H2020Индивидуална стипендия2020–2022

TETCOLON · Dissecting the role of the epigenetic regulator TET2 in colorectal cancer

„Хоризонт 2020“ — Действия „Мария Склодовска-Кюри“

Период: 2020-09-01 → 2022-08-31
Финансиране от ЕС: 183 473 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Ролята на протеина TET2 при развитието на рака на дебелото черво се анализира чрез проучване на епигенетичните му дефекти. Разбирането на тези механизми може да помогне за по-добра диагностика и създаване на по-ефективни таргетни терапии.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Dissecting the role of the epigenetic regulator TET2 in colorectal cancer

Colorectal cancer (CRC) is the second leading cause for cancer-related deaths worldwide (GLOBOCAN, 2020) and its global incidence is on the rise. CRC is a complex disease characterized by the accumulation of genetic and epigenetic alterations in colonic epithelial cells. Elucidating the molecular and cellular mechanisms involved in CRC pathogenesis may lead to better prevention, diagnosis, prognosis, and more effective targeted therapies. Recently, due to the opportunity to chemically reverse the epigenetic changes, epigenetic therapies are emerging as promising treatment options. The TET protein family dioxygenases (TET1-3) oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), and subsequently to other oxidized forms of 5mC, in an active process that supports DNA demethylation and helps maintain epigenomic stability (Figure 1). Emerging evidence indicates that TET1 is a tumorigenic driver in CRC and TET2 mutations have been identified in CRC by next generation sequencing approaches. In addition, CRCs frequently show loss of 5hmC but only a subset of these cancers has low TET1 expression, possibly involving other mechanisms, such as TET2 defects. These observations point to an important role of TET2 in CRC. However, whether TET2 defects contribute to CRC pathogenesis, or represent a bystander event, remains to be established. This project aimed to investigate the role of TET2 in colorectal tumorigenesis with a multidisciplinary approach and an innovative technology, and to lay the groundwork for future translational studies. Specifically, the main objectives of this project were: 1) to investigate the functional consequences of TET2 defects in CRC, and 2) to determine the clinical significance of TET2 defects in human CRCs. The findings made in the timeframe of TETCOLON project provided new knowledge on the molecular mechanisms and pathways implicated in the pathogenesis of CRC and they will likely be relevant for the clinical management of CRC patients.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Colorectal cancer (CRC) results from the accumulation of genetic and epigenetic changes in colonic epithelial cells. Epigenome studies revealed that virtually all CRCs contain aberrantly methylated genes and perturbed methylation patterns. Ten-Eleven Translocation (TET) protein family dioxygenases oxidize 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further to other oxidized 5mCs, supporting active DNA demethylation and helping maintain epigenomic stability. Loss of TET1 is an oncogenic driver in some CRCs. My preliminary analysis indicates that human CRCs have low TET2 mRNA levels compared to normal colorectal tissue, and suggests that low TET2 expression predicts increased mutational load and reduced overall survival. However, whether TET2 deficiency contributes to CRC pathogenesis, or represents a bystander event, remains to be established.In this proposal, I will elucidate the role of TET2 in CRC pathogenesis by testing whether TET2 knockdown induces methylome and transcriptome reprogramming, ultimately promoting (epi)genomic instability and tumor growth. I will also investigate correlations between TET2 defects and molecular/clinico-pathological parameters, and probe TET2 expression as predictive biomarker of response to CRC therapies. With these aims, I will use a multi-disciplinary approach, combining cell biology, cancer epigenetics, bioinformatics, human and mouse studies with cutting-edge techniques such as 3D cell culture and RNA-seq. This study should establish a clear causal link between TET2 loss and CRC pathogenesis, providing new insight into the mechanism of TET2-mediated tumor suppression and leading to the development of innovative therapies that exploit vulnerabilities of TET2-deficient CRC cells. Overall, this project has both basic and translational significance, and the potential to advance our understanding of CRC carcinogenesis and therapeutic response.

Оригинален текст от CORDIS (на английски).

Участници

UNIVERSITA DEGLI STUDI DI PAVIA · PaviaКоординаторИталия