Le corégulateur transcriptionnel RIP140 est un facteur ubiquitaire majeur impliqué dans la régulation de nombreux processus physiopathologiques, qui possède la capacité d’être un coactivateur ou un corépresseur des voies de signalisation selon son recrutement sur les gènes cible. Des résultats du laboratoire ont montré que RIP140 est un facteur de bon pronostic de la tumorigenèse intestinale sporadique. Ce travail s’intéresse à l’implication de ce facteur de transcription dans les cancers colorectaux familiaux et, plus particulièrement, en lien avec le syndrome de Lynch (LS). Le syndrome de Lynch est une prédisposition héréditaire aux cancers, majoritairement colorectaux, caractérisés par un défaut du système de réparation des mésappariements de l’ADN (Mismatch Repair, MMR), dû à une première mutation germinale d’un des gènes de ce système. La perte de fonctionnalité MMR est responsable du phénotype d’instabilité microsatellitaire (MSI). Cependant, il existe des formes familiales de cancers colorectaux, avec MSI, où il n’est pas retrouvé d’atteinte germinale ou somatique de l’un des gènes du système MMR. Ce sont les syndromes apparentés au syndrome de Lynch (Lynch Like Syndrome, LLS) dont la prise en charge est identique à celle du LS. L’utilisation de modèles murins et de lignées cellulaires colorectales, présentant des modulations d’expression de RIP140 ont permis de mettre en évidence l’effet positif de ce corégulateur sur la régulation transcriptionnelle de l’expression des gènes du système MMR, MSH2 et MSH6. La validité fonctionnelle de cette régulation a été explorée par des analyses d’instabilité microsatellitaire et de sensibilité à différentes molécules cytotoxiques. Des cohortes de tumeurs ont permis de confirmer la corrélation d’expression entre RIP140 et les gènes MSH2 et MSH6 chez les patients. En outre, la régulation de l’expression par RIP140 d’une polymérase translésionnelle particulière, la polymérase Polκ, a été étudiée. Cette polymérase assure la réplication des séquences microsatellitaires du génome. Nous avons démontré que RIP140 stimule l’expression du gène POLK dans nos modèles cellulaires et que son expression est corrélée à celle de RIP140 au sein des tumeurs colorectales humaines. Enfin, par séquençage de différentes lignées cellulaires, nous avons mis en évidence une mutation de RIP140 qui entraîne un décalage du cadre de lecture et génère une protéine tronquée avec perte de deux domaines répresseurs de la protéine. Un séquençage à très haut débit nous a permis de rechercher cette mutation parmi des échantillons de tumeurs colorectales avec MSI. Cette mutation est retrouvée dans 19% des tumeurs, notamment LLS (16,2%), où elle est associée à une moins bonne survie globale. Elle affecte les propriétés antiprolifératives et transrépressives de RIP140 ainsi que les régulations positives des gènes MSH2, MSH6 et POLK. Le développement d’un outil anticorps spécifique de cette mutation serait extrêmement utile pour suivre l’expression de la forme mutée au sein des tumeurs et des premiers essais ont été réalisés en ce sens. En conclusion de ce travail, RIP140 contrôle l’expression de gènes majeurs impliqués dans le maintien de l’intégrité du génome et une mutation de ce corégulateur transcriptionnel pourrait être responsable de l’instabilité microsatellitaire de certaines tumeurs où des altérations des gènes MMR ne sont pas retrouvées. Des études cliniques sur des cohortes plus conséquentes seront nécessaires pour valider son intérêt en tant que marqueur utilisable dans la prise en charge des patients. / The transcriptional coregulator RIP140 is an ubiquitous cofactor playing a major role in the regulation of many physiopathological processes. It can either act as a coactivator or as a corepressor of signaling pathways depending on its recruitment on target genes. It has been shown that RIP140 is a good prognostic marker in sporadic intestinal tumorigenesis. This work focuses on its role in familial colorectal cancers and particularly in relation to the Lynch syndrome (LS). Lynch syndrome is a hereditary cancer predisposition, mostly colorectal, characterized by a defect in the Mismatch Repair (MMR) system, due to a first germline mutation of one gene of this system. Loss of MMR function induces a microsatellite instability (MSI) phenotype. However, there are some MSI familial colorectal cancers, where neither germinal nor somatic alteration of one MMR gene is found. They are referred to as Lynch like Syndrome (LLS) and their overall management is identical to that of LS. Murine models and colorectal cell lines, harboring modulations of RIP140 expression, allowed us to demonstrate the positive transcriptional regulation of the MMR genes, MSH2 and MSH6 by RIP140. Functional validation of this regulation was explored by microsatellite instability and sensitivity to various cytotoxic drugs analyses. A positive correlation has been confirmed between RIP140 and MSH2 and MSH6 gene expression in a cohort of 396 patients. Moreover, the transcriptional regulation by RIP140 of a specialized translesional DNA polymerase, the Polκ polymerase, has been investigated. Polκ ensures microsatellite sequences replication. We have demonstrated that RIP140 positively stimulates the expression of the POLK gene in our cell models and which appears correlated with that of RIP140 in human colorectal tumors. Finally, by sequencing different cell lines, we found a frameshift mutation of RIP140, generating a truncated protein with loss of the last two repression domains. High-throughput sequencing allowed us to look for this mutation in patient MSI colorectal tumor samples. This mutation was found in 19% of these tumors, especially LLS (16,2%), where it has been associated with lower overall survival. This mutation affects the antiproliferative and transrepressive properties of RIP140, as well as the positive regulation of the MSH2, MSH6 and POLK gene. Development of a specific antibody for this mutation would be extremely useful in following the expression of this mutated form within tumors and first tests have been already carried out. In conclusion, RIP140 controls expression of major genes involved in genome integrity maintenance and a mutation of this transcriptional coregulator could be responsible for microsatellite instability of some tumors where alterations of MMR genes are not found. Clinical studies on larger cohorts will be necessary to validate its interest as a marker usable in patient management.

Colorectal cancer (CRC) is the third leading cause of cancer-related death in women and fourth in men globally. While expansions in preventative measures have increased the detection of CRC at the early stages of disease, only 40% of CRC patients are diagnosed when the disease is at a local stage. Moreover, many anti-cancer drugs fail to significantly improve the life expectancy of patients due to innate and acquired resistance, underscoring a need for better diagnostic and therapeutic strategies for CRC. Immunoglobulin-containing and proline-rich receptor-1 (IGPR-1) is a novel cell adhesion molecule (CAM) that was recently identified in our laboratory. IGPR-1 is expressed in epithelial and endothelial cells and promotes cell-cell adhesion. Expression of IGPR-1 in endothelial cells regulates angiogenesis; however, its role in epithelial cells, particularly cancer cells with an epithelial origin, remains unknown. The overall goal of this study was to investigate the possible function of IGPR-1 in CRC tumor cell growth and response to chemotherapeutic agents. Specifically, we aimed to test the hypothesis that increased expression of IGPR-1 in CRC tumor cells promotes cell survival and contributes to the resistance of tumor cells to doxorubicin. Human CRC tumor cell lines, HCT116 and HT29, were transduced via a retroviral system to express IGPR-1 or empty retroviral vector pQCXIP. The effect of overexpression of IGPR-1 in HCT116 and HT29 cells was measured by MTT assay in non-adherent 24-well plates. In addition, cells were viewed under a light microscope, and images were taken to assess multicellular aggregation. Results demonstrated that expression of IGPR-1 in HCT116 and HT29 tumor cells promoted CRC tumor cell growth, increased multicellular aggregation, and stimulated resistance to the conventional chemotherapeutic agent doxorubicin in non-adherent cell culture conditions in vitro. Intriguingly, treatment of cells with doxorubicin promoted phosphorylation of IGPR-1 at serine 220 (Ser220), suggesting a critical role for phosphorylation of IGPR-1 in the development of resistance to chemotherapeutics. In addition, non-adherent cell culture conditions promoted activation of the key pro-apoptotic kinase, p38 MAPK in CRC tumor cells. Ectopic expression of IGPR-1 reversed this activation. This data suggests that IGPR-1, by suppressing p38 activity, in part, promotes tumor cell survival and increases the resistance of tumor cells to the killing effects of doxorubicin. Our findings are the first to demonstrate that IGPR-1 promotes CRC tumor cell growth and increases the resistance of CRC tumor cells to the cytotoxic effects of chemotherapeutic agents. The data suggests that IGPR-1 plays an important role in CRC by inhibiting the cellular apoptotic response and promoting chemotherapeutic resistance. Finally, IGPR-1 phosphorylation at Ser220 in response to doxorubicin may account for the IGPR-1-mediated development of resistance to doxorubicin in CRC.

Liver metastases are the most common cause of death in colorectal cancer patients. The standard of care and potential for cure for colorectal liver metastases is resection, but often times disease it too extensive for this treatment. Over the years, cancer research has made way for advances in treating progressive disease through immunotherapy. By genetically modifying an individual’s immune system using virally transduced chimeric antigen receptor T cells (CAR-T), patients are better able to receive exquisitely specific T cells to target specific tumors. Furthermore, selective delivery strategies may enhance efficacy while limiting detrimental, systemic adverse effects. Not only this, CAR-Ts have also lead to complete remission in some liquid tumors while maintaining the potential for remission in solid tumors as well. This literature review takes readers through the emergence of the different generations of CAR-T and the various studies including clinical trials that have demonstrated the safety and efficacy of CAR-T. The second portion of this paper will outline the design for a phase II clinical trial using intrahepatic CAR-T therapy in addition to selective internal radiation therapy (SIRT) for refractory CEA+ colorectal liver metastases. Benefits and limitations of using these therapies are further discussed.

Colorectal cancer (CRC) is the fourth most common cause of cancer related deaths in the UK with the prognosis dependent on the degree of tumour invasion and presence of metastasis at diagnosis. An important step in the invasion and metastasis of solid tumours is the loss of cell-cell junctions and the acquirement of a more motile mesenchymal phenotype which is facilitated by the epithelial-mesenchymal transition (EMT). The presence of EMT is linked with a more aggressive, invasive tumour and subsequent poor prognosis. In addition to roles in motility and invasion, EMT can induce a cancer stem cell phenotype in a subset of tumour cells. Cancer stem cells (CSCs) are a subpopulation of cells capable of self-renewal and maintaining a cellular population whilst displaying increased therapeutic resistance. Induction of EMT and CSCs can be regulated by common signalling pathways with expression of EMT transcription factors inducing CSCs expression. Understanding the signalling pathways regulating EMT and CSC formation in cancer is important for preventing of metastasis and combating therapeutic resistance. Aspirin’s role in cancer prevention has been established for a number of years with aspirin treatment reducing the incidence of CRC. Recently, evidence has emerged suggesting aspirin treatment may have post-diagnosis benefits and increase survival rates of CRC patients. A potential mechanism for the post-diagnosis benefit of aspirin is the inhibition of EMT and CSC formation which both facilitate tumour progression and metastasis. Aspirin has been demonstrated to suppress the migratory and invasive capacity of lung cancer cell lines by inhibiting EMT. Whilst aspirin has been shown to inhibit platelet-induced EMT in CRC, the direct effects of aspirin on EMT in CRC cell lines has not been established. I hypothesis that aspirin inhibits cell migration, invasion and EMT in CRC which results in a reduction in the CSC population and contributes to the clinical benefit of post-diagnosis aspirin. Using CRC cell lines, I have demonstrated that aspirin treatment inhibits cell migration, invasion, motility and promotes an epithelial phenotype. These results have been confirmed in human organoids and mouse intestinal adenoma in vivo models. Aspirin also promotes a budding phenotype in Apc deficient organoids and reduces expression of stem cell markers in both mouse and human tissue. Aspirin inhibits the mTOR and Wnt signalling pathways in vivo which have the ability to regulate EMT and CSCs although signalling dependency has not been determined. Regardless, aspirin is decreasing the cancer stem cell population and promoting a non-invasive epithelial phenotype which may explain some of the previously described post-diagnosis benefits.

The nucleolus is a multifunctional organelle that, in addition to its primary role in ribosome biogenesis, has emerged as a critical stress sensor and coordinator of stress response. However, the molecular nature of how nucleoli sense stress and coordinate downstream cellular consequence remains poorly understood. NF-κB signalling is a critical regulator of stress response. Many cellular stresses that disrupt nucleolar function also stimulate the NF-κB pathway. However, the role of NF-κB as a downstream effector of nucleolar stress has not yet been examined. Aspirin, a known chemopreventative agent, stimulates the NF-κB pathway to mediate apoptosis but the upstream mechanisms are unclear. In this thesis, I identified a novel nucleolar stress response pathway that culminates in activation of NF-κB signalling, and demonstrated the significance of this nucleolar pathway in the anti-tumour effects of aspirin. Using multiple approaches, I made the novel observations that disruption of the Pol I complex activates the cytoplasmic NF-κB signalling pathway. I show that multiple stress stimuli of NF-κB pathway induce degradation of the crucial Pol I complex component, rDNA transcription initiation factor IA (TIF-IA). I identified the tumour suppressor, p14ARF and the Pol I complex component, upstream binding factor (UBF) as mediators of this degradation. I revealed that inhibition of CDK4 activity lies upstream of UBF/p14ARF-facilitated TIF-IA degradation. Furthermore, using different approaches I show that blocking aspirin/CDK4i-mediated degradation of TIF-IA blocks the effects of these agents on nucleolar morphology and NF-κB signalling. Finally, I show this nucleolar stress response pathway, containing a UBF/p14ARF/TIF-IA axis, is utilized by aspirin to kill colon cancer cells. Taken together, this data presented in this thesis advances understanding of nucleolar stress response, and has therapeutic implications with regard to the anti-tumour effects of aspirin.

Background: Colorectal cancer is one of the most frequently diagnosed cancers today. Dlg is a tumor suppressor gene commonly silenced in cancer cells. Many colorectal cancer patients are subject to vitamin D3 deficiency and/ or an altered microbiome. Treatment using vitamin D3 or probiotics shown decreased cellular proliferation, invasiveness and induction of apoptosis. This study aimed to knockdown Dlg and map genetic interactions coupled to Dlg downregulation using a Drosophila model. Vitamin D3 and probiotic treatments were performed to investigate mechanism of action and capacity for Dlg rescue. Result and discussion: After vitamin D3 treatment, PGRP-SB1 (p<0.0001) and Drsl2 (p<0.0003) expression was significantly increased. These genes are part of the immune related Toll pathway suggesting its activation. Dlg and Veli (p=0.0042) upregulation could tentatively be through vitamin D receptor regulation of Wnt-signaling pathway, or direct VDR interaction. Traf6 and MPK2 (p38α) (p=0.0049) expression increased after vitamin D3 treatment suggesting MPK2 activation through Traf6. Pro-apoptotic pathways through Fas or Bax and decreased survival through inhibition of Pi3K/Akt and Ras/Raf pathways are also possible outcomes of MPK2 activation. Probiotic treatment increased PGRP-SB1 (p<0.0001) without enhanced Drsl2 expression, possibly activating the Imd pathway. JNK-induced apoptosis through Erg (p<0.0001) induction was speculated and increased Dlg (p=0.0113) expression was seen after probiotic treatment. Conclusion: Vitamin D3 and probiotic treatments increased Dlg expression. Genes linked to polarity, growth and apoptosis were also enhanced suggesting various mechanisms of action. Further studies concerning knockdown and treatments are needed to fully understand the true mechanisms of action and interactions.

The aldehyde dehydrogenase (ALDH) superfamily is gaining momentum in regard to stem cell and cancer research. However, their regulation and expression in the cancer microenvironment is poorly understood. The aim of this work was to understand the role of selected ALDH isoforms (1A1, 1A2, 1A3, 1B1, 2, 3A1 and 7A1) in colorectal cancer (CRC) and explore the impact of hypoxia on their expression. CRC cell lines (HT29, DLD-1, SW480 and HCT116) were grown under normoxic or hypoxic conditions (0.1% O2) and HT29 and DLD-1 in spinner flasks to generate multicellular spheroids (MCS). Hypoxia was demonstrated to have an impact on the ALDH expression, which appeared cell-specific. Notably, ALDH7A1 was induced upon exposure to hypoxia in both HT29 and DLD-1 cells, shown to be expressed in the hypoxic region of the MCS variants and in 5/5 CRC xenografts (HT29, DLD-1, HCT116, SW620, and COLO205). ALDH7A1 siRNA knockdown studies in DLD-1 cells resulted in significant reduction of viable cells and significant increase in ROS levels, suggesting ALDH7A1 to possess antioxidant properties. These findings were further supported using isogenic H1299/RFP and H1299/ALDH7A1 lung cancer cell lines. ALDH7A1, however, was found not to be involved in inhibiting the pharmacological effect or causing resistance to different cytotoxic and molecularly targeted anticancer drugs. To unravel the functional role of ALDH7A1, 9 compounds obtained from a virtual screening of 24,000 compounds from the Maybridge collection of compounds were used to probe ALDH7A1 functional activity. One compound, HAN00316, was found to inhibit the antioxidant properties of ALDH7A1 and thus could be a good starting point for further chemical tool development. Although this study underpins a potential important role of ALDH7A1 in hypoxic CRC, further work is required to fully validate its potential as a biomarker and/or pharmacological target.

O câncer é a principal causa de morte nos paises economicamente desenvolvidos e a segunda em paises em desenvolvimento, resultado, em parte, da grande falta de especificidade dos tratamentos atualmente disponíveis. Por outro lado, uma aplicação clínica muito específica, denominada letalidade sintética, foi recentemente proposta. Nesta abordagem terapêutica os inibidores de poli(ADP-ribose) polimerases (PARP), também conhecidos como PARPis, mostraram-se capazes de induzir a morte celular seletiva em células tumorais com defeitos em BRCA1 e BRCA2 (ambas envolvidas no reparo de quebras duplas - DSBR). Assim, a excitante possibilidade de eliminar as células cancerígenas de maneira seletiva fez com que os PARPis passassem de interessantes ferramentas moleculares às mais promissoras drogas anticâncer da atualidade. Contudo, os mecanismos básicos envolvidos na citotoxicidade dos PARPis continuam pouco conhecidos e suas aplicações restritas a um pequeno grupo de cânceres. Por este motivo, neste trabalho, a citotoxicidade do Olaparib (um inibidor de PARP) foi investigada em um painel de linhagens de câncer colorretal (CRC). Os resultados demonstraram que o Olaparib é uma droga de ação lenta, cuja citotoxicidade pode ser modulada por defeitos genéticos em MLH1 (envolvido no reparo de bases mal-emparelhadas) e no supressor tumoral PTEN. Por outro lado, observou-se que o fenótipo MSI (Instabilidade de microssatélites) e os defeitos genéticos em p53 não influenciaram a citotoxicidade do Olaparib. Além disso, linhagens com resistência adquirida a Oxaliplatina (Oxp) e a 5-Fluorouracil (5- Fu) não apresentaram efeito refratário ao Olaparib, enquanto que linhagens com resistência adquirida a SN-38 (metabólito ativo do Irinotecano) apresentaram um forte efeito refratário. Finalmente, as associações de Oxp ou 5-Fu com Olaparib foram capazes de sensibilizar células com resistência relativa e adquirida. Juntos, estes resultados sugerem uma série de novas possibilidades para o emprego de inibidores de PARP no tratamento de CRC. / Cancer is the main cause of death in developed countries and the second in lessdeveloped countries, that results in part from the low specific treatments available. However, a very specific therapeutic approach, called synthetic lethality, was recently proposed. The best documented synthetic lethal interaction was reported between poly(ADP-ribose) polymerases inhibitors (PARPis) and defects in BRCA1 and BRCA2 (both involved in double-strand break repair - DSBR), which may induce selective cancer cells death. Therefore, the exciting possibility to selectively kill cancer cells has been moving PARPis from interesting molecular tools to the forefront of cancer therapy research. However, the basic mechanisms involved in PARPis cytotoxicity are still poorly studied and its clinical applications are restricted to a small number of malignances. Herein, the Olaparib (PARPi) cytotoxicity was investigated in a colorectal cancer (CRC) cell line panel. The results demonstrated that Olaparib is a slow action drug, which may have its effects increased in cells with MLH1 (involved in mismatch repair) and PTEN (tumor supressor) defects. On the other hand, neither the MSI (microsatellite instability) phenotype nor the p53 defects were observed to influence on Olaparib cytotoxicity. Further, neither Oxp nor 5-Fu resistant cell lines presented cross-resistance to Olaparib, whereas a pronounced cross-resistance was observed for SN-38 (Irinotecan metabolite) resistant cell line. Finally, Olaparib associations with Oxaliplatin or 5-Fluorouracil were shown to sensitize cells with both relative and acquired resistances. Together, these results suggest a series of new possible uses for PARP inhibitors in CRC treatment.

The colorectal cancer (CRC) is the third most common malignancy in the world and in Brazil, the fifth most diagnosed and the third cause of cancer deaths. The detection of molecular markers in peripheral blood applies to the early diagnosis of cancer, before and after surgery, reducing the time of identification of CCR and improving the treatment, it is less invasive and reducing costs. This work is quantified by Real Time PCR in absolute and direct, free of DNA fragments found in the serum of patients with colorectal cancer, thereby determining values that characterize the condition of carrier of tumor. For this, a method was developed in which the measurement used as reference samples of the actual fragments ALU115 and ALU247 purified and quantified. We studied 3 major groups: Control, with healthy volunteers; surgery, patients who have already been submitted to surgical removal of colorectal tumor and non-surgery, patients who have not removed the tumor through surgery. Observing the results we note that the groups differ mainly by the values of quantification ALU247. For the control group, the limits were between 91 fentogramas and 1.55 picograms. The non operated group had amounts ranging from 8.02pg to 23.54pg and the group operators, 80fg to 5.95pg. In contrary, the results presented by quantification ALU115 did not set limits defined capable of differentiating at least one of the groups. The control group presented as limits 2pg and 69.45pg and the non operated group, 9.71pg and and 381.56pg, the group operated, 10.69pg and 196.85pg. The non operated group showed a mean significant when compared to the other two groups, but showed minor differences in the quantification ALU247 (14.62 ± 4.73 pg - p <0.05). It could be concluded that direct measurement, using reference concentrations of the fragments themselves ALU115 and ALU247 is a simple methodology, low cost and with reliable results. Moreover, the quantification ALU247 is able to identify the condition of carrier of tumor. / Fundação de Amparo a Pesquisa do Estado de Alagoas / O câncer colorretal (CCR) é a terceira neoplasia maligna mais frequente no mundo, sendo no Brasil a quinta mais diagnosticada e a terceira causa de morte por câncer. A detecção de marcadores moleculares no sangue periférico aplica-se ao diagnóstico precoce de neoplasias, antes e após procedimento cirúrgico, diminuindo assim o tempo de identificação do CCR e melhorando o tratamento, que se torna menos invasivo e diminuindo os custos. O objetivo deste trabalho é quantificar, através da PCR em Tempo Real de forma absoluta e direta, os fragmentos de DNA Livre encontrados no soro de pacientes com câncer colorretal, determinando assim valores que caracterizam a condição de portador de tumor. Para isso, foi desenvolvido um método em que a quantificação utiliza como amostras de referências os próprios fragmentos ALU115 e ALU247 purificados e quantificados. Foram estudados 3 grandes grupos: Controle, com voluntários saudáveis; Operados, pacientes que já se submeteram à cirurgia para retirada de tumor colorretal; e Não-Operados, pacientes que ainda não retiraram o tumor através de cirurgia. Observando os resultados podemos notar que os grupos se diferenciam principalmente através dos valores da quantificação ALU247. Para o grupo Controle, os limites ficaram entre 91 fentogramas e 1,55 picogramas. O grupo Não-Operados apresentou quantidades que vão de 8,02pg a 23,54pg e, o grupo Operados, de 80fg a 5,95 pg. De forma contrária, os resultados apresentados pela quantificação ALU115 não permitiram estabelecer limites definidos capazes de diferenciar pelo menos um dos grupos. O grupo Controle apresentou como limites 2pg e 69,45pg; o grupo Não-Operados, 9,71pg e 381,56pg e; o grupo Operados, 10,69pg e 196,85pg. O grupo Não-Operados apresentou uma média significativa quando comparado aos outros dois grupos, porém apresentou menor heterogeneidade na quantificação ALU247 (14,62pg ± 4,73 - p<0,05). Foi possível concluir que a quantificação direta, utilizando como concentrações de referência os próprios fragmentos ALU115 e ALU247, mostrou-se uma metodologia simples, de baixo custo e com resultados confiáveis. Além disso, a quantificação ALU247 é capaz de identificar a condição de portador de tumor.

Ce manuscrit présente les travaux réalisés pour la mise au point d'un nouvel outil dédié à la détection temps-réelle assistée par ordinateur pour la détection des polypes colorectaux en vidéocoloscopie dans le cadre du dépistage précoce du cancer colorectal. Ce cancer reste aujourd'hui associé à un taux de mortalité important lorsque détecté trop tardivement. Un tel outil pourrait donc permettre d'améliorer la prise en charge.Tout d'abord, une analyse de l'état de l'art permet de mettre en évidence les limitations des méthodes actuelles. Il est alors possible de déterminer le positionnement scientifique et technique à adopter pour créer un outil innovant dédié à cette tâche de détection.Une première phase dédiée à l'analyse d'images fixes permet de confirmer ou d'infirme les choix scientifiques possibles et ainsi de développer une approche en accord avec les contraintes imposées par une utilisation clinique (temps de traitement, performances en particulier). Cette première méthode est ainsi capable de détecter les polypes en moins de 40 millisecondes par image, soit compatible avec le temps réel, en ayant de bonnes performances (F1 Score de 47.55%).Logiquement, on s'intéresse ensuite à la détection des polypes dans les vidéos, qui permet de se rapprocher d'examens réels. En particulier, on propose plusieurs optimisations (comme la cohérence temporelle) permettant de tirer bénéfice de la vidéo. L'outil est alors capable d'alerter le médecin sur la présence de polypes dans 97.6% des cas (36 vidéos) en temps-réel avec, en moyenne, seulement 23 millisecondes pour traiter une image.Au final, cet outil, capable d'alerter le médecin sur la présence de polypes colorectaux en temps-réel durant l'examen, pourrait donc s'intégrer dans la routine clinique de la vidéocoloscopie. Des essais cliniques à venir permettront d'identifier les possibles limitations à lever. / This manuscript presents the work carried out for the development of a new tool dedicated to real-time computer-assisted detection for the detection of colorectal polyps in videocoloscopy, in the context of early detection of colorectal cancer. This cancer remains today associated with a high mortality rate when detected too late. A such tool could help to improve medical care.First of all, an analysis of the state of the art makes it possible to highlight the limitations of current methods. It is then possible to determine the scientific and technical positioning to adopt in order to create an innovative tool dedicated to this detection task.A first phase dedicated to the analysis of still frames confirms or invalidates the possible scientific choices and thus develops an approach in accordance with the constraints imposed by clinical use (processing time, performance in particular). This first method is able to detect polyps in less than 40 milliseconds per image, which is compatible with real time, with good performance (F1 Score of 47.55%).Logically, we are interested in the detection of polyps in videos, which allows to get closer to real exams. In particular, several optimizations (such as temporal coherence) are proposed to benefit from video. The tool is then able to alert the doctor about the presence of polyps in 97.6% of cases (on a set of 36 videos) in real time with only an average processing time of 23 milliseconds per frame.In the end, this tool, which can alert the doctor of the presence of colorectal polyps in real time during the examination, could therefore be part of the clinical routine of videocoloscopy. Future clinical trials will identify possible limitations to be overcome.