Histone modifications are crucial in activities such as transcriptional activation, gene silencing, and epigenetic cellular memory. In particular, lysine acetylation via lysine (K) acetyltransferases (KATs) has been implicated in cancer development. Interestingly, KAT5, also known as Tip60 (tat-interactive protein-60kDa), has been reported to possess both tumor promoting and tumor suppressing properties depending on the context of malignancy. Herein we report that KAT5 contributes to tumorigenesis in epidermal growth factor receptor (EGFR) mutated lung cancer, and Kat5-knockout mice models demonstrate significantly reduced lung tumor burden. To probe the aberrant modification of KAT5, we demonstrated that KAT5 binds to and is phosphorylated by oncogenic EGFR in co-immunoprecipitation experiments. Next, to investigate whether KAT5 is involved in cell proliferation and survival, H1975 cells harboring L858R-T790M double-activating mutations were transfected with doxycycline inducible short helical RNA (shRNA) targeting KAT5 (shKAT5). Following treatment, shKAT5 cells were observed to have suppressed proliferation rates. Pharmacological inhibition using TH1834, a known KAT5 inhibitor, also suppressed proliferation rates in shKAT5 cells; in contrast BEAS2B cells, an immortalized normal human bronchial cell line, surprisingly exhibited increased viability compared to transformed human lung H1975 cells. This finding supports KAT5’s context-dependent role in in normal and abnormal cell homeostasis. To further investigate KAT5 in lung tumorigenesis in vivo, we generated EGFR-mutant conditional Kat5 knockout mice using a tetracycline-induced Cre/loxP system. Following doxycycline treatment for 10 weeks, isolated mice lungs for EGFRTL/CCSP-rtTA/Cre/Kat5F/F possessed significantly lower tumor volume compared to EGFRTL/CCSP-rtTA/Cre/Kat5wt/F and EGFRTL/CCSP-rtTA/Cre/Kat5wt/wt mice lungs. Hemotoxylin and eosin staining showed no evident hyperproliferation in lungs isolated from EGFRTL/CCSP-rtTA/Cre/Kat5F/F mice whereas lungs isolated from EGFRTL/CCSP-rtTA/Cre/Kat5wt/wt and EGFRTL/CCSP-rtTA/Cre/Kat5wt/F did, signifying that KAT5 has a potential regulatory role in cellular proliferation. RNA-Seq analysis of shKAT5 H1975 cells identified downstream targets involved in tumorigenic pathways. Subsequent quantitative polymerase chain reaction (PCR) of shKAT5 cells served to validate the reported targets. Taken together, these data offer insight into a KAT5 mediated oncogenic pathway that can provide novel therapeutic approaches in treating lung cancer.

Aberrations in Epidermal Growth Factor Receptor (EGFR/ErbB1) signalling are the most common oncogenic stimuli in human glioblastoma multiforme (GBM). Interactions between mutant and wildtype ErbB family members in GBMs are of biological and potential therapeutic importance. In this thesis, we describe our work developing and optimizing a novel in situ proximity ligation assay (PLA) for dimerization and activation analysis of EGFR mutants prevalent in GBMs. Utilizing this novel in situ platform for EGFR dimerization analysis, we seek to systematically interrogate the dimerization capacity and activation status amongst EGFR and EGFR mutants. Our in vitro analysis using this platform demonstrates the aberrant homo-/hetero-dimeric properties of EGFRvIII and EGFRc958 mutants, the two most common mutants associated with EGFR amplification in GBMs. In addition, dimer phospho-activation status can be detected using in situ PLA with ≥ 16-fold sensitivity and ≥ 17-fold signal-to-noise than phospho-EGFR measurements currently undertaken with IHC or IF. These aberrant features are not overexpression dependent but appear independent of cellular expression levels, suggesting inherent properties of the mutant receptors. This EGFR dimerization/activation detection platform may also be useful for evaluating novel anti-EGFR therapeutics. Our data suggests that various EGFR monoclonal antibody therapies have unique dimerization blocking abilities and that certain mutant EGFR dimer configurations can evade blockage by anti-EGFR treatments. Furthermore, we report for the first time the detection of wt- and EGFRvIII dimerization in GBM specimens, in keeping with our prior cell line data, and a potential feature of prognostic or diagnostic value in GBMs harbouring them. Additionally, we demonstrate the utility of this platform for measuring pEGFR and total EGFR expression on tissue samples, which has not been efficacious to date with conventional antibody-mediated techniques. Results from this thesis may therefore provide novel insights into the interaction and activation characteristics of EGFR mutants prevalent in GBMs, as well as the efficacy of current anti-EGFR therapies to target these mutants. In summary, these findings demonstrate the successful application of a novel in situ EGFR molecular detection platform which may have clinical utility in diagnostic evaluation or stratification of GBM patient subgroups for prognosis and treatment. Furthermore, since PLA allows specimen assessment of not only expression and activation, but also dimerization, which is not evaluated by current IHC techniques, it will likely serve as a way to evaluate promising anti-EGFR strategies directed at preventing EGFR dimerization and activation.

Aberrations in Epidermal Growth Factor Receptor (EGFR/ErbB1) signalling are the most common oncogenic stimuli in human glioblastoma multiforme (GBM). Interactions between mutant and wildtype ErbB family members in GBMs are of biological and potential therapeutic importance. In this thesis, we describe our work developing and optimizing a novel in situ proximity ligation assay (PLA) for dimerization and activation analysis of EGFR mutants prevalent in GBMs. Utilizing this novel in situ platform for EGFR dimerization analysis, we seek to systematically interrogate the dimerization capacity and activation status amongst EGFR and EGFR mutants. Our in vitro analysis using this platform demonstrates the aberrant homo-/hetero-dimeric properties of EGFRvIII and EGFRc958 mutants, the two most common mutants associated with EGFR amplification in GBMs. In addition, dimer phospho-activation status can be detected using in situ PLA with ≥ 16-fold sensitivity and ≥ 17-fold signal-to-noise than phospho-EGFR measurements currently undertaken with IHC or IF. These aberrant features are not overexpression dependent but appear independent of cellular expression levels, suggesting inherent properties of the mutant receptors. This EGFR dimerization/activation detection platform may also be useful for evaluating novel anti-EGFR therapeutics. Our data suggests that various EGFR monoclonal antibody therapies have unique dimerization blocking abilities and that certain mutant EGFR dimer configurations can evade blockage by anti-EGFR treatments. Furthermore, we report for the first time the detection of wt- and EGFRvIII dimerization in GBM specimens, in keeping with our prior cell line data, and a potential feature of prognostic or diagnostic value in GBMs harbouring them. Additionally, we demonstrate the utility of this platform for measuring pEGFR and total EGFR expression on tissue samples, which has not been efficacious to date with conventional antibody-mediated techniques. Results from this thesis may therefore provide novel insights into the interaction and activation characteristics of EGFR mutants prevalent in GBMs, as well as the efficacy of current anti-EGFR therapies to target these mutants. In summary, these findings demonstrate the successful application of a novel in situ EGFR molecular detection platform which may have clinical utility in diagnostic evaluation or stratification of GBM patient subgroups for prognosis and treatment. Furthermore, since PLA allows specimen assessment of not only expression and activation, but also dimerization, which is not evaluated by current IHC techniques, it will likely serve as a way to evaluate promising anti-EGFR strategies directed at preventing EGFR dimerization and activation.

En els malalts amb càncer, la hiperactivitat del receptor del factor epidèrmic de creixement (EGFR) té mal pronòstic. L'EGFR està sobreexpressat en diferents tipus de tumors, entre els que destaquen el càncer de colon, pulmó, pàncrees i cap i coll. La majoria d'aquestes neoplàsies requereixen tractament amb radioteràpia amb el que s'aconsegueix, en un elevat percentatge de casos, una bona resposta. No obstant, la persistència després de la radioteràpia de cèl·lules resistents a la radiació enfosqueix el control tumoral.La recerca d'estratègies per a contrarestar aquesta resistència ha donat lloc a tractaments de radioteràpia hiperfraccionada i de concomitància (radioquimioteràpia) que han mostrat un augment significatiu del control local, tot i que a expenses d'una major toxicitat. Recentment, la síntesi d'inhibidors de l'EGFR i la translació a la clínica d'aquestes substàncies ha demostrat l'existència d'una estratègia menys tòxica per a compensar la resistència tumoral, essent paradigmàtic l'augment de supervivència en tumors de cap i coll localment avançat tractats amb la combinació de radioteràpia i cetuximab. L'èxit d'aquesta combinació ha provocat un creixent interès en el desenvolupament d'estudis clínics per avaluar el seu ús com a potencial tractament adjuvant. D'acord amb aquesta idea, vam iniciar un programa d'investigació preclínica per avaluar el paper de l'anticòs monoclonal anti-EGFR cetuximab com a tractament adjuvant.En aquesta tesi hem demostrat que la irradiació indueix, en les cèl·lules que sobreviuen a la radioteràpia, un fenotip agressiu que implica un creixement tumoral accelerat i que cetuximab bloqueja el creixement dels xenoempels derivats de cèl·lules radioresistents. Aquest bloqueig es tradueix en una inhibició de l'angiogènesi i proliferació cel·lular per diferents vies moleculars. En conjunt, els resultats obtinguts en aquest treball tenen rellevància clínica i proporcionen una base per a la conducció d'estudis clínics per examinar el manteniment de cetuximab després de la radioteràpia. / Hyperactivity of Epidermal Growth Factor Receptor (EGFR) in cancer patients is associated with poor prognosis. EGFR is overexpressed in a wide range of tumors, including lung, pancreas and head and neck carcinomas. Most of these tumors require treatment with radiation therapy which is effective in a high percentage of cases. However, the persistence of radioresistant cells after radiotherapy leads to the appearance of recurrences. Recently, it has been developed different EGFR inhibitors such as cetuximab which is a chimeric human-mouse antibody that binds specifically to human EGFR (ErbB1) blocking receptor activation. EGFR overexpression is present in most head and neck squamous cell carcinomas (HNSCCs) and cetuximab has been found to have an antitumorigenic effect when added to radiotherapy in the treatment of locally advanced HNSCCs. The success of radiotherapy and cetuximab has fueled interest in cetuximab as a potential adjuvant treatment following radiotherapy. The main objective of this study was to assess the effects of adjuvant cetuximab in a mouse model on tumors derived from a subpopulation of previously irradiated cells, and investigated the mechanisms of action. Our results showed that the subpopulation of cells that survived to radiation displayed an increase in EGFR pathway activity associated with an aggressive tumor phenotype involving an accelerated tumor growth. In addition, cetuximab efficiently inhibited tumor progression despite the malignant growth characteristics of tumors derived from irradiated cells. Furthermore, cetuximab inhibited angiogenesis and cellular proliferation through different molecular mechanisms. Overall, the results reported here have clinical relevance and provide a basis for conducting clinical studies to examine the maintenance of cetuximab after radiotherapy.

Thioredoxin-1 (Trx-1) is a redox protein that is overexpressed in many tumors where it is associated with tumor growth, inhibited apoptosis and decreased patient survival. Through redox reactions, Trx-1 is able to reduce a number of proteins including transcription factors. Sp1 activation has been implicated in the regulation of many genes involved in cellular growth and survival and its overexpression in certain cancer correlates with decreased patient survival. We demonstrate that Trx-1 is able to activate Sp1 in a redox dependent manner. Trx-1 overexpression increases Sp1 transactivation and DNA binding whereas a redox inactive Trx-1 has no effect on Sp1 DNA binding.Sp1 has been implicated in vascular endothelial growth factor regulation and we have shown that Trx-1 expression results in increased hypoxic VEGF expression and increased tumor permeability in vivo. Trx-1 overexpression results in an increase in VEGF expression that is dependent upon Sp1, as inhibition of Sp1 expression with siRNA prevented the induction of VEGF expression by Trx-1. These results suggest that Trx-1 increases VEGF expression under normoxic conditions through a redox dependent increase in the DNA binding of the Sp1 transcription factor. VEGF regulation by Sp1 could increase angiogenesis in relatively perfused areas contributing to the stimulation of tumor growth by Trx-1.We hypothesized that Trx-1 regulation of Sp1 may be part of the mechanism of Trx-1 induction of cellular growth. Sp1 regulates many genes involved in cellular growth including epidermal growth factor receptor (EGFR) and insulin-like growth factor I receptor (IGF-IR). These two growth factor receptors are important for cellular growth and have been shown to be important therapeutic targets for cancer treatment. We report that treatment with the Trx-1 inhibitor PX-12 results in decreased Sp1 DNA binding as well as decreased Sp1 activation and transactivation of VEGF, EGFR, and IGF-IR. These results indicate that Trx-1 promotes cellular growth and survival, in part, through the redox regulation of Sp1 responsive growth genes EGFR and IGF-IR. Inhibition of Trx-1, via PX-12, results in a decrease in EGFR and IGF-IR expression and suggests a new mechanism by which Trx-1 inhibition is clinically effective for treating cancer.

Cancer is the second leading cause of death in the USA and it is expected to surpass heart diseases making it important to understand the underlying mechanisms of cancer. The efforts to target single signaling molecule showed little success in increasing the patient survival and it can be due to increased compensation for cell survival by alternative pathway activations. Hence comprehensive understanding of the alternative signaling pathways may help us treat cancer better. Chronic inflammation is attributed to increased risk of cancer and emerging studies show the growing importance of both canonical and non-canonical IκB kinases such as IKKα, IKKβ, IKBKE and TBK1 in human cancer pathogenesis. Initially identified as activator of NFκB pathway, IKBKE was shown to play an important oncogenic role by regulating multiple pathways downstream. Although IKBKE is implicated in tumorigenesis for over a decade, therapeutic targeting of this pathway has been a challenge. Recently, amlexanox and CYT387, which are in clinical trials for Type II diabetes and myeloproliferative disorders respectively, were identified as potential IKBKE inhibitors. In this study, we uncovered specific novel mechanisms of activation of IKBKE in tumor cells and the outcomes of targeting IKBKE pathway. Oncogenic mutations are a cause of several human malignancies. Mutations in EGFR are observed in 15% of non-small cell lung cancer patients. While cells expressing these mutations respond better to the first generation TKIs, patients become resistant to these inhibitors due to secondary mutations in EGFR. These mutations were shown to make EGFR constitutively active even in the absence of ligands. Direct targeting of EGFR with secondary mutations has been challenging as EGFR acquires novel mutations upon inhibitor treatment, which confer resistance to the EGFR-TKIs. Hence, it is important to improve our knowledge of the downstream signaling pathways of EGFR. Although PI3K, MEK signaling are well established, mutant EGFR was shown to activate several novel signaling pathways such as miRNA processing and autophagy that are implicated in resistance to EGFR-TKIs. Here, we show that IKBKE acts downstream of mutant EGFR to activate the NFκB and AKT pathways. In addition, we show that mutant EGFR but not wildtype EGFR can directly phosphorylate IKBKE at Tyrosine 153 and Tyrosine 179 residues that are important for activation of IKBKE kinase. We also found that the IKBKE/TBK1 inhibitor Amlexanox exhibits increased efficacy in inhibiting cell viability in NSCLC cells with activating EGFR mutations. Furthermore, we also found that IKBKE inhibitors activate the MAPK pathway, and EGFR-TKI resistant NSCLCs exhibit enhanced response to co-treatment with IKBKE inhibitors and MEK inhibitors. Similar to lung cancer, pancreatic cancer is a challenging disease due to lack of direct inhibitors of the KRas mutations that are observed in more than 95% of pancreatic cancer patients. IKBKE/TBK1 pathway is important for KRas signaling, but the efficacy of IKBKE inhibitors in pancreatic cancers is not well studied. Here, we show that IKBKE is an important target in pancreatic cancers that regulates pancreatic cell viability, cell migration and cancer stem cells. Importantly, we provide mechanistic insights into the effects of IKBKE inhibitors on specific signaling pathways. We found that IKBKE inhibition results in significantly increased expression of RTKs, such as ErbB3 and IGF1-R, which increases ERK1/2 activation. Our findings provide support for novel combination strategies for pancreatic cancer. Metastasis is a poor prognostic factor for ovarian cancer. Although patients with early stage ovarian cancer with no distal metastasis exhibit a 70% 5-year survival rate, Stage IV patients with distal metastasis exhibit only 20% 5-year survival rate. Hence, ongoing efforts are aimed at targeting the pathways that regulate metastasis in ovarian cancers. IKBKE is upregulated in ovarian cancer patients, and IKBKE expression is known to regulate the expression of several genes important for cell motility in ovarian cancers. IKBKE is also implicated in chemo-resistance in ovarian cancer, and siRNA knockdown of IKBKE increases sensitivity towards chemotherapy. However, the mechanistic role of IKBKE in chemo-resistance in ovarian cancer is not known. EphA2 is another well studied oncogene in ovarian cancer as 70% of ovarian cancer patients exhibit elevated levels of EphA2. By activating Focal Adhesion Kinases (FAK), EphA2 can induce metastasis in ovarian cancers. In this study, we show that the clinical PARP inhibitor Olaparib (AZD2281) activates IKBKE by EphA2-mediated tyrosine phosphorylation. We also found that phosphorylation of EphA2 or IKBKE expression can be used as a biomarker for olaparib resistance. Together, these studies have shed light on novel mechanisms of regulation of IKBKE and their importance in therapy resistance. These observations form a strong pre-clinical proof-of-concept to study the inhibitors further in the clinic.

No description available.

L'inactivation des gènes p53 et pten présente un facteur de mauvais pronostic et de résistance à différents traitements anticancéreux incluant les thérapies ciblées. Le cétuximab (Erbitux®) est un anticorps monoclonal chimérique dirigé contre le domaine extracellulaire du récepteur à l'EGF. Son mécanisme d'action est fortement lié à la fonctionnalité des voies de signalisation de PI3KJAKT et des MAPK. Nous avons évalué l'influence de la réintroduction des gènes p53 et pten par vectorisation non viral à base de polyéthylènimine, couplée ou non à l'internalisation photochimique sur l'induction de l'apoptose et l'inhibition de la croissance cellulaire dans des cellules P53 et pten mutés d'une part, et sur l'impact de ce transfert de gène sur la fonctionnalité des voies de signalisation impliquées dans la réponse cellulaire au cétuximab. Nous avons montré que la transfection des gènes suppresseurs de tumeurs p53 et pten par polyétylènimine couplé à la PCI rétablit l'expression de P53 et de PTEN et permet de restaurer l'inhibition de croissance et l'induction de l'apoptose. Associée au traitement par cétuximab La restauration de PTEN et P53 réprime l'activation constitutive des voies de signalisation PI3K et MAPK et potentialise l'inhibition de la croissance et l'induction de l'apoptose induites par le cétuximab. Ces résultats montrent que l'inactivation de p53 et pten pourrait être prédictive de la résistance au cétuximab à travers l'activation constitutive de la voie de signalisation PI3/AKT et confirme que la détennination de la fonctionnalité des voies de signalisation des rtiveaux d'expression des phosphoprotéines de signalisation permettrait de prédire la réponse au cétuximab et de proposer des options thérapeutiques originales. / P53 and PTEN abnormalities are early events in carcinogenesis and are associated with poor prognosis and resistance to cancer therapies including targeted therapy. Cetuxirnab (Erbitnx®) is a IgG chimeric monoclonal antibody, directed against the extracellular dornain of EGFR. !ts activity has been shown to be dependent on the functionality of PI3KJAKT and MAPK signaling pathways as weil as the apoptosis induction capacity of the cells . The present study was designed to evaluate the influence of pten and p53 gene transfer using polyethylenimine with or without photochemical internalisation on cell apoptosis induction and cell growth in cells bearing p53 and pten mutations and on the response to cetuximab. The results presented show that pten and p53 gene transfer using polyethertimine and PCI restored P53 and PTEN expression, cell growth inhibition and apoptosis induction. Associated with cetuximab treatrnent, pten and p53 reintroduction, restored the functionality of AKTIPI3K and MAPK signaling pathways and increased cell growth inhibition and apoptosis induction by cetuximab. The results achieved in the present study show that pten and p53 mutations could be predictive of cell response to cetuximab through the functional impact of these mutations on cell signaling. The data presented put forward the interest of the analysis of EGFR phosphoproteins downstream signalling to evaluate the functionality of the signaling pathways implicated in the cell response to cetuximab and could be used to propose the original targeted therapies.

Various ion channels are expressed in human cancers where they are intimately involved in proliferation, angiogenesis, migration and invasion. Expression of functional voltage-gated sodium (Nav) channels is implicated in the metastatic potential of breast, prostate, colon, cervical and lung cancer cells. However, the cellular mechanisms that regulate Nav channel expression in cancer remain largely unknown. Growth factors are attractive candidates; they not only play crucial roles in cancer progression but are also key regulators of ion channel expression and activity in non-cancerous cells. Here, the role of epidermal growth factor receptor (EGFR) signalling and Nav channels in non-small cell lung cancer (NSCLC) cell lines have been examined. It is shown that functional expression of Nav1.7 promotes invasion in strongly metastatic H460 NSCLC cells. However, in non-invasive A549 NSCLC cells, Nav1.7 is completely absent. Inhibition of Nav1.7 either pharmacologically by tetrodotoxin (TTX) or genetically by small interfering RNA (siRNA) reduces H460 cell invasion by up to 50%. Whilst EGFR signalling enhances proliferation, migration and invasion of H460 cells, EGFR-mediated upregulation of Nav1.7 specifically, is required to promote invasive behaviour in these cells. Examination of Nav1.7 expression at the mRNA, protein and functional levels further reveals that EGFR signalling via the ERK1/2 pathway controls transcriptional regulation of Nav1.7 expression to promote cellular invasion in NSCLC. The role of Nav channels in promoting cancer cell invasion is also unclear. Therefore, the effect of Nav channel activity on two likely downstream contributors to cellular invasion, intracellular calcium concentration, [Ca2+]i, and intracellular pH, pHi, have been examined. It is shown that functional expression of Nav1.7 likely drives H460 NSCLC cell invasion via H+ efflux from the cell in an uncharacterised mechanism potentially involving NHE1, resulting in extracellular acidification of the perimembrane space. However, much more work is needed to understand this Na+-dependent invasive mechanism. Immunohistochemistry (IHC) of patient biopsies confirms the clinical relevance of Nav1.7 expression in NSCLC. Thus, Nav1.7 has significant potential as a novel target for therapeutic intervention, possibly in conjunction with existing EGFR inhibitors, and/or as a diagnostic/prognostic marker in NSCLC.

Le facteur XII (FXII) est une sérine protéase de 80 kDa produite et sécrétée par le foie qui initie la voie intrinsèque de la coagulation. Diverses études ont montré un rôle délétère du FXII dans des pathologies cérébrales telles que l'accident vasulaie cérébral, la maladie d'Alzheimer et la slérose en plaques. Néanmoins, l'impact direct du FXII sur le devenir des cellules neuronales reste inconnu. De plus, l'expression du FXII dans le système nerveux central (SNC) n'a pas encore été étudiée. Le premier objectif de nos travaux a été d'étudier le rôle du FXII dans l'apoptose neuronale puis dans un second temps d'étudier l'expession du FXII dans le SNC. Dans notre étude, nous avons constaté que le FXII protège les neurones en culture de la mort apoptotique. Les effets bénéfiques du FXII résultent de l'interaction directe du FXII avec le récepteur du facteur de croissance épidermique (EGFR). L'activation de l'EGFR par le FXII déclenche les voies signalétiques antiapoptotiques MAPK. Il est intéressant de noter que la forme double chaîne du FXII, αFXIIa, exerce des effets protecteurs complémentaires en convertissant le précurseur du facteur de croissance hépatocytaire en sa forme mature, ce qui active à son tour le récepteur MET. Enfin, dans notre étude, nous avons observé que le FXII était exprimé dans le SNC (à la fois l'ARNm et la protéine). Cette expression est notamment retrouvée au niveau des neurones corticaux. Ce travail décrit un nouveau mécanisme d'action du FXII et décrit les neurones en tant que cellules cibles pour les effets facteur de croissance du FXII. Dans l'ensemble, ces travaux devraient donc aider à mieux comprendre comment le FXII agit dans les pathologies cérébrales en tant que sérine-protéase unique à l'interface de la thrombose, de l'inflammation et de la survie cellulaire. / Factor XII (FXII) is an 80 kDa serine protease produced and secreted by the liver that participates in the intrinsic coagulation pathway. Various studies have shown a deleterious role of FXII in cerebral pathologies like stroke, Alzheimer disease and multiple sclerosis. Nevertheless, the direct impact of FXII on neuronal cell fate remains unknown. In addition, the expression of FXII in the central nervous system (CNS) has not been investigated yet. The first objective of our work was to study the role of FXII in neuronal apoptosis and then to study the expression of FXII in the CNS. In our work, we found that FXII protects cultured neurons from apoptotic death by a growth factorlike effect. The beneficial effects of FXII result from the direct interaction with the epidermal growth factor receptor (EGFR). Activation of EGFR by FXII triggers antiapoptotic signaling MAPK pathways. Iteestigl, the to hai fo of FXII, αFXIIa, eets opleeta potetie effets oetig the hepatocyte growth factor (HGF) precursor into its mature form, which in turn activates MET receptor. Finally in our work we observed FXII expression in the CNS (both mRNA and protein). This expression is particularly found in cortical neurons. This work describes a novel mechanism of action of FXII and discloses neurons as target cells for growth factor effects of FXII. Overall, these works should thus help further understanding how FXII acts in brain diseases as a unique serine-protease at the interface of thrombosis, inflammation and cell survival.