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Meta-analysis of expression and the targeting of cell adhesion associated genes in nine cancer types - A one research lab re-evaluationBorodins, Olegs, Broghammer, Felix, Seifert, Michael, Cordes, Nils 15 May 2024 (has links)
Cancer presents as a highly heterogeneous disease with partly overlapping and partly distinct (epi)genetic characteristics. These characteristics determine inherent and acquired resistance, which need to be overcome for improving patient survival. In line with the global efforts in identifying druggable resistance factors, extensive preclinical research of the Cordes lab and others designated the cancer adhesome as a critical and general therapy resistance mechanism with multiple druggable cancer targets. In our study, we addressed pancancer cell adhesion mechanisms by connecting the preclinical datasets generated in the Cordes lab with publicly available transcriptomic and patient survival data. We identified similarly changed differentially expressed genes (scDEGs) in nine cancers and their corresponding cell models relative to normal tissues. Those scDEGs interconnected with 212 molecular targets from Cordes lab datasets generated during two decades of research on adhesome and radiobiology. Intriguingly, integrative analysis of adhesion associated scDEGs, TCGA patient survival and protein-protein network reconstruction revealed a set of overexpressed genes adversely affecting overall cancer patient survival and specifically the survival in radiotherapy-treated cohorts. This pancancer gene set includes key integrins (e.g. ITGA6, ITGB1, ITGB4) and their interconnectors (e.g. SPP1, TGFBI), affirming their critical role in the cancer adhesion resistome. In summary, this meta-analysis demonstrates the importance of the adhesome in general, and integrins together with their interconnectors in particular, as potentially conserved determinants and therapeutic targets in cancer.
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Caracterização do genoma e da resposta imune no microambiente tumoral de neoplasias PTEN-deficientes / Characterization of the genome and immune response in the tumor microenvironment of PTEN-deficient cancersVidotto, Thiago 22 March 2019 (has links)
Alterações no genoma de células tumorais são eventos comuns durante a carcinogênese. Tais aberrações genômicas - como mutações e variações estruturais - são diretamente relacionadas a detecção e morte de células neoplásicas pelo sistema imune. Além da contribuição da perda de função de genes supressores tumorais (GSTs) no desenvolvimento neoplásico, GSTs também influenciam a resposta imune no câncer. Por exemplo, o GST PTEN afeta diretamente a via interferon através da desfosforilação do fator regulador de interferon 3 (IRF3). No entanto, se mantém inconclusivo se a inativação de PTEN diretamente influencia a resposta imune através de IRF3 ou por provocar altos níveis de instabilidade genômica. Para responder essa questão, conduzimos uma análise PanCancer de 33 tipos tumorais da coorte The Cancer Genome Atlas para identificar se existem associações entre a inativação do gene PTEN e alterações genômicas específicas que podem suprimir ou ativar a resposta imune antitumoral. O status de inativação de PTEN foi determinado a partir de dados de variação no número de cópias e presença de mutações de ponto. Nesse estudo, investigamos o efeito da inativação de PTEN nas alterações genômicas de tumores e na abundância de 22 células do sistema imune derivadas do algoritmo CIBERSORT. Observamos que a inativação de PTEN foi significantemente associada com níveis elevados de aneuploidia, mutações, e heterogeneidade intratumoral. Além disso, nossos achados mostraram que a inativação de PTEN é altamente específica para cada tipo tumoral. Da mesma maneira, observamos que pacientes com tumores PTEN-inativos podem apresentar variações na resposta a imunoterapia. Tal observação deriva da correlação significativa entre a inativação de PTEN e a expressão dos alvos terapêuticos proteína programada 1 da morte celular (PD1), seu ligante (PDL1), e indoleamina 2,3 dioxigenase (IDO1). Na análise PanCancer, a inativação de PTEN também foi significativamente associada à composição de células do sistema imune no microambiente tumoral, incluindo células T regulatórias (Treg) e células CD8+. A partir desses achados, conduzimos uma análise aprofundada de tumores de próstata primários e metastáticos com a perda de PTEN. Através de uma análise in silico, nós observamos que tumores primários e metastáticos apresentam maiores densidades de Treg quando há perda da proteína PTEN. Nós também observamos que, dependendo do local de metástase prostática, a deficiência de PTEN é associada a um perfil de células imunes supressivas no microambiente tumoral. A partir da análise de uma coorte brasileira composta por 94 tumores primários de próstata, observamos que a perda de PTEN se associa a uma maior densidade de Tregs e uma maior expressão da proteína imunossupressora IDO1. Além disso, tumores PTEN-deficientes com altas densidades de Tregs apresentaram o pior prognóstico entre pacientes. Coletivamente, nós demonstramos que a inativação de PTEN é associada a um estado imunossuprimido no microambiente tumoral. Ademais, a perda de PTEN possivelmente se associa a resposta imune antitumoral através da combinação de duas diferentes vias - uma dependente de IRF3 e outra relacionada ao efeito no genoma de células cancerosas. Ensaios funcionais são necessários para validar os achados desse estudo; porém, sugerimos que a avaliação do status de inativação de PTEN pode ter alto potencial para discernir pacientes que responderão à imunoterapia. / Cancer-cell genomes undergo several abnormalities during carcinogenesis. Indeed, many of the tumor-specific genomic changes, such as mutations and chromosomal aberrations, are related to how the host immune system responds to detect and kill tumor cells. In addition to these general effects, loss of function of specific tumor suppressor genes (TSG) contributes to tumor development and progression and at the same time also regulates several facets of the immune response in cancer. For instance, the TSG phosphatase and tensin homolog (PTEN) was shown to directly regulate the anti-viral interferon response by licensing the interferon regulatory factor 3 (IRF3). However, it is still unclear whether PTEN directly influences the immune response through the interferon network or by provoking higher levels of genomic instability. To address this question, we conducted a PanCancer analysis of 33 tumor types from The Cancer Genome Atlas to determine whether there were associations between PTEN inactivation and specific genomic features that are linked to immunosuppressive states in cancer. PTEN inactivation status was determined by combining copy number and point mutation data. Then, we performed a parallel analysis of genomic instability and immune-cell abundances derived from the CIBERSORT algorithm comparing PTEN deficient to intact tumors. We found that PTEN inactivation was strongly associated with enhanced levels of aneuploidy, mutation load, immunogenic mutations, and tumor heterogeneity. Furthermore, we found that the outcome of PTEN inactivation status was highly specific to each tumor type and the induced changes appeared to lead to variation in immune responses in different cancers. Response to current immunotherapeutic approaches depends on the expression of targeted immune checkpoints, and we found that tumors with PTEN deficiency had altered expression of programmed death protein 1 (PD1), its ligand (PDL1), and the immunosuppressive protein indoleamine 2,3-dioxygenase (IDO1). We also found that PTEN inactivation led to a distinct immune-cell composition in the tumor microenvironment, including regulatory T cells and CD8+ T cells. Lastly, we performed an in-depth analysis of the immune-cell content of prostate tumors that harbored PTEN protein loss. Through an in silico analysis of 622 tumors, we found that both primary and metastatic lesions had higher densities of regulatory T cells when PTEN was lost. Then, the analysis of 94 primary prostate tumors from Brazil demonstrated that PTEN protein loss was significantly associated with high Treg density and IDO1 protein expression. Moreover, PTEN-null tumors with high Treg density exhibited the worse outcome among patients. We also found that, depending on the prostate cancer metastatic site, PTEN deficiency was linked to variation in the immunosuppressive immune cell landscape. Collectively, we show that PTEN inactivation associates with the anti-tumor immune response likely through direct avenues (via licensing of IRF3) and indirectly by influencing the genome of cancer cells. Functional studies are required to validate our in silico findings; however, we speculate that determining PTEN inactivation status may allow clinicians to distinguish patients that are more likely to respond to current immunotherapies.
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Integrative and Comprehensive Pancancer Analysis of Regulator of Chromatin Condensation 1 (RCC1)Wu, Changwu, Duan, Yingjuan, Gong, Siming, Kallendrusch, Sonja, Schopow, Nikolas, Osterhoff, Georg 11 December 2023 (has links)
Regulator of Chromatin Condensation 1 (RCC1) is the only known guanine nucleotide
exchange factor that acts on the Ras-like G protein Ran and plays a key role in cell cycle regulation.
Although there is growing evidence to support the relationship between RCC1 and cancer, detailed
pancancer analyses have not yet been performed. In this genome database study, based on The
Cancer Genome Atlas, Genotype-Tissue Expression and Gene Expression Omnibus databases, the
potential role of RCC1 in 33 tumors’ entities was explored. The results show that RCC1 is highly
expressed in most human malignant neoplasms in contrast to healthy tissues. RCC1 expression is
closely related to the prognosis of a broad variety of tumor patients. Enrichment analysis showed
that some tumor-related pathways such as “cell cycle” and “RNA transport” were involved in the
functional mechanism of RCC1. In particular, the conducted analysis reveals the relation of RCC1
to multiple immune checkpoint genes and suggests that the regulation of RCC1 is closely related
to tumor infiltration of cancer-associated fibroblasts and CD8+ T cells. Coherent data demonstrate
the association of RCC1 with the tumor mutation burden and microsatellite instability in various
tumors. These findings provide new insights into the role of RCC1 in oncogenesis and tumor
immunology in various tumors and indicate its potential as marker for therapy prognosis and
targeted treatment strategies.
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