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Molecular mechanisms underlying normal and neoplastic mammary stem cells, progression to metastasis and resistance to therapy

English title Molecular mechanisms underlying normal and neoplastic mammary stem cells, progression to metastasis and resistance to therapy
Applicant Bentires-Alj Mohamed
Number 184673
Funding scheme Project funding (Div. I-III)
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Experimental Cancer Research
Start/End 01.12.2019 - 30.11.2023
Approved amount 672'000.00
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Keywords (3)

Breast cancer; PI3K; metastasis

Lay Summary (French)

Lead
Mécanismes moléculaires régulant les cellules souches mammaires normales et néoplasiques, la progression vers les métastases et la résistance au traitement
Lay summary

Le cancer du sein est la deuxième cause de décès par cancer chez les femmes. Chaque année, le cancer du sein est diagnostiqué chez 2,1 millions nouvelles patientes. Alors que 98% des patientes survivent 5 ans ou plus après le diagnostic d'un cancer du sein localisé (confiné au site primaire), ce nombre chute à 15-25% si le cancer s'est métastasé à des organes distants. La guérison du cancer du sein métastatique représente clairement un besoin médical non satisfait. Cependant, les mécanismes cellulaires et biochimiques qui orchestrent les étapes menant aux métastases pharmacorésistantes restent largement inconnus. Leur identification, qui est l'objectif principal de ce projet, devrait renforcer le développement de thérapies ciblées pour cette maladie actuellement incurable.

Nos objectifs globaux sont d’identifier les mécanismes moléculaires sous-jacents aux cellules souches mammaires normales et néoplasiques, la progression vers les métastases et la résistance au traitement.

Nos données préliminaires utilisant une approche de mutagenèse insertionnelle par transposon ont révélé que ce système augmente l'auto-renouvellement des cellules souches mammaires normales et néoplasiques et les métastases, et entraîne une résistance au traitement. Les sites d'intégration des Transposon ont identifié de nouveaux régulateurs potentiels de l'auto-renouvellement des cellules mammaires et de la résistance au traitement.

 Nos objectifs spécifiques sont de:

1- Valider les régulateurs potentiels des cellules souches mammaires normales et néoplasiques identifiés.

2- Identifier les voies de signalisation importantes pour la tumorigenèse et les métastases du sein par mutagenèse in vivo.

3- Valider les mécanismes potentiels de résistance à la thérapie in vivo.

Direct link to Lay Summary Last update: 25.04.2019

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
166428 Molecular mechanisms of breast tumorigenesis, metastasis, and resistance to therapy in tumors with a mutated PI3K pathway 01.12.2016 Project funding (Div. I-III)
143372 Roles of the protein tyrosine phosphatase SHP2 in metastatic breast cancer 01.07.2013 Project funding (Div. I-III)

Abstract

Breast cancer is the second leading cause of cancer death in women and 2.1 million new patients are diagnosed with breast cancer annually. While 98% of patients survive 5 years or more after diagnosis of a localized (confined to the primary site) breast cancer, this number drops to 15-25% if the cancer has metastasized to distant organs. Curing metastatic breast cancer clearly represents an unmet medical need. Yet, the cellular and biochemical mechanisms orchestrating the steps leading to drug resistant metastases remain largely unknown. Their identification, which is the overarching goal of this application, should enhance the development of targeted therapies for this presently incurable disease.A thorough understanding of cellular pathways involved in tumor initiation, metastasis, and resistance to therapy is the appropriate basis to tailor therapy to the patient. Indeed, several inhibitors of the most common oncogenic pathways have been tested in preclinical models and are already included in the care of patients. Despite the specificity of many of these approaches, the clinical translation of most single therapies has been sub-optimal; they were either ineffective or transiently effective with subsequent emergence of resistance. Therefore, the mechanisms of limited therapeutic responses must be carefully assessed in order to better tailor the therapy to each cancer patient and to rationally design combinations of therapies. The overarching goals of this proposal are to assess the molecular mechanisms underlying normal and neoplastic mammary stem cells, progression to metastasis and resistance to therapy.Our preliminary data using the PiggyBac (PB) transposon insertional mutagenesis approach has revealed that this system increases self-renewal of normal and neoplastic mammary stem cells and metastasis, and results in resistance to therapy. Transposon integration sites in these preclinical models were revealed by splinkerette PCR and by next-generation sequencing, and potential new candidate regulators of self-renewal and resistance to therapy have been identified. Our specific aims are to: 1-Validate the identified candidate regulators of normal and neoplastic mammary stem cells.2-Assess pathways important for breast tumorigenesis and metastasis by in vivo mutagenesis.3-Validate the identified potential mechanisms of resistance to therapy by in vivo mutagenesis.This multiprong project uses both hypothesis-driven and unbiased state-of-the-art genetic approaches to identify and validate novel molecular mechanisms of normal and neoplastic stem cells, metastasis, and resistance to therapy, which should ultimately improve the clinical management of patients with metastatic breast cancer.
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