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Molecular mechanisms of breast tumorigenesis, metastasis, and resistance to therapy in tumors with a mutated PI3K pathway

English title Molecular mechanisms of breast tumorigenesis, metastasis, and resistance to therapy in tumors with a mutated PI3K pathway
Applicant Bentires-Alj Mohamed
Number 166428
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 01.12.2016 - 30.11.2019
Approved amount 834'000.00
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Keywords (3)

PI3K; metastasis; Breast cancer

Lay Summary (French)

Lead
Mécanismes moléculaires de la tumorigenèse, des métastases et de la résistance à la thérapie des tumeurs du sein dont la voie PI3K est mutée.
Lay summary

Le cancer du sein est diagnostiqué chez ~1,5 million de femmes dans le monde et ~500 000 patientes succombent à cette maladie chaque année. Les métastases sont la cause de la grande majorité des décès liés au cancer du sein. Il y a un besoin urgent de nouvelles thérapies pour traiter le cancer du sein métastatique. De nouvelles thérapies émergeront d’une meilleure compréhension des modifications des voies de signalisations dans les cellules cancéreuses. La phosphoinositide 3-kinase (PI3K) est une kinase lipidique composée d'une sous-unité catalytique et d'une sous-unité régulatrice. La voie de signalisation PI3K est hyperactive dans ~70% des cancers du sein. Le but de ce projet est d’identifier de nouveaux mécanismes moléculaires de la tumorigenèse, des métastases et de la résistance à la thérapie des tumeurs du sein dont la voie PI3K est mutée. Pour ce, nous utilisons la mutagenèse insertionnelle médiée par des transposons. Il s’agit de séquences d’ADN capables de se déplacer dans le génome, et par conséquent d’activer des oncogènes ou inactiver des gènes suppresseurs de tumeurs. Nos résultats préliminaires montrent que l’expression des transposons accélère la tumorigenèse et induit la formation de métastases. Les objectifs principaux de ce projet sont de valider ces résultats préliminaires, d’utiliser la mutagenèse insertionnelle médiée par des transposons afin d’identifier (et de valider) d’une part les altérations géniques qui coopèrent avec la mutation PI3K dans l’initiation et la progression des tumeur in vivo, et d’autre part les mécanismes de résistance aux inhibiteur de la voie PI3K dans les cancers mammaires. Les résultats de nos recherches devront identifier de nouvelles cibles thérapeutiques et participer à l’implémentation et/ou le développement rationnel de thérapies ciblées pour le traitement du cancer du sein.

Direct link to Lay Summary Last update: 29.03.2016

Responsible applicant and co-applicants

Employees

Collaboration

Group / person Country
Types of collaboration
M R Jensen / Novartis Switzerland (Europe)
- Industry/business/other use-inspired collaboration
Z Varga / Institute of Pathology and Molecular Pathology, University Hospital Zurich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
R Rad/Institute of Molecular Oncology and Functional Genomics Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
K.D. Mertz / Institute of Pathology Liestal, Cantonal Hospital Baselland Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
M Stadler, FMI Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Presentation at the Basel Breast Consortium project talk seminar series Individual talk Forward genetic screen to identify resistance mechanisms towards PI3K alpha inhibition in breast cancer 10.03.2020 Basel, Switzerland Auf der Maur Priska;
FARO PRIOR seminars Individual talk NFIB promotes metastatic colonization in breast cancer via angiogenesis 14.01.2020 Basel, Switzerland Zilli Federica;
4th Basel Breast Consortium Annual Meeting Poster Forward genetic screen to identify resistance mechanisms towards PI3K alpha inhibition in breast cancer 14.11.2019 Basel, Switzerland Auf der Maur Priska; Zilli Federica; Bentires-Alj Mohamed;
BBC annual meeting Poster NFIB promotes metastatic colonization in breast cancer via angiogenesis 14.11.2019 Basel, Switzerland Auf der Maur Priska; Bentires-Alj Mohamed; Zilli Federica;
Personalized Oncology meeting Poster Forward genetic screen to identify resistance mechanisms towards PI3K alpha inhibition in breast cancer 23.06.2019 Basel, Switzerland Zilli Federica; Auf der Maur Priska; Bentires-Alj Mohamed;
PhD Retreat Schwarzenburg Talk given at a conference Forward genetic screen to identify resistance mechanisms towards PI3K alpha inhibition in breast cancer 13.06.2019 Schwarzenburg , Switzerland Auf der Maur Priska;
BBC seminar Individual talk NFIB is a key regulator of metastatic colonization in breast cancer 11.06.2019 Basel, Switzerland Zilli Federica;
11th European Network for Breast Development and Cancer Workshop Poster Forward genetic screen to identify resistance mechanisms towards PI3K alpha inhibition in breast cancer 16.05.2019 Weggis, Switzerland Bentires-Alj Mohamed; Auf der Maur Priska; Zilli Federica;
3rd Basel Breast Consortium Annual Meeting Poster Forward genetic screen to identify resistance mechanisms towards PI3K alpha inhibition in breast cancer 15.11.2018 Basel, Switzerland Auf der Maur Priska; Zilli Federica; Bentires-Alj Mohamed;
PhD Retreat Poster Transposon-mediated genome-wide mutagenesis screen identifies potential drivers of breast cancer 07.06.2018 Quarten-Walensee, Switzerland Auf der Maur Priska; Bentires-Alj Mohamed; Zilli Federica;
Gordon Research Conference for Mammary Gland Biology Talk given at a conference Forward genetic screen to identify resistance mechanisms towards PI3K alpha inhibition in breast cancer 26.05.2018 Barga, Italy Auf der Maur Priska;
Gordon Research Conference on Mammary Gland Biology Poster Transposon-mediated genome-wide mutagenesis screen identifies potential drivers of breast cancer 26.05.2018 Lucca, Italy Bentires-Alj Mohamed; Zilli Federica; Auf der Maur Priska;
Presentation at the Basel Breast Consortium project talk seminar series Individual talk Forward genetic screen to identify resistance mechanisms towards PI3K alpha inhibition in breast cancer 22.03.2018 Basel, Switzerland Auf der Maur Priska;
10th European Network for Breast Development and Cancer Workshop Poster Forward genetic screen to identify resistance mechanisms towards PI3K alpha inhibition in breast cancer 15.03.2018 Weggis, Switzerland Zilli Federica; Auf der Maur Priska; Bentires-Alj Mohamed;
ENBDC meeting Poster Transposon-mediated genome-wide mutagenesis screen identifies potential drivers of breast cancer 15.03.2018 Weggis, Switzerland Zilli Federica; Bentires-Alj Mohamed; Auf der Maur Priska;
BBC seminar Individual talk Piggy Bac transposon mutagenesis screen identifies potential drivers of breast cancer 06.02.2018 Basel, Switzerland Zilli Federica;
2nd Basel Breast Consortium Annual Meeting Poster Forward genetic screen to identify resistance mechanisms towards PI3K alpha inhibition in breast cancer 16.11.2017 Basel, Switzerland Zilli Federica; Bentires-Alj Mohamed; Auf der Maur Priska;
EMBO Technical Course, Techniques for Mammary Gland Research Poster Forward genetic screen to identify resistance mechanisms towards BYL719 treatment in breast cancer 24.05.2017 Heidelberg, Germany Auf der Maur Priska;
PhD Retreat Quarten Poster Forward genetic screen to identify resistance mechanisms towards PI3K alpha inhibition in breast cancer 18.05.2017 Quarten, Switzerland Bentires-Alj Mohamed; Zilli Federica; Auf der Maur Priska;


Awards

Title Year
BBC meeting 2019 award: Patient Advocate Award 2019

Associated projects

Number Title Start Funding scheme
170809 Super Resolution and Endoscopic Two Photon Microscopy - Imaging of Cell Migration in Inflammation, Metastasis and Regeneration 01.01.2017 R'EQUIP
184673 Molecular mechanisms underlying normal and neoplastic mammary stem cells, progression to metastasis and resistance to therapy 01.12.2019 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

Each year, breast cancer is diagnosed in over 1.5 million women worldwide and more than 500,000 lives are lost to this disease. Although some progress has been made in broadly understanding breast tumor biology, we still do not understand the pathophysiology of this disease sufficiently to explain why certain patients do well following surgery and adjuvant therapy whereas the disease recurs in others. Metastasis is the fatal step in cancer progression and its underlying cellular and molecular mechanisms are still poorly understood. New therapies are likely to arise only from a more thorough understanding of key oncogenic signaling networks controlling metastatic spread and resistance to therapy. The main goal of this project is to identify novel molecular mechanisms of breast tumorigenesis, metastasis, and resistance to therapy in tumors with a mutated phosphoinositide 3-kinase (PI3K) pathway. The PI3K pathway, a central regulator of diverse normal cellular functions, is very often subverted during neoplastic transformation, including ~70% of breast tumors. We hypothesize that in tumors with PI3K mutations additional pathways or factors synergize with PI3K activation during tumorigenesis, progression to metastasis, and resistance to therapy. Our preliminary data using cancer cell lines in vivo and the PiggyBac (PB) transposon insertional mutagenesis system show that application of the latter decreases tumor latency and increases metastatic dissemination, and thus supports our hypothesis. Transposon integration sites in these metastatic lines were identified by splinkerette PCR and by next-generation sequencing, revealing potential tumor- and metastasis-promoting genes. Our specific aims are to: 1-Validate the identified candidate breast cancer aggravating genes/pathways.2-Identify (and validate) PIK3CA-interacting pathways important for breast tumorigenesis and metastasis by in vivo mutagenesis.3-Determine mechanisms of resistance to PI3K inhibition by in vivo mutagenesis.These studies not only use state-of-the-art ex vivo and in vivo models for studying breast cancer pathophysiology and combine hypothesis-driven and unbiased approaches, but also cross the boundaries between basic science and clinical applications. Our research should ultimately lead to the identification of novel prognostic and/or predictive biomarkers and to the rational design of targeted therapies that will improve the clinical management of patients with metastatic breast cancer.
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