CINCANCER · Dissecting the Role of Chromosome Instability in Cancer
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2012-01-01 → 2015-12-31
- Финансиране от ЕС
- 100 000 €
- Участници
- 1
- Схема
- MC-CIG
Линиите свързват координатора с партньорите.
Накратко на български
Хромозомната нестабилност при рак се изследва чрез миша модели, за да се разбере кога грешките при деленето на клетките ускоряват туморите или ги спират. Това помага да се разбере защо някои ракови клетки стават устойчиви на терапия и причиняват рецидив.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Dissecting the Role of Chromosome Instability in Cancer
Chromosomal instability (CIN), the inability to correctly segregate sister chromatids during mitosis, is a hallmark of cancer cells. Overexpression of the mitotic checkpoint protein Mad2, commonly found in human tumors, leads to CIN and the development of aneuploid tumors in mouse models. However, recent observations from various laboratories suggest that aneuploidy can promote or suppress tumorigenesis depending on the context. This proposal is aiming to understand the relationship between aneuploidy and tumor formation and to identify in what context aneuploidy acts oncogenically and those in which it acts as a tumor suppressor. We have generated inducible mouse models that recapitulate the aneuploidy state of human tumors, to investigate the role of CIN in promoting or suppressing cancer. Preliminary results show that while Mad2 induces aneuploid tumors in vivo and cooperates with oncogenic Kras in lung tumorigenesis, its overexpression is detrimental in breast tumorigenesis. In addition, we had shown that CIN facilitates escape from oncogene addiction (the dependence of tumor cells on their initiating lesion for survival) and that this CIN could be responsible for tumor relapse after targeted therapies in a model of Kras induced lung cancer. Recent data from our laboratory suggests that despite the detrimental effect of Mad2 overexpression in breast cancer, it also facilitates relapse in these models. Therefore, we are investigating how CIN potentiates oncogene independence. It is possible that some CIN cells in the primary tumor are already independent of the initiating oncogene prior to treatment. Alternatively, CIN cells are more susceptible of acquiring additional mutations and evolve to become independent of the initiating lesion.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Chromosomal instability (CIN), the inability to correctly segregate sister chromatids during mitosis, is a hallmark of cancer cells. Overexpression of the mitotic checkpoint protein Mad2, commonly found in human tumors, leads to CIN and the development of aneuploid tumors in mouse models. However, recent observations from various laboratories suggest that aneuploidy can promote or suppress tumorigenesis depending on the context. This proposal aims to understand the relationship between aneuploidy and tumor formation and to identify in what context aneuploidy acts oncogenically and those in which it acts as a tumor suppressor. We propose to generate inducible mouse models that recapitulate the aneuploidy state of human tumors, to investigate the role of CIN in promoting or suppressing cancer.In addition, we have shown that CIN facilitates escape from oncogene addiction (the dependence of tumor cells on their initiating lesion for survival) and may be responsible for tumor relapse after targeted therapies. Due to the clinical relevance of these findings, we will investigate how CIN potentiates oncogene independence. It is possible that some CIN cells in the primary tumor are already independent of the initiating oncogene prior to treatment. Alternatively, CIN cells are more susceptible of acquiring additional mutations and evolve to become independent of the initiating lesion. We will develop an innovative three-dimensional in vitro culture system to isolate and characterize surviving cells after de-induction of the transgenes. It is necessary to understand the molecular mechanisms that lead to CIN and the consequences it has in tumor initiation, suppression and relapse, hoping that the genes or proteins identified could be targeted therapeutically.Finally, if human tumors are characterized by an overactive checkpoint we should validate the therapeutic potential of acute downregulation of mitotic checkpoint function in vivo.
Оригинален текст от CORDIS (на английски).
Участници
- EUROPEAN MOLECULAR BIOLOGY LABORATORY · HeidelbergКоординаторГермания
Връзки
Данни: CORDIS, © Европейски съюз