Matrix metalloproteinase-11 promotes mouse mammary gland tumor progression Bing Tan To cite this version: Bing Tan. Matrix metalloproteinase-11 promotes mouse mammary gland tumor progression. Ge- nomics [q-bio.GN]. Université de Strasbourg, 2018. English. NNT : 2018STRAJ047. tel-02870898 HAL Id: tel-02870898 https://tel.archives-ouvertes.fr/tel-02870898 Submitted on 17 Jun 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. UNIVERSITÉ DE STRASBOURG ÉCOLE DOCTORALE DES SCIENCES DE LA VIE ET DE LA SANTÉ Thèse présentée par Bing TAN Pour obtenir le grade de Docteur de l’Université de Strasbourg Sciences du Vivant Aspects Moléculaires et Cellulaires de la Biologie La métalloprotéase matricielle-11 facilite la progression des tumeurs de la glande mammaire murine Matrix metalloproteinase-11 promotes mouse mammary gland tumor progression Soutenue publiquement le 13 septembre 2018 Devant le jury composé de: Examinateur: Madame le Docteur Isabelle GRILLIER-VUISSOZ Rapporteurs Externe: Madame le Docteur Emmanuelle LIAUDET-COOPMAN Monsieur le Docteur Stéphane DEDIEU Rapporteur Interne: Monsieur le Docteur Olivier LEFEBVRE Directeur de Thèse: Madame le Docteur Catherine-Laure TOMASETTO Acknowledgements The completion of my PhD thesis is attributed to many people’s support. First, I want to extend my heartfelt gratitude to my supervisor Dr. Catherine-Laure TOMASETTO, whose patient guidance, constant encouragement and valuable suggestions make me successfully complete this thesis. Her modest, open-minded personality and conscientious academic spirit will inspire me in future study. If without her help in daily life, I can’t imagine what my four years in France would be like! Second, I would give my greatest thanks to Dr. Nassim DALI-YOUCEF, he not only provided lots of guidance in my research, but also answered my questions extremely patient. I would like to say many thanks to Dr. Fabien ALPY for his good suggestions and technical help in my research, especially how to analysis my data. My thanks go to the laboratory members for their help, including Dr. Marie- Christine RIO, we spent and enjoyed a very pleasure time; my thanks go to the IGBMC animal facility, ICS histopathology service and CBI image center; and my thanks go to the friends and the people whose name are not mentioned but give me a lot of help during my study, etc. Thanks for the jury members Docteur Emmanuelle LIAUDET-COOPMAN, Docteur Stéphane DEDIEU, Docteur Isabelle GRILLIER-VUISSOZ and Docteur Olivier LEFEBVRE. I would give my special thanks to my parents, my brother, my girlfriend, and my uncle Jinxiang TAN for their support. Last, acknowledgements give to La Ligue Contre Le Cancer and China Scholarship Council for provide me the scientific fundings. THANK YOU ALL MERCI À TOUTES/TOUS i Table of Contents Acknowledgements……………………………...…………………………………….i Table of Contents..………………………….….……………………………….……ii List of Figures and Tables…….….……………………….…………………..…...viii List of Abbreviations……..………………………………………………..…..….….x Summary………...………………………………………………….………...……....1 CHAPTER 1 Introduction and Review……………………………………….…..2 1.1 MMPs family…………………………………...…………………….…………..2 1.1.1 MMPs classification…………………………………………….…………..2 1.1.1.1 Collagenases……………………………………….…………………4 1.1.1.2 Gelatinases……………………………………….…………………..4 1.1.1.3 Stromelysins………………………………………………………….4 1.1.1.4 Matrilysins……………………………………………………………5 1.1.1.5 MT-MMPs………………………………...………………………….5 1.1.1.6 Other MMPs………………………………………………………….5 1.1.2 MMPs structures……………..……………………………………….…….6 1.1.3 MMPs substrates……………………………………………………………7 1.1.4 Regulation of MMPs………………………………………………………11 1.1.4.1 The expression of MMPs genes…………………………………….11 1.1.4.2 The MMPs compartmentalization…………………………………..12 1.1.4.3 The activation of pro-MMPs………………………………………..12 1.1.4.4 The inhibition of MMPs…………………………………………….14 1.1.5 Biological functions of MMPs………………………………………….....15 1.1.5.1 MMPs and mouse mammary gland development…………………..15 1.1.5.2 MMPs trigger bone growth…………………………………………18 1.1.5.3 MMPs in wound healing and cell migration………………………..19 1.1.5.4 MMPs and vascular development…………………………………..20 1.1.5.5 MMPs and immune response……………………………………….21 1.1.5.6 MMPs associate with adipogenesis and body metabolism…………22 1.1.5.7 MMPs functions from mutant mice………………………………...23 1.1.6 MMPs and cancer………………………………………………………….27 1.1.6.1 MMPs in cancer cell proliferation………………………………..…27 ii 1.1.6.2 MMPs in cancer cell apoptosis……………………………………...28 1.1.6.3 MMPs in cancer angiogenesis………………………………………29 1.1.6.4 MMPs in cancer lymphangiogenesis…………………………….….31 1.1.6.5 MMPs in cancer epithelial to mesenchymal transition……………..32 1.1.6.6 MMPs in cancer migration………………………………………….32 1.1.6.7 MMPs in cancer invasion and metastasis…………………………...34 1.1.6.8 MMPs in cancer immune surveillance…………………………...…37 1.1.6.9 MMPs have nonproteolytic functions………………………………40 1.2 MMP-11………………………………………………………………………….43 1.2.1 MMP-11 discovery………………………………………………………...43 1.2.2 MMP-11 genomic organization…………………………………………...43 1.2.3 MMP-11 protein structure…………………………………………………45 1.2.4 MMP-11 crystal structure………………………………………………….45 1.2.5 MMP-11 secretion and activation…………………………………………46 1.2.6 MMP-11 nature and recombinant protein…………………………………47 1.2.7 MMP-11 substrates………………………………………………………..47 1.2.8 MMP-11 is a paracrine factor………………………………………….…..48 1.2.9 MMP-11 physiological functions………………………………….………49 1.2.9.1 MMP-11 and embryonic development……………………………...49 1.2.9.2 MMP-11 and mammary gland involution…………………………..50 1.2.9.3 MMP-11 and adipogenesis………………………………………….51 1.2.10 MMP-11 pathological functions………………………………………….53 1.2.10.1 MMP-11 and cancer……………………………………………….53 1.2.10.1.1 MMP-11 and breast cancer…………………………………53 1.2.10.1.2 MMP-11 and other cancers…………………………………55 1.2.10.2 MMP-11 and other diseases……………………………………….57 1.2.11 The summary of MMP-11 functions……………………………………..58 1.3 Adipocytes are involved in mammary gland tumor progression………..…...60 1.3.1 Cancer-associated adipocytes……………………………………………...60 1.3.2 Adipokines………………………………………………………………...61 1.3.3 Inflammation………………………………………………………………62 1.3.4 Sex hormones……………………………………………………………...62 1.3.5 Insulin signalling and IGF-I axis…………………………………………..63 iii 1.3.6 Lipid metabolism………………………………………………….…….....63 1.4 Thesis project………………………...………………………………………….65 CHAPTER 2 Results……………………………………………………………...69 Part I The impact of MMP-11 on MMTV-PyMT mouse breast cancer progression…………………………………………………………………………..69 2.1.1 Identification of the GOF and LOF mice genotypes………………………69 2.1.2 MMP-11 decreases MMTV-PyMT mice body weight……………………70 2.1.3 MMP-11 promotes MMTV-PyMT mice mammary tumor growth……….71 2.1.4 MMP-11 plays anti-necrosis and anti-apoptotic roles in MMTV-PyMT mice at early stage of mammary tumor development…………………………...73 2.1.5 MMP-11 plays a proliferative role at early stage of tumor development in MMTV-PyMT mice and induces the insulin-like growth factor-1 signalling pathway……………………………………………………………………….…74 2.1.6 MMP-11 increased lipid uptake and utilization and promotes metabolic switch……………………………………………………………………………76 2.1.7 MMP-11 increases endoplasmic reticulum stress response and alters mitochondrial unfolded protein response………………………………………..78 2.1.8 MMP-11 promotes MMTV-PyMT mice mammary tumor stroma fibrosis at limited time points…………………………………………………………….…81 2.1.9 MMP-11 does not modulate mammary tumor angiogenesis and EMT in MMTV-PyMT mice……………………………………………………………..83 2.1.10 MMP-11 reduces dissemination of mammary tumor to the lung in MMTV- PyMT mice………………………………………………………………………84 Research article: Matrix metalloproteinase-11 promotes mouse mammary gland tumor progression. Tan et al., in preparation Part II The impact of MMP-11 overexpression restricted to adipocytes on mammary gland tumorigenesis………………………………………...…………..86 2.2.1 Generation of aP2-mMMP11-IRES-GFP-polyA construct……………….86 2.2.1.1 Amplification of IRES-GFP sequence by PCR……………………..87 2.2.1.2 To obtain the same cutting ends of IRES-GFP and aP2-mMMP11- polyA………………………………………………………………………..88 2.2.1.3 Ligation of IRES-GFP and aP2-mMMP11-polyA………………….88 2.2.1.4 Validation of aP2-mMMP11-IRES-GFP-polyA plasmid in vitro…..89 iv 2.2.1.5 Linearization of aP2-mMMP11-IRES-GFP-polyA plasmid………..90 2.2.2 Characterization of aP2-mMMP11-IRES-GFP-polyA transgenic mice lines……………………………………………………………………………...91 2.2.2.1 Verification of germline transmission of aP2-mMMP11-IRES-GFP- polyA transgenic mice lines………………………………………………...91 2.2.2.2 Verification of MMP-11 and GFP expression of the aP2-mMMP11- IRES-GFP-polyA # 18 transgenic line……………………………………...92 2.2.3 Adipocyte-specific MMP-11 promotes E0771 mouse breast tumor growth……………………………………………………………………………94 Part III The impact of ITPP on MMTV-PyMT mouse breast cancer progression…………………………………………………………………………..96 2.3.1 ITPP promotes mammary gland hyperplasia and tumor incidence………..96 2.3.2 ITPP did not promoted mammary tumor metastasis to lung………………97 CHAPTER 3 Conclusions, Discussion and Perspectives……………………….99 Part I……………………………………………...……………………………….....99 3.1.1 MMP-11 promotes mammary tumor