H2020Индивидуална стипендия2017–2019

MSCFate · Fate of mammary stem cells during tumorigenesis and clinical implications

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

Период: 2017-09-01 → 2019-08-31
Финансиране от ЕС: 175 420 €
Участници: 1
Схема: MSCA-IF-EF-ST

Линиите свързват координатора с партньорите.

Накратко на български

Млечните стволови клетки (Procr+) се проучват, за да се разбере как те се превръщат в ракови при определени мутации. Това помага да се обясни разнообразието на туморите при жените и причините за прогресирането на болестта.

Този кратък обзор е генериран от изкуствен интелект

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

Резултати накратко

Fate of mammary stem cells during tumorigenesis and clinical implications

Breast cancer, the most frequent tumor type in women, is a heterogeneous disease classified into different histological and molecular subtypes presenting distinct outcomes. In addition to this inter-tumor heterogeneity, breast tumors exhibit intra-tumor heterogeneity. In Clinics, tumor heterogeneity is hold responsible for disease progression and therapy failure. The current key question in breast cancer biology is therefore to elucidate origins of breast cancer heterogeneity. The cell-of-origin concept has been proposed to explain inter-tumor heterogeneity: the first transformed cell defines the tumor type. The contribution of mammary stem cells (MSCs) to tumorigenesis and their clinical implications are still unknown and poorly investigated. A population of MSCs was recently identified on the basis of expression of the Protein C Receptor (Procr) in humans and mice. By using transgenic mouse models, we conditionally introduced mutations and a fluorescent reporter within Procr+ MSCs. The main objectives were to: 1. Decipher the fate of MSCs (Procr+ cells) upon oncogenic perturbations (lineage tracing) and define their molecular characteristics; 2. Analyze the mammary tumors evoked by different mutations in Procr+ MSCs, and to assess the stem-like properties and metastatic potential of Procr+ cancer cells; At the end of the funding, we have achieved our main objectives by showing that: • Procr+ MSCs are cells of origin of mammary tumors • Mutant-Procr+ MSCs give rise to poorly differentiated tumors enriched in mesenchymal and stem cells features • Mutant-Procr+ MSCs have Cancer Stem Cells properties

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

Цел на проекта

One of the most challenging questions in breast cancer biology is to elucidate the origin of tumor heterogeneity and its contribution to therapy failure. Accumulating evidence suggests that the cell-of-origin, the cell that acquires the first oncogenic event, may define the molecular portrait of the resulting tumor. The fate of mammary Stem Cells (MSC) upon oncogenic perturbation has been poorly explored. Moreover, the Phosphoinositide 3-kinase (PI3K) pathway regulates proliferation/differentiation of MSC and is found hyperactive in breast cancer cells, for example through mutations in PIK3CA, the gene coding for its catalytic subunit. I hypothesize that expression of PIK3CA mutations will perturb mammary tissue homeostasis, initiate mammary cancer and trigger formation of stem-like cancer cells. Using state-of-the-art in situ genetic lineage tracing, I will determine the fate of MSC (identified recently as Procr+ cells) after conditional expression of PIK3CA hotspot mutations (H1047R, E545K). I will also characterize early molecular events responsible for promotion of transformation (Aim 1). When tumors develop, I will determine tumor phenotype and eventual progression to metastasis (Aim 2). Consequently, this study will generate a new mouse model of breast cancer that will be useful for preclinical studies. A panel of PI3K inhibitors is currently under Clinical investigation and clinical reports have shown that the combination of standard chemotherapy with PI3K inhibitors reduces tumor growth but drug-resistance often occurs. To identify resistance mechanisms to PI3K inhibitors, I will generate in vivo models of drug-resistance (Aim 3). My studies will use both hypothesis driven and unbiased approaches, they should: 1. better elucidate transformation of MSC and the resulting tumor heterogeneity, 2. pinpoint novel targets/biomarkers. Ultimately this knew knowledge should result in better therapies for patients.

Оригинален текст от CORDIS (на английски).

Участници

UNIVERSITAT BASEL · BaselКоординаторШвейцария