H2020Индивидуална стипендия2020–2023

MechTransition · Regulatory mechanisms controlling a new mechanical Epithelial to Mesenchymal Transition in zebrafish

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

Период: 2020-09-01 → 2023-01-04
Финансиране от ЕС: 224 934 €
Участници: 1
Схема: MSCA-IF

Линиите свързват координатора с партньорите.

Накратко на български

Механизмите, чрез които раковите клетки напускат тъканите и се разпространяват в тялото, се проучват чрез наблюдение на прозрачна кожа на ембриони от зебра риба. Това помага да се разбере как точно започва метастазирането и как клетките променят свойствата си.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Regulatory mechanisms controlling a new mechanical Epithelial to Mesenchymal Transition in zebrafish

Although metastasis is the predominant cause of mortality in patients with cancer, how tumour cells invade to form metastases is not well understood. For a cancer cell to metastasise, it must first invade from sites where most solid tumours originate, the epithelia, the skin that lines our organs, and then trans-differentiate to acquire a malignant phenotype. The prevailing metastasis model suggests that as cells mutate to become cancerous, they first form primary tumours from which accumulate mutations that disrupt these epithelia to become more motile (mesenchymal) cells that can move through the body in a process typically referred to as Epithelial-to-Mesenchymal Transition (EMT). Despite this model, our understanding of how tumour cells invade and transition to become a rogue migratory cell has been hindered by our ability to see this process live in real organisms. To visualise this process live, we have developed the transparent embryonic zebrafish skin as a model for the simple epithelia where cancers form, allowing us to directly film cell invasion. By following oncogenically transformed cells within this transparent skin, we found that cells can invade directly from the epithelium before they become actual cancers and independently from primary tumour masses. To do this, they co-opt a process that normally drives epithelial cell death - a process we discovered- called epithelial cell extrusion. Moreover, oncogenic hijacking of this process not only allows cells to invade and migrate throughout the body, but it also causes the cells to simultaneously pinch off the top of the cell, containing essential components that dictate their epithelial behaviour. Thus, invasion causes these cells to lose epithelial traits and become primordial. These cells then transition to a variety of different, more aggressive cell types that form big internal cell masses, similar to metastatic tumours. In this proposal I investigated how these primordial cells become mesenchymal and aggressive to metastasise.

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

Цел на проекта

While cancer biologists have long assumed that developmental Epithelial to Mesenchymal Transitions (EMT) transcriptional programs also control cancer metastasis, our lab has recently found that cancer EMT instead uses a mechanical-based two-step process. Typically, epithelial cells fated to die get extruded apically into the lumen. However, oncogenic mutations that drive metastatic cancers hijack this process, causing cells to either form masses or to extrude basally back into the tissue at separate sites. Basal extrusion causes transformed cells to not only invade but also to lose their entire apical membranes, including their E-cadherins, which are critical to epithelial identity. Later, invading cells migrate using a stable-bleb type motility typical of cells in confined spaces and then transdifferentiate into a variety of different cell types. While our lab has established that basal extrusion causes invasion and loss of epithelial identity, it is unclear what later causes cells to become mesenchymal. Using the transparent zebrafish embryo, I will investigate the mechanisms that promote the second step of EMT by answering the following questions: 1) Does mechanical stress following basal extrusion cause trans-differentiation of invading cells? 2) What programs promote EMT of transformed cells? 3) What environments allow invading cells to colonise specific tissues? Our new EMT model represents a paradigm shift in our understanding of how tumour cells initiate metastasis, survive in different environments, and become distinct cell types. Thus, addressing these aims could impact our ability to finally treat metastatic disease.

Оригинален текст от CORDIS (на английски).

Участници

KING'S COLLEGE LONDON · LondonКоординаторОбединеното кралство