Role of Bone Marrow-Derived Myelomonocytic Cells  G-One Ahn,
Volume 39, Issue 5, Pages (November 2013)
Volume 24, Issue 5, Pages (November 2013)
Tumor-Derived Jagged1 Promotes Osteolytic Bone Metastasis of Breast Cancer by Engaging Notch Signaling in Bone Cells  Nilay Sethi, Xudong Dai, Christopher.
MEF Promotes Stemness in the Pathogenesis of Gliomas
Volume 15, Issue 1, Pages (April 2016)
Volume 18, Issue 3, Pages (September 2013)
Volume 18, Issue 8, Pages (February 2017)
Impact of NAD(P)H:Quinone Oxidoreductase-1 on Pigmentation
Volume 137, Issue 1, Pages (July 2009)
Whole Chromosome Instability Caused by Bub1 Insufficiency Drives Tumorigenesis through Tumor Suppressor Gene Loss of Heterozygosity  Darren J. Baker,
Volume 137, Issue 2, Pages e2 (August 2009)
Volume 2, Issue 4, Pages (April 2008)
Modulation of K-Ras-Dependent Lung Tumorigenesis by MicroRNA-21
A Conditional Zebrafish MITF Mutation Reveals MITF Levels Are Critical for Melanoma Promotion vs. Regression In Vivo  James A. Lister, Amy Capper, Zhiqiang.
Effects of Betulinic Acid Alone and in Combination with Irradiation in Human Melanoma Cells  Edgar Selzer, Emilio Pimentel, Volker Wacheck, Werner Schlegel,
Oncogenic BRAF Regulates Oxidative Metabolism via PGC1α and MITF
Volume 25, Issue 4, Pages (April 2014)
Regulation of Human Melanoma Growth and Metastasis by AGE–AGE Receptor Interactions  Riichiro Abe, Tadamichi Shimizu, Hiroshi Sugawara, Hirokazu Watanabe,
Volume 8, Issue 6, Pages (December 2005)
Short Telomeres Limit Tumor Progression In Vivo by Inducing Senescence
Volume 16, Issue 4, Pages (July 2016)
Volume 19, Issue 6, Pages (June 2011)
Volume 24, Issue 5, Pages (November 2013)
Volume 21, Issue 1, Pages (January 2012)
Volume 143, Issue 6, Pages e5 (December 2012)
Notch Activation as a Driver of Osteogenic Sarcoma
Volume 39, Issue 5, Pages (November 2013)
Transdifferentiation of Melanoma Cells by the Reprogramming Factors Attenuates Malignant Nature In Vitro and In Vivo  Mikiro Takaishi, Shigetoshi Sano 
Makoto Takeo, Christopher S. Hale, Mayumi Ito 
Volume 22, Issue 5, Pages (November 2012)
Volume 29, Issue 4, Pages (April 2016)
Volume 14, Issue 10, Pages (March 2016)
AKT1 Activation Promotes Development of Melanoma Metastases
Volume 123, Issue 6, Pages (December 2005)
Melanoma Suppressor Functions of the Carcinoma Oncogene FOXQ1
Volume 22, Issue 6, Pages (December 2012)
Volume 23, Issue 10, Pages (October 2016)
Einar K. Rofstad, Bjørn A. Graff  Journal of Investigative Dermatology 
Volume 25, Issue 3, Pages (March 2014)
Karin E. de Visser, Lidiya V. Korets, Lisa M. Coussens  Cancer Cell 
MiR-135b Stimulates Osteosarcoma Recurrence and Lung Metastasis via Notch and Wnt/β-Catenin Signaling  Hua Jin, Song Luo, Yun Wang, Chang Liu, Zhenghao.
Animal Models of Melanoma
Christina I. Selinger, PhD, Wendy A
Overexpression of CD109 in the Epidermis Differentially Regulates ALK1 Versus ALK5 Signaling and Modulates Extracellular Matrix Synthesis in the Skin 
Suppression of E-Cadherin Function Drives the Early Stages of Ras-Induced Squamous Cell Carcinoma through Upregulation of FAK and Src  Addy Alt-Holland,
Matrix Metalloproteinase-9 Is Required for Tumor Vasculogenesis but Not for Angiogenesis: Role of Bone Marrow-Derived Myelomonocytic Cells  G-One Ahn,
Volume 22, Issue 3, Pages (September 2012)
Rita U. Lukacs, Sanaz Memarzadeh, Hong Wu, Owen N. Witte 
Volume 7, Issue 1, Pages (January 2008)
Volume 13, Issue 4, Pages (April 2013)
An Osteopontin/CD44 Axis in RhoGDI2-Mediated Metastasis Suppression
Volume 6, Issue 1, Pages (July 2009)
Volume 15, Issue 3, Pages (March 2009)
Inhibition of PAX3 by TGF-β Modulates Melanocyte Viability
Volume 18, Issue 8, Pages (February 2017)
Haploinsufficiency at the Nkx3.1 locus
Volume 44, Issue 4, Pages (April 2016)
Laralynne Przybyla, Johnathon N. Lakins, Valerie M. Weaver 
LncRNA TRERNA1 Function as an Enhancer of SNAI1 Promotes Gastric Cancer Metastasis by Regulating Epithelial-Mesenchymal Transition  Huazhang Wu, Ying.
Volume 26, Issue 5, Pages e6 (January 2019)
Volume 16, Issue 4, Pages (April 2009)
A Transcriptionally Inactive ATF2 Variant Drives Melanomagenesis
Volume 29, Issue 5, Pages (May 2016)
Volume 15, Issue 11, Pages (June 2016)
Paracrine Apoptotic Effect of p53 Mediated by Tumor Suppressor Par-4
Volume 21, Issue 5, Pages (May 2012)
Volume 14, Issue 2, Pages (August 2008)
Presentation transcript:

Volume 20, Issue 6, Pages 741-754 (December 2011) β-Catenin Signaling Controls Metastasis in Braf-Activated Pten-Deficient Melanomas  William E. Damsky, David P. Curley, Manjula Santhanakrishnan, Lara E. Rosenbaum, James T. Platt, Bonnie E. Gould Rothberg, Makoto M. Taketo, David Dankort, David L. Rimm, Martin McMahon, Marcus Bosenberg  Cancer Cell  Volume 20, Issue 6, Pages 741-754 (December 2011) DOI: 10.1016/j.ccr.2011.10.030 Copyright © 2011 Elsevier Inc. Terms and Conditions

Figure 1 β-Catenin Loss Inhibits Melanoma Formation in Pten/Braf-driven Melanomas (A) Survival analysis of Pten/Braf cohorts after perinatal/generalized tumor induction. (B) Comparison of Pten/Braf/Bcat+/− (top) and Pten/Braf/Bcat-KO (bottom) tumor burden at 28 days of age. Metastasis to inguinal lymph node is also shown (right panels). (C) H&E stained Pten/Braf/Bcat-KO flank tumor, scale 300 μM (top) and 10 μM (bottom). (D) Quantification of metastasis to the inguinal lymph nodes in Pten/Braf/Bcat-KO mice (n = 13) compared to Pten/Braf mice (n = 8). Error bars represent SEM. See also Figure S1. Cancer Cell 2011 20, 741-754DOI: (10.1016/j.ccr.2011.10.030) Copyright © 2011 Elsevier Inc. Terms and Conditions

Figure 2 β-Catenin Stabilization Accelerates Pten/Braf-Driven Melanomagenesis (A) Survival analysis of cohorts with β-catenin stabilization after perinatal tumor induction. (B) Survival analysis of Pten/Braf littermates, either with or without β-catenin stabilization, after perinatal tumor induction. (C) Tumor phenotype in Pten/Braf/Bcat-STA mice (top panels) compared to non-tumor prone mice (bottom panels) at 21 days of age. (D) H&E stained Pten/Braf/Bcat-STA flank tumor, scale 500 μM. Right panel: high power of outlined field, scale 20 μM. (E) H&E stained tumor-draining lymph node from a Pten/Braf/Bcat-STA mouse, scale 400 μM. High power of outlined field, scale 20 μM, right panel. (F) H&E stained nevi (left panel) and tumor (right panel, arrow) from a Braf/Bcat-STA mouse, scale 500 μM (left) and 500 μM (right). See also Table S1. Cancer Cell 2011 20, 741-754DOI: (10.1016/j.ccr.2011.10.030) Copyright © 2011 Elsevier Inc. Terms and Conditions

Figure 3 β-Catenin Signaling Controls the Ability of Melanomas to Metastasize to Lung, Bowel, and Spleen (A) Lungs from a perinatally treated Pten/Braf/Bcat-STA mouse at 27 days of age (left panel) and a perinatally treated Pten/Braf/Bcat-KO mouse at 56 days of age (right panel). (B) Comparison of number of lung metastases visible on the surface of the lung in perinatally treated litters. Error bars represent SEM. (C) Lung metastasis from a perinatally treated Pten/Braf/Bcat-STA mouse, scale 100 μM. (D) Bowel metastasis from a perinatally treated Pten/Braf/Bcat-STA mouse. (E) Comparison of number of bowel metastases in perinatally treated litters. (F) H&E stained spleen metastasis from a perinatally treated Pten/Braf/Bcat-STA mouse, scale 200 μM. (G) Comparison of number of spleen metastases in perinatally treated litters. See also Figure S2. Cancer Cell 2011 20, 741-754DOI: (10.1016/j.ccr.2011.10.030) Copyright © 2011 Elsevier Inc. Terms and Conditions

Figure 4 Locally Induced Melanomas are Highly Metastatic and Can Form Lethal Metastases (A) Survival analysis of cohorts after localized tumor induction. Mice were euthanized when tumors reached 1 cm. (B) H&E stained sections of locally induced tumors from a Pten/Braf/Bcat-STA mouse (top panels, scale 20 μM left, 20 μM right), a Pten/Braf mouse (upper middle panels, scale 100 μM left, 50 μM right), a Pten/Braf/Bcat-KO mouse (lower middle panels, scale 400 μM left, 50 μM right), and a Braf/Bcat-STA/Pten+/− mouse (bottom panels, scale 400 μM left, 50 μM right). (C) Quantification of lung (left panel) and lymph node (right panel) metastasis in mice with focally induced melanomas. Error bars represent SEM. See also Figure S3 and Table S2. Cancer Cell 2011 20, 741-754DOI: (10.1016/j.ccr.2011.10.030) Copyright © 2011 Elsevier Inc. Terms and Conditions

Figure 5 Enhanced Metastasis in Pten/Braf/Bcat-STA Melanomas Is Accompanied by an Increase In Melanocytic Differentiation Markers (A) Locally induced flank melanoma (upper left panel) with H&E (upper right panel, scale 400 μM) and draining lymph node (lower left panel, scale 500 μM) with H&E (lower right panel, scale 500 μM) in a Pten/Braf/Bcat-STA mouse. (B) Locally induced flank melanoma (upper left panel) with H&E (upper right panel, scale 400 μM) and draining lymph node (lower left panel, scale 500 μM) with H&E (lower right panel, scale 500 μM) in a Pten/Braf mouse. (C) Mean expression of Mitf-M determined by qRT-PCR from Pten/Braf/Bcat-STA, Pten/Braf, and Pten/Braf/Bcat-KO melanomas (n = 4 per genotype). Expression levels normalized to GAPDH control. Error bars represent SEM. (D) Western blots using protein lysates prepared directly from uncultured flank melanomas. M, normal cultured melanocytes. (E) Tyrp1 immunofluorescence of locally induced Pten/Braf/Bcat-STA (left panel) and Pten/Braf (right panel) flank melanomas, scale 200 μM. (F) S100 immunohistochemistry of a locally induced Pten/Braf/Bcat-STA melanoma from an albino mouse, scale 100 μM. (G) Survival analysis of Pten/Braf/Bcat-STA mice with or without E-cadherin inactivation after perinatal tumor induction. NS, not statistically significantly different. (H) Quantification of lung metastases in perinatally induced Pten/Braf/Bcat-STA mice with or without E-cadherin inactivation. Error bars represent SEM. See also Figure S4 and Table S3. Cancer Cell 2011 20, 741-754DOI: (10.1016/j.ccr.2011.10.030) Copyright © 2011 Elsevier Inc. Terms and Conditions

Figure 6 β-Catenin Stabilization Is Associated with Hyperactivation of PI3K/Akt and MAPK/Erk Signaling (A–C) Western blots using protein lysates prepared from uncultured flank melanomas. M, Normal cultured melanocytes. See also Figure S5. Cancer Cell 2011 20, 741-754DOI: (10.1016/j.ccr.2011.10.030) Copyright © 2011 Elsevier Inc. Terms and Conditions

Figure 7 Pten/Braf/Bcat-STA Murine Melanomas Faithfully Recapitulate Human Melanomas (A) Fold-change in expression of individual transcripts relative to mean for each transcript compared between human and murine melanomas. PBB, Pten/Braf/Bcat-STA; PB, Pten/Braf. (B) GSEA was performed on human melanomas with β-catenin stabilizing mutation using a subset of differentially regulated transcripts identified using murine melanomas, p < 0.001. (C) Western blot analysis using protein lysates prepared from human melanoma cell lines. β-catenin status indicated for each sample. (D) Regression analysis comparing MITF, TYRP1, and PIN1 expression in a large human melanoma expression data set. (E) Contingency table of pigmentation status in human melanomas based on cadherin clusters (Kreizenbeck et al., 2008). O, observed; E, expected. Green, less than expected by chance; red, greater than expected by chance. See also Figure S6 and Table S4. Cancer Cell 2011 20, 741-754DOI: (10.1016/j.ccr.2011.10.030) Copyright © 2011 Elsevier Inc. Terms and Conditions

Figure 8 Signaling and Phenotypic Overview of Murine Melanoma Models (A) Pten/Braf/Bcat-STA melanomas are characterized by rapid growth, high degree of melanocytic differentiation, and extensive metastasis. These phenotypes are associated with increased MAPK/Erk and PI3K/Akt signaling, as well as elevated Mitf and Pin1 levels. Bold text, relatively increased levels and/or activity compared to other models; blue shading, relatively decreased compared to other models; red shading, genetically inactivated; ∗, stabilized. (B) Pten/Braf melanomas exhibit rapid tumor growth but only intermediate melanocytic differentiation and metastasis. Signaling pathway activation, Mitf, and Pin1 are intermediate in this model. (C) Pten/Braf/Bcat-KO melanomas exhibit tumor growth but significantly reduced melanocytic differentiation and almost no metastasis. Inactivation of β-catenin in this model is associated with reduced PI3K/Akt signaling and Mitf levels. (D) Braf/Bcat-STA melanomas are characterized by long latency and slow tumor growth, as well as lack of metastases. These tumors are differentiated and heavily pigmented because of high Mitf levels but show reduced PI3K/Akt pathway activation. (E) A three-pathway synergy is observed when MAPK/Erk, PI3K/Akt, and β-catenin/Mitf signaling pathways are simultaneously activated in melanoma. If any of these three changes are not present, the metastatic melanoma phenotype is abrogated. Cancer Cell 2011 20, 741-754DOI: (10.1016/j.ccr.2011.10.030) Copyright © 2011 Elsevier Inc. Terms and Conditions