Cell Polarity and Cancer

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1 Cell Polarity and Cancer Pr Jean-Paul Borg

2 Features of malignant cells

3

4 Steps in Malignant Progression

5 Cell polarity, cell adhesion, morphogenesis and tumorigenesis pathways Feigen and Muthuswamy, Curr. Op. Cell. Biol. 2009

6

7 E-cadherin mediated junctions MDCK Stable cell adhesion E-cadherin based

8 Cell adhesion molecules

9 Epithelial-mesenchymal transition (EMT) 1. Loss of cell-cell contacts 2. Acquisition of a mesenchymal morphology 3. Manifest a migratory phenotype 4. Increase of extracellular proteolytic activity 5. Proliferation

10 Colon Cancer (E-cadherin in brown)

11 Cellular changes during EMT Lost or decreased 1. Epithelial adhesion receptors - E-cadherin, Occludin, Claudins 2. α-catenin, β-catenin frequently translocates to nucleus (Wnt) 3. Circumferential F-actin fibers 4. Epithelial cytokeratins 5. Apico-basal polarity Acquired 1. Intermediate filament protein - Vimentin 2. Matrix metalloproteinases secreted, produced 3. Fibronectin secretion 4. N-cadherin 5. α-smooth muscle actin (myofibroblasts) 6. αvβ6 integrin 7. Motility, Invasiveness

12 EMT during embryonic development Neural Crest Delamination Epithelial Mesenchymal

13 EMT in the Adult - epithelia wound healing (skin) - tissue fibrosis in response to injury (lung, kidney, liver) - epithelial cancer metastasis Skin wound healing Slug expression

14 The Snail family of transcriptional repressors SNAG Domain Zinc Fingers Snail Slug Smuc Scratch

15 E-cadherin Loss/Downregulation 1. Mutation - Seen in gastric carcinoma and lobular breast cancer 2. Post-transcriptional down-regulation 3. Promoter methylation 4. Transcriptional Repression

16 E-cadherin transcriptional repression Wnt BMP Notch

17 E-cadherin transcriptional repression + Snail

18

19 Epithelial cell polarity complexes Borg and Margolis, J Cell Sci 2005

20 Epithelial cell polarity complexes Feigen and Muthuswamy, Curr Op. Cell, Biol. 2009

21 Protein interaction domains from Pawson et al.

22 Binding specificities of PDZ domains PSD-95 Discs Large ZO-1 Class I S/TxV Class II ΨxΨ Class III DxV

23 The tumor suppressor Scribble is conserved during evolution dpatj Scribble Patj Scrib LRR PDZ

24 Studies on the Scribble tumor suppressor gene in Drosophila and humans WT scrib Scrib -/- RasV12 Scrib -/- Ras12 tumors +++ +/- +++ metastasis Bilder and Perrimon, Nature 2000

25 Studies on the Scribble tumor suppressor gene in humans Breast carcinoma Ductal Lobular Scribble Scribble localization E-cadherin Navarro et al., Oncogene 2005

26 Purification and identification of proteins bound to Scribble in epithelial cells IP: control Scrib1 Scrib2 Lano 175 * * Cdc42 GTP Cdc42 GDP βpix GIT1 Scrib 47.5 ARF6 GTP ARF6 GDP Audebert et al., Curr. Biol 2004

27 LRR PDZ localization signaling

28

29 Human BC Xenografted mice

30

31 Prostatic intraepithelial neoplasia (PIN)

32 Scribble is a bona fide tumor suppressor

33 Scribble is a sensor of extracellular cues Scribble actin Primary astrocytes -HRG + HRG T47D cells Osmani et al., Curr Biol 2006 Nola et al., Hum.Mol.Genet. 2008

34 Scribble-deficient cells have a defect of cell migration Nola et al., Hum. Molec. Genet 2008

35

36 The mammalian Scribble complex LRR PDZ Cdc42 GTP Cdc42 GDP PAK βpix GIT1 Scribble ARF6 GTP ARF6 GDP Audebert et al., Current Biology 2004 Lahuna et al., EMBO J Osmani et al., Curr. Biol Nola, et al., Hum. Mol. Genet. 2008

37 Compartimentalization of signals

38 Compartimentalization of EGFR signaling

39 Compartimentalization of EGFR signaling EGFR ErbB2 ErbB3 ErbB4

40 Compartimentalization of EGFR signaling

41 Compartimentalization of TGFβ signaling

42 Compartimentalization of TGFβ signaling Barios-Rodiles et al., 2005

43 Deregulated cell signaling drives cell polarity defects

44 Compartimentalization of PTEN signaling

45 Compartimentalization of PTEN signaling

46 3D models MDCK cells

47 Compartimentalization of PTEN signaling

48 Roles of β-catenin

49 Adenomatous Polyposis Coli

50 Primary cilium

51 Cell signaling in the primary cilium

52 Peutz-Jeghers Syndrome ~70% of PJS patients have LKB1 mutation Autosomal dominant Benign harmatomatous polyps Mucocutaneous hyperpigmentation on lips and hands Increased risk of cancer

53 Structure of LKB1

54 LKB1 mutations in Cancer Germ line mutations in PJS Somatic mutations in LKB1 Pancreatic Pulmonary Biliary Melanomas

55 Animal Model LKB1-/- mutation in mice is lethal Midgestation Neural-tube defects Severely impaired vascular development LKB1+/- mice: gastrointestinal polyposis, similar to PJS patients Different distribution of polyps in GI tract Similar histology of polyps Mouse model for PJS

56 Cell Polarity and pathogens

57 Human Papilloma Virus (HPV) Over 100 Different Subtypes High risk of cervical cancer associated with types 16, 18, 31, 33

58 Human Papilloma Virus (HPV) Early Genes: E1: Viral replication; maintains episome E2: Transcriptional regulation, co-factor for viral replication E4: Disrupts cytokeratins E5: Interacts with growth factor receptors E6: Transforming protein; p53 and PDZ proteins degradation E7: Transforming protein; Rb binding Late Genes: L1: major capsid protein L2: minor capsid protein

59 The HPV-16 E6 oncoprotein

60 E6 E6 TQL MUPP1 Scrib Dlg1 CASK LIN-7 Thomas et al., 2008 Audebert, S.

61 PDZ proteins Human Fly Worm Yeast 253 (148 proteins) Class I S/TxV Class II ΨxΨ Class III DxV

62 PDZ-containing targets of papillomavirus oncoproteins Thomas et al., 2008

63 Thomas et al., 2008

64 Helicobacter pylori

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