H2020Индивидуална стипендия2018–2020

SKin SCiENCE · Skin Keratinocyte Stem CEll proliferatioN in field CancErisation

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

Период: 2018-06-01 → 2020-05-31
Финансиране от ЕС: 183 455 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Механизмите на активиране на бета-HPV вирусите в кожата се анализират чрез мишани модели и човешки тъкани. Разбирането на тези процеси помага да се установи как тези вируси допринасят за развитието на плоскоклетъчен рак при хора с отслабена имунна система.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Skin Keratinocyte Stem CEll proliferatioN in field CancErisation

The objective of the action was to strength the idea that β-HPV reactivation is involved in the development of SCC and finding the molecular mechanism that drives it. In immune compromised patients, the cancer that occurs can be due to the reactivation of viruses which replication is usually kept under control by the immune system. In the case of β-HPV, that is a virus normally present on the skin of individual, its replication is maintained under control by the immune system. When a situation of immunosuppression occurs, the immune system fails to control the replication. Researchers to date suspect that development of SCC is attribute to β-HPV, but yet a link was missing. Previous works proved the presence of β-HPV viral protein and genome amplification in premalignant lesion of human skin. Moreover, a mouse model expressing the early genes of HPV8 (CER-HPV8), spontaneously develop SCC and has been used in the action. We have previously identified that there is an expansion of Lrig1 HF-JZ-KSC population in CER-HPV8 and also in the human field cancerization lesion. In this project I have taken observations on the aforementioned mouse model of viral induced skin carcinogenesis to unpick the biology of field cancerisation. The mouse models either express all the 5 early region genes from β-HPV (HPV8-CER) or individual early region genes (HPV8-E2, HPV8-E6 HPV8-E6/E7). With the action, I investigated the molecular mechanism involved in the reactivation of β-HPV and in more detail: Obj. 1 Identify the HPV8 early region gene that is responsible for ΔNp63 overexpression. Obj. 2. Determine which signalling pathway(s) is/are activated in HPV8tg-CER mice, resulting in ΔNp63 overexpression. Obj. 3. Determine the pathway(s) is/are responsible for ΔNp63 overexpression in human skin FC Obj. 4. Determine whether immunosuppression promotes SCC formation in HPV8 transgenic mice.

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

Цел на проекта

Epithelia provide a protective barrier that exposes them to environmental carcinogens. Cancers of epithelial tissues, called carcinoma, account for 85% of all cancers and 78% of all cancer associated mortality. Epithelia undergo continual proliferation and renewal with hierarchical differentiation dependent upon long lived adult tissue stem cell. Many carcinomas arise from pre-malignant transformation, intraepithelial neoplasia referred to as field cancerisation (FC), which is an area that can give rise to multiple primary cancers. FC is a feature of malignancies involving the head and neck,oesophagus, stomach, lungs, cervix, vulva, bladder, colon, breast, ovary, pancreas, prostate and skin. By studying skin FC in a rare genetic disease, Epidermodysplasia verruciformis, and utilising a mouse model of HPV8 infection, I uncovered a novel keratinocyte stem cell (KSC) basis, driven by ΔNp63 expression, common to all causes of skin FC. I now propose to build on this original finding and utilising an innovative approach to determine the cell signalling pathway involved in expansion of this novel KSC population. I hypothesise that the common mechanism in skin FC, potentially relevant to FC in other tissues, arises from dysregulation of a signalling pathway that results in a switch from p63 TA to ΔN isoforms resulting in expansion of a KSC population that is susceptible to transformation. I propose to use multiple strategies to: 1)Identify the HPV8 gene that is responsible for ΔNp63 overexpression, 2)Determine which signalling pathway(s) is/are activated in HPV8tg mice, resulting in ΔNp63 overexpression 3)Determine the pathway(s) is/are responsible for ΔNp63 overexpression in human skin FC; and 4)Determine whether immunosuppression promotes SCC formation in HPV8tg mice. I have assembled expert international collaborations and relevant partner organisation to help me in this project, so that I can identify novel therapeutic targets for future drug discovery and development.

Оригинален текст от CORDIS (на английски).

Участници

CARDIFF UNIVERSITY · CARDIFFКоординаторОбединеното кралство