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1.
Front Immunol ; 14: 1264093, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38022675

RESUMO

Background: Deconvoluting the heterogenous prognosis of Human Papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OSCC) is crucial for enhancing patient care, given its rapidly increasing incidence in western countries and the adverse side effects of OSCC treatments. Methods: Transcriptomic data from HPV-positive OSCC samples were analyzed using unsupervised hierarchical clustering, and clinical relevance was evaluated using Kaplan-Meier analysis. HPV-positive OSCC cell line models were used in functional analyses and phenotypic assays to assess cell migration and invasion, response to cisplatin, and phagocytosis by macrophages in vitro. Results: We found, by transcriptomic analysis of HPV-positive OSCC samples, a ΔNp63 dependent molecular signature that is associated with patient prognosis. ΔNp63 was found to act as a tumor suppressor in HPV-positive OSCC at multiple levels. It inhibits cell migration and invasion, and favors response to chemotherapy. RNA-Seq analysis uncovered an unexpected regulation of genes, such as DKK3, which are involved in immune response-signalling pathways. In agreement with these observations, we found that ΔNp63 expression levels correlate with an enhanced anti-tumor immune environment in OSCC, and ΔNp63 promotes cancer cell phagocytosis by macrophages through a DKK3/NF-κB-dependent pathway. Conclusion: Our findings are the first comprehensive identification of molecular mechanisms involved in the heterogeneous prognosis of HPV-positive OSCC, paving the way for much-needed biomarkers and targeted treatment.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Infecções por Papillomavirus , Humanos , Papillomavirus Humano , Infecções por Papillomavirus/complicações , Neoplasias de Cabeça e Pescoço/genética , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética
2.
Int J Mol Sci ; 24(13)2023 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-37446353

RESUMO

Head and neck squamous cell carcinomas (HNSCCs) are heterogeneous tumors, well known for their frequent relapsing nature. To counter recurrence, biomarkers for early diagnosis, prognosis, or treatment response prediction are urgently needed. miRNAs can profoundly impact normal physiology and enhance oncogenesis. Among all of the miRNAs, the miR-30 family is frequently downregulated in HNSCC. Here, we determined how levels of the 3p passenger strands of miR-30a and miR-30e affect tumor behavior and clarified their functional role in LA-HNSCC. In a retrospective study, levels of miR-30a-3p and miR-30e-3p were determined in 110 patients and correlated to overall survival, locoregional relapse, and distant metastasis. miR-30a/e-3p were expressed in HNSCC cell lines and HNSCC patient-derived tumoroids (PDTs) to investigate their effect on tumor cells and their microenvironment. Both miRNAs were found to have a prognosis value since low miR-30a/e-3p expression correlates to adverse prognosis and reduces overall survival. Low expression of miR-30a/e-3p is associated with a shorter time until locoregional relapse and a shorter time until metastasis, respectively. miR-30a/e-3p expression downregulates both TGF-ßR1 and BMPR2 and attenuates the survival and motility of HNSCC. Results were confirmed in PDTs. Finally, secretomes of miR-30a/e-3p-transfected HNSCC activate M1-type macrophages, which exert stronger phagocytic activities toward tumor cells. miR-30a/e-3p expression can discriminate subgroups of LA-HNSCC patients with different prognosis, making them good candidates as prognostic biomarkers. Furthermore, by targeting members of the TGF-ß family and generating an immune-permissive microenvironment, they may emerge as an alternative to anti-TGF-ß drugs to use in combination with immune checkpoint inhibitors.


Assuntos
Neoplasias de Cabeça e Pescoço , MicroRNAs , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Estudos Retrospectivos , Neoplasias de Cabeça e Pescoço/genética , Recidiva Local de Neoplasia/genética , MicroRNAs/genética , Regulação Neoplásica da Expressão Gênica , Microambiente Tumoral/genética
3.
Cancers (Basel) ; 13(12)2021 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-34207120

RESUMO

The EGFR-targeting antibody cetuximab (CTX) combined with radiotherapy is the only targeted therapy that has been proven effective for the treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Recurrence arises in 50% of patients with HNSCC in the years following treatment. In clinicopathological practice, it is difficult to assign patients to classes of risk because no reliable biomarkers are available to predict the outcome of HPV-unrelated HNSCC. In the present study, we investigated the role of Caveolin-1 (Cav1) in the sensitivity of HNSCC cell lines to CTX-radiotherapy that might predict HNSCC relapse. Ctrl- and Cav-1-overexpressing HNSCC cell lines were exposed to solvent, CTX, or irradiation, or exposed to CTX before irradiation. Growth, clonogenicity, cell cycle progression, apoptosis, metabolism and signaling pathways were analyzed. Cav1 expression was analyzed in 173 tumor samples and correlated to locoregional recurrence and overall survival. We showed that Cav1-overexpressing cells demonstrate better survival capacities and remain proliferative and motile when exposed to CTX-radiotherapy. Resistance is mediated by the Cav1/EREG/YAP axis. Patients whose tumors overexpressed Cav1 experienced regional recurrence a few years after adjuvant radiotherapy ± chemotherapy. Together, our observations suggest that a high expression of Cav1 might be predictive of locoregional relapse of LA-HNSCC.

4.
Front Immunol ; 12: 635166, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33790905

RESUMO

The extracellular matrix (ECM) molecule Tenascin-C (TNC) is well-known to promote tumor progression by multiple mechanisms. However, reliable TNC detection in tissues of tumor banks remains limited. Therefore, we generated dromedary single-domain nanobodies Nb3 and Nb4 highly specific for human TNC (hTNC) and characterized the interaction with TNC by several approaches including ELISA, western blot, isothermal fluorescence titration and negative electron microscopic imaging. Our results revealed binding of both nanobodies to distinct sequences within fibronectin type III repeats of hTNC. By immunofluroescence and immunohistochemical imaging we observed that both nanobodies detected TNC expression in PFA and paraffin embedded human tissue from ulcerative colitis, solid tumors and liver metastasis. As TNC impairs cell adhesion to fibronectin we determined whether the nanobodies abolished this TNC function. Indeed, Nb3 and Nb4 restored adhesion of tumor and mesangial cells on a fibronectin/TNC substratum. We recently showed that TNC orchestrates the immune-suppressive tumor microenvironment involving chemoretention, causing tethering of CD11c+ myeloid/dendritic cells in the stroma. Here, we document that immobilization of DC2.4 dendritic cells by a CCL21 adsorbed TNC substratum was blocked by both nanobodies. Altogether, our novel TNC specific nanobodies could offer valuable tools for detection of TNC in the clinical practice and may be useful to inhibit the immune-suppressive and other functions of TNC in cancer and other diseases.


Assuntos
Anticorpos Neutralizantes/imunologia , Camelus/imunologia , Anticorpos de Domínio Único/imunologia , Tenascina/antagonistas & inibidores , Animais , Anticorpos Neutralizantes/farmacologia , Especificidade de Anticorpos , Sítios de Ligação de Anticorpos , Adesão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Colite Ulcerativa/imunologia , Colo/imunologia , Ensaio de Imunoadsorção Enzimática , Células HEK293 , Humanos , Imuno-Histoquímica , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/secundário , Ligação Proteica , Anticorpos de Domínio Único/farmacologia , Tenascina/administração & dosagem , Tenascina/imunologia
5.
Cancers (Basel) ; 11(6)2019 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-31181806

RESUMO

The management of locally advanced head and neck squamous cell carcinoma (HNSCC) with Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), achieves only moderate response rates, and clinical trials that evaluated EGFR-blockade with tyrosine kinase inhibitors (TKI) yielded disappointing results. Inter-tumor heterogeneity may hinder the therapeutic efficiency of anti-EGFR treatments. HNSCC heterogeneity was addressed in several studies, which all converged towards the definition of molecular subgroups. They include the basal subgroup, defined by the deregulated expression of factors involved in the EGFR signaling pathway, including the epiregulin EGFR ligand encoded by the EREG gene. These observations indicate that basal tumors could be more sensitive to anti-EGFR treatments. To test this hypothesis, we performed a screen of a representative collection of basal versus non-basal HNSCC cell lines for their sensitivity to several anti-EGFR drugs (Cetuximab, Afatinib, and Gefitinib), tested as monotherapy or in combination with drugs that target closely-linked pathways [Mitogen-activated protein kinase kinase/ extracellular signal-regulated kinases (MEK), mammalian Target of Rapamycine (mTOR) or Human Epidermal growth factor Receptor 2 (HER2)]. Basal-like cell lines were found to be more sensitive to EGFR blockade alone or in combination with treatments that target MEK, mTOR, or HER2. Strikingly, the basal-like status was found to be a better predictor of cell response to EGFR blockade than clinically relevant mutations [e.g., cyclin-dependent kinase Inhibitor 2A (CDKN2A)]. Interestingly, we show that EGFR blockade inhibits EREG expression, and that EREG knock-down decreases basal cell clonogenic survival, suggesting that EREG expression could be a predictive functional marker of sensitivity to EGFR blockade in basal-like HNSCC.

6.
Oncotarget ; 7(28): 44023-44038, 2016 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-27281619

RESUMO

At the time of diagnosis, 60% of patients with head and neck squamous cell carcinoma (HNSCC) present tumors in an advanced stage (III-IV) of disease and 80% will relapse within the first two years post-treatment, due to their frequent radio(chemo)resistance. To identify new molecular targets and companion biomarkers, we have investigated the miRNome of 75 stage III-IV oropharynx tumors without relapse (R) or with loco-regional relapse (non-responder, NR) within two years post-treatment. Interestingly, miR-422a was significantly downregulated in NR tumors, in agreement with the increase in cell proliferation and adhesion induced by miR-422a inhibition in vitro. Furthermore, we identified CD73/NT5E oncogene as target of miR-422a. Indeed, modulation of the endogenous level of miR-422a inversely influences the expression and the enzymatic activity of CD73. Moreover, knocking down CD73 mimics the effects of miR-422a upregulation. Importantly, in tumors, miR-422a and CD73 expression levels are inversely correlated, and both are predictive of relapse free survival - especially considering loco(regional) recurrence - in vitro two independent cohorts of advanced oropharynx or HNSCC (N=255) tumors. In all, we reported, for the first time, that MiR-422a and its target CD73 are involved in early loco(regional) recurrence of HNSCC tumors and are new targets for personalized medicine.


Assuntos
5'-Nucleotidase/genética , Carcinoma de Células Escamosas/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , MicroRNAs/genética , 5'-Nucleotidase/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Adesão Celular/genética , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/genética , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Interferência de RNA
7.
Oral Oncol ; 51(9): 848-56, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26121938

RESUMO

OBJECTIVES: Human Papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OSCC) patients have improved prognosis compared to other head and neck (HNSCC) cancers. Since poor prognosis is associated with tumour hypoxia, we studied whether the hypoxic response is different in HPV-related cells and tumours. MATERIAL AND METHODS: HPV-positive and -negative cells were incubated in hypoxia and analyzed by qRTPCR, western blotting and cell proliferation assays. Tumours formed by xenografting these cells in nude mice were studied by IHC. HNSCC patient samples were analyzed by unsupervised clustering of hypoxia-related gene expression, quantitative real-time PCR (qRTPCR) and immunohistochemical (IHC) detection of neo-blood vessels. RESULTS AND CONCLUSION: HPV-positive and -negative cells responded differently to hypoxia, in terms of gene expression (HIF-1α, PHD-3, GLUT-1 and VEGF-A) and cell survival. Tumour xenografts formed by HPV-positive cells had fewer hypoxic areas than those formed by HPV-negative cells. HPV related tumours were less hypoxic, expressed lower levels of hypoxia-responsive genes, and had a higher density of neo-blood vessels. HPV-related OSCC display lower tumour hypoxia, which could be linked to the distinct intrinsic abilities of HPV-positive tumour cells to adapt to hypoxia and to their better prognosis.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Neoplasias Orofaríngeas/metabolismo , Infecções por Papillomavirus/metabolismo , Animais , Western Blotting , Hipóxia Celular/fisiologia , Sobrevivência Celular/fisiologia , Feminino , Expressão Gênica/fisiologia , Humanos , Masculino , Camundongos , Camundongos Nus , Reação em Cadeia da Polimerase em Tempo Real
8.
BMC Syst Biol ; 9: 28, 2015 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-26080803

RESUMO

BACKGROUND: Estrogen receptor alpha36 (ERalpha36), a variant of estrogen receptor alpha (ER) is expressed in about half of breast tumors, independently of the [ER+]/[ER-] status. In vitro, ERalpha36 triggers mitogenic non-genomic signaling and migration ability in response to 17beta-estradiol and tamoxifen. In vivo, highly ERalpha36 expressing tumors are of poor outcome especially as [ER+] tumors are submitted to tamoxifen treatment which, in turn, enhances ERalpha36 expression. RESULTS: Our study aimed to validate ERalpha36 expression as a reliable prognostic factor for cancer progression from an estrogen dependent proliferative tumor toward an estrogen dispensable metastatic disease. In a retrospective study, we tried to decipher underlying mechanisms of cancer progression by using an original modeling of the relationships between ERalpha36, other estrogen and growth factor receptors and metastatic marker expression. Nonlinear correlation analyses and mutual information computations led to characterize a complex network connecting ERalpha36 to either non-genomic estrogen signaling or to metastatic process. CONCLUSIONS: This study identifies ERalpha36 expression level as a relevant classifier which should be taken into account for breast tumors clinical characterization and [ER+] tumor treatment orientation, using a generic approach for the rapid, cheap and relevant evaluation of any candidate gene expression as a predictor of a complex biological process.


Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Biologia Computacional/métodos , Progressão da Doença , Receptor alfa de Estrogênio/genética , Variação Genética , Neoplasias da Mama/classificação , Neoplasias da Mama/patologia , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Metástase Neoplásica , Prognóstico
9.
Clin Cancer Res ; 19(15): 4174-84, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23757353

RESUMO

PURPOSE: Distant metastasis after treatment is observed in about 20% of squamous cell carcinoma of the head and neck (HNSCC). In the absence of any validated robust biomarker, patients at higher risk for metastasis cannot be provided with tailored therapy. To identify prognostic HNSCC molecular subgroups and potential biomarkers, we have conducted genome-wide integrated analysis of four omic sets of data. EXPERIMENTAL DESIGN: Using state-of-the-art technologies, a core set of 45 metastasizing and 55 nonmetastasizing human papillomavirus (HPV)-unrelated HNSCC patient samples were analyzed at four different levels: gene expression (transcriptome), DNA methylation (methylome), DNA copy number (genome), and microRNA (miRNA) expression (miRNome). Molecular subgroups were identified by a model-based clustering analysis. Their clinical relevance was evaluated by survival analysis, and functional significance by pathway enrichment analysis. RESULTS: Patient subgroups selected by transcriptome, methylome, or miRNome integrated analysis are associated with shorter metastasis-free survival (MFS). A common subgroup, R1, selected by all three omic approaches, is statistically more significantly associated with MFS than any of the single omic-selected subgroups. R1 and non-R1 samples display similar DNA copy number landscapes, but more frequent chromosomal aberrations are observed in the R1 cluster (especially loss at 13q14.2-3). R1 tumors are characterized by alterations of pathways involved in cell-cell adhesion, extracellular matrix (ECM), epithelial-to-mesenchymal transition (EMT), immune response, and apoptosis. CONCLUSIONS: Integration of data across several omic profiles leads to better selection of patients at higher risk, identification of relevant molecular pathways of metastasis, and potential to discover biomarkers and drug targets.


Assuntos
Carcinoma de Células Escamosas/genética , Metilação de DNA/genética , Neoplasias de Cabeça e Pescoço/genética , MicroRNAs/genética , Metástase Neoplásica/genética , Transcriptoma/genética , Adulto , Idoso , Apoptose/genética , Biomarcadores Tumorais , Carcinoma de Células Escamosas/patologia , Variações do Número de Cópias de DNA/genética , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Metástase Neoplásica/patologia , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço
10.
Cancer Res ; 73(16): 5040-52, 2013 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-23774208

RESUMO

The DNA repair protein damaged DNA-binding 2 (DDB2) has been implicated in promoting cell-cycle progression by regulating gene expression. DDB2 is selectively overexpressed in breast tumor cells that are noninvasive, but not in those that are invasive. We found that its overexpression in invasive human breast tumor cells limited their motility and invasiveness in vitro and blocked their ability to colonize lungs in vivo, defining a new function for DDB2 in malignant progression. DDB2 overexpression attenuated the activity of NF-κB and the expression of its target matrix metalloprotease 9 (MMP9). Mechanistic investigations indicated that DDB2 decreased NF-κB activity by upregulating expression of IκBα by binding the proximal promoter of this gene. This effect was causally linked to invasive capacity. Indeed, knockdown of DDB2-induced IκBα gene expression restored NF-κB activity and MMP9 expression, along with the invasive properties of breast tumor cells overexpressing DDB2. Taken together, our findings enlighten understanding of how breast cancer cells progress to an invasive phenotype and underscore potential clinical interest in DDB2 as a prognostic marker or therapeutic target in this setting.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , NF-kappa B/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Feminino , Humanos , Proteínas I-kappa B/genética , Proteínas I-kappa B/metabolismo , Células MCF-7 , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Inibidor de NF-kappaB alfa , NF-kappa B/metabolismo , Invasividade Neoplásica , Prognóstico , Regiões Promotoras Genéticas , Transcrição Gênica , Regulação para Cima/genética
11.
Int J Cancer ; 132(2): E26-36, 2013 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-22890882

RESUMO

Patients with human papillomavirus (HPV)-related oropharyngeal tumors display improved prognosis. The biological basis of this tumor phenotype is poorly understood. We investigated whether increased lymphocyte infiltrate in HPV-positive oropharyngeal squamous cell carcinomas could account for better prognosis. We previously identified, in an Affymetrix GeneChip analysis of 83 HPV-unrelated and 11 HPV-related squamous cell carcinoma of the oropharynx, several candidate genes, including CD8α and CD3ζ. Their expression was validated in this study by qRT-PCR on an independent clinical series of 144 oropharyngeal tumors. Immunohistochemical staining of tumor specimens was performed to evaluate infiltration of tumor stroma by CD8+ and CD4+ lymphocytes. The prognostic value of CD8α and CD3ζ expression levels was measured by Kaplan-Meier and Cox regression model analyses. Immune response-related signaling pathways were found to be deregulated in HPV-positive oropharyngeal tumors. Expression of CD8α, CD3ζ, granzyme K, CD28 and integrin αL RNAs was upregulated in HPV-positive lesions when compared with HPV-unrelated tumors (p < 0.05). Stroma of HPV-positive tumors was frequently and strongly infiltrated by CD8α- and CD3ζ-positive T cells. CD8α RNA expression correlated with both improved global (Kaplan-Meier; p = 0.005; Cox regression: p = 0.003) and disease-free (Cox regression: p = 0.04) survival. CD3ζ RNA expression correlated with improved overall survival (Cox regression: p = 0.024). These results suggest that an increased cytotoxic T-cell-based antitumor immune response is involved in improved prognosis of patients with HPV-positive tumors.


Assuntos
Antígenos CD8/metabolismo , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/imunologia , Neoplasias Orofaríngeas/imunologia , Infecções por Papillomavirus/imunologia , Alphapapillomavirus/genética , Complexo CD3/genética , Complexo CD3/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Intervalo Livre de Doença , Feminino , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imunidade Celular/genética , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/metabolismo , Neoplasias Orofaríngeas/mortalidade , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/virologia , Infecções por Papillomavirus/mortalidade , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Prognóstico , Modelos de Riscos Proporcionais , Análise de Regressão , Transcriptoma , Microambiente Tumoral
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