Letteratura scientifica selezionata sul tema "Dormance tumorale"

Background: Cystic, sporadic hemangioblastomas (HBLs) represent a unique, therapeutically challenging subset of central nervous system tumors, mainly due to their unpredictable growth patterns and potential for symptomatic progression. This study aims to explore the complexities surrounding the diagnosis, treatment, and long-term management of these lesions. Methods: A comprehensive literature review was performed, and a detailed case study of a 56-year-old patient with a cystic, sporadic cerebellar HBL was produced. Results: The case highlights the multiphasic growth pattern typical of cystic, sporadic HBLs, characterized by periods of dormancy and subsequent rapid expansion. An initial surgical intervention offered temporary control. Tumor recurrence, mainly through cystic enlargement, was treated by SRS. A subsequent recurrence, again caused by cystic growth, eventually led to the patient’s death. The intricacies of treatment modalities, focusing on the transition from surgical resection to stereotactic radiosurgery (SRS) upon recurrence, are discussed. Parameters indicating impending tumor growth, coupled with symptomatic advances, are also explored. Conclusions: The management of cystic, sporadic cerebellar HBLs requires a strategic approach that can be informed by radiological characteristics and tumoral behavior. This study underscores the importance of a proactive, individualized management plan and suggests guidelines that could inform clinical decision making.

The prospective study, which took place from February 2011 to March 2014, included respondents who were sent for computerized dermoscopy because of non-melanocytic skin tumours. Respondents were divided into 2 groups. The first one, group A (45 respondents), consisted of respondents who had expressed concern about the observed changes in the skin and the desire for examination. The second one, group B (50 respondents) were respondents that did not come for examination due to changes on the skin, but for other reasons, so they had indirectly detected suspicious skin lesions. The aim of this study is to analyse the importance of early suspicion of non-melanocytic malignant skin tumours by specialists in primary and secondary health care. Parameters for comparison were respondents' subjective attitude of non-pigment skin lesions and dermoscopy and/or PH findings. It has been shown that changes in the skin that bleed are sometimes highly suspect of NMSC because group A had 5 such cases and NMSC was detected in 4 cases, and group B had 7 respondents with haemorrhage and there were 4 with NMSC. In group B, out of 12 respondents who said that they had found suspicious skin lesions caused by trauma, there were 8 NMSC, while in group A there were 3 cases, which is a statistically significant difference. In group B, out of 16 respondents who claimed that they had had suspicious skin changes dormant for years, NMSC has been proven in 3 cases, and in group A there was not NMSC which is also a statistically significant difference. It was confirmed that the claims of the respondents are unreliable and that all patients should be addressed to computer dermoscopy, in patients with visible changes that arise even a slightest suspicion of NMSC.

Background: Tongue tumors show intra and inter-tumoral heterogenicity with high incidence, relapse and mortality rates necessitating further research. Recurrence/metastasis that occurs after surgical resection of primary cancer is often the reason for poor survival in these patients. Lymph nodes are the most common site of metastasis in tongue tumors. Therefore, premetastatic molecular changes can be best evaluated in lymph nodes which may epitomize the earliest events in the metastasis cascades. The presence of circulating tumor cells(CTCs) in the absence of nodal disease (N0) may represent tumor aggressiveness, suggesting an immune escape which may have high metastatic potential. This trial was developed to investigate the earliest pre-metastatic changes which may regulate tumor dormancy and predict metastasis. A better understanding of organotropism or pre-metastatic changes can help in theragnostic, thereby preventing the outbreak of overt metastasis. Methods: A single-institutional prospective observational cohort study. This trial will be conducted at a tertiary care Centre (Amrita Institute of Medical Sciences Kochi). Eligible patients will be enrolled after obtaining informed consent. The dissected lymph nodes will be subjected to histopathological and immunohistochemical analyses for premetastatic niche (PMN) formation. In addition, circulating tumor cells will be evaluated before treatment and 6 months after treatment. The patients will be followed up for a period of two years to correlate the findings with the recurrence-free survival. Expected results: The pre-metastatic changes, if detected will be a predictive biomarker. It may help to define future drug targets for metastasis chemoprevention . CTCs may define the tumor aggressiveness ,there by prognostication and helps in better disease management. Ethics and dissemination: The study has received the following approval: Ethics Committee of Amrita School of Medicine (ECASM-AIMS-2022-048).Trial Registered Prospectively( CTRI/2022/03/041256 ) on 22/03/2022 under Clinical Trial Registry of India

Abstract Pulmonary diseases are ranked fourth for the high mortality rate, after those tumoral, cardiological or even strokes, which immediately lead to the fatal loss of life. Smoking is listed among the main causes of pulmonary diseases. In addition, another risk factor is air pollution. The main air pollutants are: Carbon monoxide, CO, Dioxide of carbon CO2, Sulfur dioxide SO2, Nitrogen dioxide NO2, fine particles PM, Ozone level O3, Volatile organic compounds (VOC, Lead (Pb)). Pollution can irritate the lungs and lead to their destruction, so it is advisable to live in an environment away from dust and smoke. Other risk factors include chemicals and infections. In Albania, an increase in the number of women affected by smoking is observed. Referring to recent studies conducted on this issue, they show that about 30-40% of Albanians are allergic, while 3% of the population suffers because of asthma. Some of the symptoms of this disease are obstructions in breathing, tightness in the chest or even cough with secretions. Cancer can lie dormant for 20 years and afterwards it may appear. Environmental pollution, genetic transmission, lung infections and smoking are the most common causes of lung cancer. The main pulmonary diseases that affect the citizens of Shkodra are: TB, COPD, Pneumonia, Bronchopneumonia, Pleural effusion, Bronchial asthma, TEP thromboembolism, TU Pneumonia, Bilateral Bronchitis, Diffuse Bronchitis, Hemoptysis, Pulmonary Edema. The presence of green spaces promotes the connection with nature and it can therefore lead to better human well-being. The presence of greenery reduces stress, respiratory diseases, heart diseases as well as helps in connecting with nature. This study is carried out in the infectious disease department of the Regional Hospital of Shkodra from 2021-2023. The results of this study serve as evidence that sheds light on the high prevalence of touch from pulmonary diseases in hospitalized patients in the district of Shkodra. External factors and internal factors must be evident in order for people to become aware of their health problems and to take care in order to prevent the occurrence of these very dangerous diseases.

Abstract Pancreatic Ductal Adenocarcinoma (PDAC) frequently metastasizes into the peritoneum forming peritoneal carcinomatosis, which are so far not treatable effectively. Metastasis-initiating cells need to acquire beneficial traits including cell plasticity, immune evasion, dormancy state control and organ colonization. These characteristics can be summarized in broad terms into two main processes, epithelial-to-mesenchymal transition (EMT) and stemness. Hyaluronic acid (HA), an extracellular matrix component, is a crucial factor in regulating these processes in PDAC, but it is so far not successfully targetable. Analyzing publicly available databases by gene set enrichment analysis (GSEA), a signature related to HA binding was enriched in tumor samples compared to normal tissue. Hyaluronan And Proteoglycan Link Protein 1 (HAPLN1) was the top contributor to the enrichment score, being the 8th most enriched gene overall. We found that higher HAPLN1 expression correlated with shorter overall survival and that HAPLN1high patients had both, basal subtype and EMT signatures enriched. Moreover, these patients had a signature for peritoneal metastasis significantly enriched, suggesting a higher risk for peritoneal carcinomatosis. To study the role of HAPLN1 on PDAC in vitro, we stably overexpressed HAPLN1 in the murine PDAC cell line KPC. KPC-HAPLN1 cells expressed more EMT markers, more stem-related genes and changed the proteoglycan production from Aggrecan to Versican, which is known to be pro-metastatic. We found that spheroid formation, a feature of stemness, was improved in KPC-HAPLN1 vs KPC. Additionally, embedding these spheroids into matrigel led to an increased invasion of KPC-HAPLN1 cells. KPC-HAPLN1 cells improved KPC cell invasion capacities when co-cultured, indicating a paracrine effect. In vivo, intraperitoneal injection of luciferase expressing KPC cells resulted in higher luciferase activity when tumor cells expressed HAPLN1. Analyzing the peritoneal lavage (PL) from these mice, we obtained significantly more tumor cells in KPC-HAPLN1 injected mice. RNAseq data of tumor cells isolated from tumor nodules and PL showed that KPC-HAPLN1 cells acquired an increased metastatic potential and a strong immunomodulatory phenotype. Thus, we evaluated the immune cell composition of the PL by flow cytometry. Neutrophil and monocyte percentages were drastically reduced in KPC-HAPLN1 bearing mice. On the contrary, these mice had a significant increase in macrophages, which showed a reduction in pro-inflammatory gene expression. We conclude that HAPLN1 expression in tumor cells promotes a hyperplastic phenotype that facilitates invasion and colonization of the peritoneum, among others by creation of a pro-tumoral immune microenvironment. Citation Format: Lena Wiedmann, Francesca De Angelis Rigotti, Nuria Vaquero-Siguero, Elisa Donato, Elisa Espinet, Andreas Trumpp, Andreas Fischer, Juan Rodriguez-Vita. HAPLN1 increases peritoneal carcinomatosis by inducing tumor cell hyperplasticity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 960.

Osteosarcoma is the most common primary tumor of the bone with the highest incidence in the first two decades of life. The incidence rate with 95% confidence is 4 for the range of 0-14 and 5 for the range of 0-19 cases pre million per year. Osteosarcoma is a rare malignant mesenchymal tumor with presence of mesenchymal cells and production of osteoid matrix (1). Distinct histological subtypes have been defined, but the biological behavior and the conventional approach to treatment have been similar for last couple of decades without improvement in outcome. The biology of osteosarcoma is characterized with a high rate of lung metastasis. Disorganized genome seems to be the best description of genetic aberrations and changes in gene expression in osteosarcoma, with the most consistent finding, beside the p53 and RB dysregulation,significant aneuploidy and some evidence of massive disruption in the chromosomal structure (2). The metastatic cascade represents a process where cell leaves primary tumor and invades the surrounding tumormicroenvironment with intravascular and also extravascular invasion to the distant sites enabling the blood supply and growth to the secondary site and reengage to the new microenvironment. Meanwhile, metastaticcell could be dormant in the „protective“ environment and then move to the secondary distant sites (3). The microscopic metastases are usually responsible for disease progression, so targeting geneticand epigenetic alterations will certainly improve the outcome (2). Recent studies showed that metastatic clones often do not correspond to the dominant clones in the primary tumor, but may evolve monoclonal and polyclonal, showing the clonal/subclonal heterogeneity of osteosarcoma. At the same time, immune response is a complex process that combines recognition of tumor cells, and response of effector and regulatory immune cells. Tumor cells by soluble factors secretion lead to downmodulation of the immune system. The well known immune „escape“ is the hallmark of cancer when immune system play a dual function, slowing down the tumor progression at first and then facilitating the tumor growth after the modelling phase of tumor cells. How to switch immunotolerance which contribute to permissive microenvironment beneficial for tumor cells to immunocompetent environment, is the challenge of immunotherapy (4). Two mains immunotherapeutic approaches are proposed for bone sarcomas. The first one is based on targeting the pro-tumoral effectors including M2 macrophages, i.e. muramyl tripeptide phosphatidylethanolamine (MTP-PE), interferon gamma (IFNγ) and the molecules associated with immune checkpoints; programmed death-ligand 1 (PD-L1) with it's receptor, programmed cell death protein (PD1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). The other one is based on the stimulation of anti-tumoral effectors; dendritic cells (DC), nitrogen containing bisphosphonates (N-BPs) and natural killer cells (NK). MTP-PE is a drug registered by European Medicinal Agency (EMA) for postoperative treatment of high-grade osteosarcoma. Recently, we have started to apply MTP-PE in Croatia, and in time, we will see the results. The concept of chimeric antigen receptor (CAR) T-lymphocytes (CAR T-cells) has been developed to bypass the human leukocyte antigen restrictions, so diverse CAR T-cells have been developed based on this concept (CAR T-cells targeting B7-H3) (5). The SARC028 clinical trial revealed an interesting clinical response which highlight a major difference between adult and pediatric cancers that may be explained by low expression of neoantigens in addition to their specific microenvironment. Attenuated oncolytic viruses inoculated directly into tumor mass or delivered by macrophages have been proposed as one of the options also. However, the low immunogenicity of pediatric tumors will require other approaches with full molecular profiling of all bone sarcomas. This is mandatory in order to establish targetable biomarkers for better identification and selection of patients for specific therapies.

AbstractCellular plasticity contributes to intra-tumoral heterogeneity and phenotype switching, which enable adaptation to metastatic microenvironments and resistance to therapies. Mechanisms underlying tumor cell plasticity remain poorly understood. SOX10, a neural crest lineage transcription factor, is heterogeneously expressed in melanomas. Loss of SOX10 reduces proliferation, leads to invasive properties, including the expression of mesenchymal genes and extracellular matrix, and promotes tolerance to BRAF and/or MEK inhibitors. We identify the class of cellular inhibitor of apoptosis protein-1/2 (cIAP1/2) inhibitors as inducing cell death selectively in SOX10-deficient cells. Targeted therapy selects for SOX10 knockout cells underscoring their drug tolerant properties. Combining cIAP1/2 inhibitor with BRAF/MEK inhibitors delays the onset of acquired resistance in melanomas in vivo. These data suggest that SOX10 mediates phenotypic switching in cutaneous melanoma to produce a targeted inhibitor tolerant state that is likely a prelude to the acquisition of resistance. Furthermore, we provide a therapeutic strategy to selectively eliminate SOX10-deficient cells.

La radiothérapie utilise les radiations dans le but d’éradiquer les cellules cancéreuses, principalement par la génération de cassures double-brin de l’ADN. Un des effets secondaires de la radiothérapie est l’émergence de seconds cancers, préférentiellement en bordure du volume traité, où des cellules normales reçoivent un niveau de dose non létal. Ces seconds sarcomes se développent principalement après une période de latence de 3 à 20 ans. Nous avons déterminé la distribution des dommages à l’ADN (CSB et CDB) dans le champ d’irradiation et en bordure de celui-ci, après différentes conditions d’irradiations. Nous avons évalué les dommages à l’ADN et l’induction de sénescence après un traitement fractionné. La détection des foyers XRCC1 et 53BP1 par immunofluorescence a été utilisé comme marqueurs des CSB et CDB respectivement. Enfin, la sénescence a été évaluée par la mesure de l’activité de l’enzyme SA-beta-galactosidase. Nous avons également développé un modèle théorique d’évolution cellulaire, avec pour objectif le suivi des cellules après l’action d’un traitement géno-toxique, tel que la radiothérapie ou la chimiothérapie. Les caractéristiques principales de cycle cellulaire, d’endommagement et de réparation de l’ADN, et de la diffusion chimique ont été incluses. Le modèle d’évolution cellulaire est basé sur la théorie des chaines de Markov. Deux applications du modèle sont présentées (survie cellulaire et effet bystander)
Radiotherapy uses ionizing radiations in order to eradicate cancer cells mainly through the generation of DNA double-strand breaks. A side effect of radiotherapy is the emergence of second cancer, preferentially at the border of the treated volume, where normal cells receive some non-lethal leaking radiations. These second cancers are mainly sarcomas and develop with a latency of 3 to 20 years. We have determine the distribution of DNA damage (SSBs and DSBs) both in-and at the border of the irradiation field following various conditions of irradiation. We also investigated DNA damages and induction of senescence after multi-session of treatment. Fluorescent detection of 53BP1 and XRCC1 foci was used as a marker of DSBs and SSBs respectively. Finally senescence state has been tested by measurement of SA-beta-galactosidase activity. We also developped a theoretical agent-based model of cell evolution under the action of cytotoxic treatments, such as radiotherapy or chemotherapy. The major features of cell cycle and proliferation, cell damage and repair, and chemical diffusion are included. Cell evolution is based on a discrete Markov chain. Two showcase applications of the model are then presented (survival curves and bystander effect)

État de l’art : La dormance tumorale est une stratégie de résistance utilisée par les cellules cancéreuses. Elle constitue un obstacle majeur dans la thérapie du cancer, puisqu’elle mène à la maladie résiduelle minimale (MRD) et augmente le risque de rechute. Bien que cliniquement significatifs, les mécanismes derrière la dormance tumorale et la MRD ne sont pas bien compris. Nous avons utilisé deux modèles murins syngéniques de leucémie myéloïde et de mélanome élaborés par le laboratoire pour explorer les profils génétiques, épigénétiques, transcriptomiques et protéomiques liés à la dormance tumorale. Par cette approche multi-omique, nous avons cherché à découvrir les processus moléculaires conduisant à la MRD et à identifier des cibles thérapeutiques potentielles.Résultats :Nous avons réalisé une analyse multi-omique complexe incluant le séquençage de l'exome entier (WES), l'analyse des variations du nombre de copies (CNV), l'immunoprécipitation de la chromatine suivie du séquençage (ChIP-seq) et des investigations du transcriptome et du protéome. L'analyse WES a identifié un chevauchement subtil de mutations génétiques entre les modèles de dormance de mélanome et de leucémie, avec de nombreuses mutations trouvées exclusivement dans les cellules de dormance. Ces signatures génétiques spécifiques suggèrent que les pressions sélectives durant la MRD peuvent conférer une résistance au microenvironnement ou aux traitements. En combinant les données CNV, les marques d'histones et les signatures d'expression génique transcriptomique avec l'analyse d'enrichissement de Gene Ontology (GO), nous avons identifié des rôles fonctionnels potentiels de ces gènes mutés et obtenu des informations sur les voies impliquées dans la MRD. De plus, en comparant les "gènes MRD murins" avec les données correspondantes aux maladies humaines provenant de bases de données publiques,nos travaux soulignent des caractéristiques communes liées à la progression de la maladie. L'analyse protéomique, combinée aux investigations génétiques multiomiques,a révélé une signature protéique distincte dans les cellules de dormance avec une implication minimale des mécanismes génétiques. L'analyse 'enrichissement des voies a mis en évidence les processus métaboliques, de différenciation et de remodelage du cytosquelette impliqués dans la MRD. Enfin, nous avons identifié 11 protéines exprimées différemment dans les cellules de dormance de ces deux pathologies. Conclusions : Notre recherche met en évidence la nature complexe de la dormance tumorale,impliquant à la fois des éléments génétiques et non génétiques. En comparant les données génomiques, transcriptomiques, protéomiques et épigénomiques, nous fournissons un aperçu approfondi du paysage moléculaire associé à la MRD. Ces résultats posent une base solide pour de futures études et suggèrent des directions prometteuses pour le développement de thérapies ciblées pour la MRD chez les patients atteints de leucémie et de mélanome. Cela souligne la nécessité de prendre en compte à la fois des facteurs génétiques et non génétiques dans les stratégies de traitement
Background : Tumor dormancy, a resistance strategy used by cancer cells, is a major impediment in cancer therapy, leading to minimal residual disease (MRD) and increasing the risk of relapse. Although clinically significant, the mechanisms behind tumor dormancy and MRD are not well understood. In this research, we employed two syngeneic murine models of myeloid leukemia and melanoma to explore the genetic,epigenetic, transcriptomic, and proteomic profiles linked to tumor dormancy. By applying a multiomics approach, we aimed to uncover the molecular processes driving MRD and identify possible therapeutic targets. Results : We performed a comprehensive omics analysis that included whole-exome sequencing (WES), copy number variation (CNV) analysis, chromatin immunoprecipitation followed by sequencing (ChIP-seq), and investigations of the transcriptome and proteome. The WES analysis identified a limited overlap of gene mutations between the melanoma and leukemia dormancy models, with many mutations found exclusively in dormant cells. These unique genetic signatures suggest that selective pressures during MRD may provide resistance to the surrounding microenvironment or treatments. Combining CNV data, histone marks, and transcriptomic gene expression signatures with Gene Ontology enrichment analysis,we identified the potential functional roles of these mutated genes and gained insights into the pathways involved in MRD. Furthermore, by comparing "murine MRD genes"with corresponding human disease data from public databases, we identified common features related to disease progression. Proteomic analysis, integrated with multi-omics genetic investigations, revealed a distinct protein signature in dormant cells with minimal involvement of genetic mechanisms. Pathway enrichment analysis pointed to the metabolic, differentiation, and cytoskeletal remodeling processes involved in MRD. Ultimately, we identified 11 proteins that were differentially expressed in dormant cells across both types of pathology. Conclusions : Our research highlights the intricate nature of tumor dormancy, involving both genetic and non-genetic elements. Through the comparison of genomic,transcriptomic, proteomic, and epigenomic data, we deliver an extensive overview of the molecular landscape associated with minimal residual disease. These findings laya solid groundwork for future studies and suggest promising directions for developing targeted therapies for MRD in leukemia and melanoma patients. This underscores the necessity of incorporating both genetic and non-genetic factors into treatment strategies

Le cancer colorectal est la première pathologie cancéreuse de la sphère digestive, tant en terme de fréquence que de mortalité par an. Chaque année, 41 000 nouveaux cas sont diagnostiqués et 17 000 décès sont dus à ce cancer en France. Deux paramètres cliniques expliquent la mortalité de ce cancer; d'une part le fait qu'un patient sur deux est diagnostiqué au stade métastatique ou va présenter des lésions métastatiques durant l'histoire de sa pathologie, d'autre part le fait que les patients après traitement vont fréquemment présenter une récidive de leur pathologie. L'utilisation de régimes de chimiothérapies avant et après résection métastatique améliore la survie sans récidive à court terme, mais à 2 ans post chirurgie l'avantage apporté est perdu. Ainsi, la compréhension des mécanismes d'échappement à la chimiothérapie et régissant la croissance tumorale est d'intérêt pour tenter de limiter la récidive tumorale. L'objectif de ce travail de thèse a consisté en l'analyse de sous-populations obtenues sous pression de chimiothérapie au 5-Fluorouracile (5FU) dérivées de la lignée cancéreuse colique HT29, ainsi que les mécanismes moléculaires associés. Notre clone le plus chimiorésistant isolé, le modèle cellulaire 5F31, quitte le compartiment prolifératif sous traitement à fortes doses de 5FU, ceci étant associé à une perturbation de la voie de signalisation de la Src kinase c-Yes et de son partenaire, le co-activateur transcriptionnel YAP. Sous traitement, les cellules chimiorésistantes entrent en quiescence, le complexe protéique entre c-Yes et YAP est perdu et la quantité totale et nucléaire de YAP diminue de manière significative (Igoudjil, Touil, Corvaisier et al. 2014 Clinical Cancer Research). Dès lors, la suite des travaux a consisté en l'étude du rôle potentiel de YAP sur la balance quiescence/prolifération sous 5FU. L'inhibition pharmacologique ou l'inhibition transitoire de l'expression de YAP et de son paralogue, la protéine TAZ, dans plusieurs lignées cancéreuses coliques induit l'augmentation de la fraction de cellules quiescentes, associée au ralentissement significatif de la croissance tumorale. A l'inverse, la surexpression d'une forme constitutivement active de YAP demeurant nucléaire sous 5FU maintient les cellules 5F31 en prolifération et sensibilise les cellules à la chimiothérapie. Au niveau des effecteurs protéiques, l'induction de quiescence (par traitement à la chimiothérapie ou inhibition de YAP/TAZ) est associée à la perte d'expression de la Cycline E1 et du facteur de transcription c-Myc. A l'inverse, la surexpression du dominant constitutivement actif de YAP dans les cellules 5F31 conduit à l'expression soutenue de la Cycline E1 sous 5FU, expression nécessitant l'activation du facteur de transcription CREB. L'inhibition de la Cycline E1 permet d'induire la quiescence cellulaire, proposant cette protéine comme l'un des effecteurs des protéines YAP/TAZ dans la régulation entre la quiescence et la prolifération cellulaire (Corvaisier et al, Oncotarget, 2016). En conclusion, nos données montrent l'importance du rôle des protéines YAP/TAZ dans le maintien des cellules en prolifération via l'expression notamment de la Cycline E1. Nos résultats sur cohorte de patients atteints de métastases hépatiques de cancers colorectaux montrent que l'expression des co-activateurs YAP/TAZ est liée à un index prolifératif plus important, confortant nos données sur le rôle de ces protéines dans la croissance tumorale. De plus, l'expression élevée de YAP et TAZ est associée en analyses multivariées à une récidive plus précoce et à une survie globale plus faible. Ainsi, l'étude de l'expression et du niveau d'activation de ces acteurs serait un marqueur pronostic intéressant dans l'anticipation de la récidive métastatique ; ainsi que des cibles thérapeutiques intéressantes pour tenter de limiter la rechute tumorale
Colorectal cancer is the most frequent and lethal cancerous pathology from the digestive system. Each year in France, 41 000 new cases are diagnosed and 17 000 patients die due to this pathology. This high mortality is mainly due to the rate of patients with liver metastatic lesions and the early relapse of those metastases after treatment. The use of chemotherapy prior to surgery induces a decrease of early relapse, however 2 years after resection this advantage is lost. Thus, understanding the mechanisms underlying escape to treatment is required to try to delay or prevent tumor recurrence.The aim of this doctoral work was to analyze clonal chemoresistant subpopulations derived from the colorectal cancer cell line HT29 after chronic exposure to 5-Fluorouracil (5FU) and molecular mechanisms associated with chemoresistance. The most chemoresistant clonal subpopulation, 5F31, stops its proliferation after treatment with high dose of 5FU, this behavior being associated with the modulation of the c-Yes/YAP axis. After treatment, 5F31 cells enter quiescence, interaction between c-Yes and YAP is lost and total and nuclear YAP protein expression reduces significantly (Igoudjil, Touil, Corvaisier et al. 2014, Clinical Cancer Research). The next step was to study functions of YAP protein in this chemotherapy- induced quiescence.Pharmacological or transient inhibition of YAP and its homolog TAZ, induces quiescence and reduces cellular growth in several colorectal cancer cell lines. On the other hand, overexpression of a constitutively active form of YAP in 5F31 cells forces cells to remain proliferative under 5FU treatment, enhancing 5F31 cell chemosensitivity to 5FU.Regarding proteic effectors, quiescence (either induced by 5FU or YAP/TAZ inhibition) is associated with loss of expression of the transcription factor c-Myc and Cyclin E1. In 5F31 cells expressing the active mutant form of YAP, Cyclin E1 expression is sustained after 5FU treatment through the activation of the transcription factor CREB. Cyclin E1 inhibition is sufficient to induce quiescence, therefore introducing this protein as one of the final effectors of YAP/TAZ co-activators in the regulation of the proliferation/quiescence switch in colorectal cancer cells (Corvaisier et al. 2016, Oncotarget).To conclude, our work reveals the importance of YAP/TAZ proteins for the maintenance of colorectal cancer cells proliferation through Cyclin E1 expression. Our work on liver metastases from patients with colorectal cancer shows that high expression of YAP/TAZ is connected to a higher proliferative index in metastatic lesions. Moreover, high YAP/TAZ expression is associated with shorter patient progression-free survival and shorter overall survival. Studying the expression and level of YAP/TAZ activation could be an interesting prognosis marker to anticipate metastatic relapse and potent druggable target to delay tumoral recurrence

Le cancer du sein est la tumeur maligne la plus fréquemment diagnostiquée chez les femmes dans le monde. En fonction du stade et du grade, les protocoles de gestions thérapeutiques du cancer du sein sont généralement efficaces, cependant, certaines cellules cancéreuses parviennent à échapper à ces tentatives et entrent en dormance. Les cellules cancéreuses dormantes sont des cellules viables et non prolifératives qui peuvent conserver ces propriétés pendant plusieurs années, voire des décennies, alors que le patient est considéré comme cliniquement guéri. Le réveil des cellules tumorales dormantes est un réel problème de santé, puisque les patientes présentant des récidives ont un mauvais pronostique de survie. Dans le cancer du sein, tout comme lors du développement métastatique de ces mêmes tumeurs, les cellules cancéreuses évoluent au milieu d'un stroma dit « réactif », contenant de nombreux types cellulaires ainsi que des composants de la matrice extracellulaire (MEC). De nombreuses évidences expérimentales suggèrent que ces facteurs micro-environnementaux initient la réactivation des cellules cancéreuses dormantes, conduisant à une rechute du patient. Les macrophages sont l'un des principaux types de cellules favorisant le développement des tumeurs primaires et métastatiques dans le microenvironnement tumoral. Bien que les macrophages puissent favoriser le développement du cancer par divers mécanismes, leur implication dans l'échappement à la dormance n'a encore jamais été démontrée.En utilisant la lignée cellulaire D2.OR - un modèle de dormance à la fois in vitro et in vivo - mes travaux expérimentaux démontrent pour la première fois que les interactions fonctionnelles entre les cellules cancéreuses dormantes et les macrophages entraînent le réveil des cellules cancéreuses. J'ai découvert que les macrophages actives entraine le réveil des cellules tumorales dormantes via la sécrétion de facteurs paracrines et le remodelage de la MEC. En effet, mes travaux de thèse montrent que le remodellage de la MEC par un milieu conditionné dérivé des macrophages est suffisant pour induire le réveil des cellules dormantes, ce qui indique que les des modifications de la MEC par les macrophages sont responsable du réveil des cellules tumorales. De plus, je démontre que les activités catalytiques des enzymes MMP9 et LOX sont essentielles dans ce processus.Afin de mieux caractériser le rôle des macrophages dans le réveil des cellules cancéreuses, j'ai également cherché à savoir quelles sont les voies de signalisation activées dans les cellules D2.OR et qui sont responsables du reveil. Mes resultats montrent que le remodelage de la matrice par les macrophages entrainent la voie de signalisation intégrine-B1/FAK/Src/Her2 dans les cellules tumorales, entrainant ainsi leur reveil. Cela aboutit à l'activation de la kinase ERK, favorisant ainsi la transition de la dormance à un état prolifératif. Comprendre les mécanismes moléculaires qui régulent l'influence de l'inflammation sur le réveil des cellules tumorales dormantes est essentiel pour découvrir de nouvelles cibles thérapeutiques potentielles pour le développement de thérapies ciblées afin de prévenir la récidive des patients
Breast cancer is the most frequently diagnosed malignant tumor in women worldwide. Breast cancer therapeutic management protocols are usually considered to be successful, however, relapses are frequent as some cancer cells can manage to escape from these attempts by undergoing dormancy. Dormant cancer cells are viable, non-proliferative cells that preserve their status for years or even decades while the patient is considered as clinically free of cancer. However, when these cells awaken, patient relapse occurs with poor survival outcome. In breast carcinoma, cancer cells co-evolve with a reactive stroma containing extracellular matrix (ECM) components and cancer-promoting cellular elements. Evidence suggests that these microenvironmental factors can initiate the awakening of the dormant cancer cells, which can eventually lead to patient relapse. Macrophages are one of the major tumor-promoting cell type within the tumor microenvironment. Although macrophages can support cancer development via various mechanisms, their direct involvement in dormancy escape has never been demonstrated.Using the D2.OR cell line - a well-established model for cancer dormancy both in vitro and in vivo - we demonstrated for the first time that functional interactions between dormant cancer cells and macrophages result in cancer cell awakening. We found that macrophages mediate dormancy escape via the secretion of paracrine factors. Furthermore, we showed that priming the extracellular matrix with macrophage-derived conditioned media is sufficient to induce the awakening of dormant cells, indicating that macrophages mediate dormancy escape through ECM modifications. Moreover, we discovered that MMP9 and LOX enzyme activities have essential functions in this process.Biochemistry and cellular biology analysis of the D2.OR intracellular signalling pathways revealed that signals from the ECM, following macrophage-mediated ECM remodelling, induce an integrin-B1/FAK/Src axis that triggers Her2 receptor tyrosine kinase activation in a ligand-independent manner. This culminates to an ERK/MAP Kinase activation, thus promoting the transition from dormancy to a proliferative status.Understanding the molecular mechanisms that regulate dormancy or the switch to a proliferative state is critical for discovering novel targets for the development of targeted therapies to prevent patient recurrence