Fate of mammary stem cells during tumorigenesis and clinical implications

Project Information

MSCFate

Grant agreement ID: 750812

DOI

10.3030/750812

Project closed

EC signature date 8 March 2017

Start date 1 September 2017

End date 31 August 2019

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 175 419,60

EU contribution

€ 175 419,60

Coordinated by

UNIVERSITAT BASEL
Switzerland

Periodic Reporting for period 1 - MSCFate (Fate of mammary stem cells during tumorigenesis and clinical implications)

Reporting period: 2017-09-01 to 2019-08-31

Summary of the context and overall objectives of the project

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

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

We have investigated the fate of Mammary Stem Cells (Procr-positive cells) when they are insulted by oncogenic alterations. To achieve the aims of this project, we created a new transgenic mouse model relevant for studying initiation of mammary tumors and their progression. Also, we needed to adapt our strategy to induce mammary tumorigenesis in mice. These adaptations delivered unique results as Procr-positive cells being cells of origin for poorly differentiated mammary tumors. We also discovered that mutant-Procr+ cells harbor Cancer Stem Cells features. We are now about to elucidate the molecular circuits of these Procr+ Cancer Stem Cells.
The results will be exploited through a research article. Regarding the novelty of the study and the importance in Clinics, we expect to publish in high-profile journal during 2020/2021. We are now compiling data and working on a draft manuscript. We will submit the research paper when the human relevance will be fully established.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Tumor heterogeneity results in therapy failures and it is therefore crucial to understand its origin. Plus, CSCs are described as being responsible for therapy failure and new molecular insights about these CSCs would lead to new therapeutic opportunities.
During this funding, incidentally, I have created new mouse model relevant for the study of many solid cancers. The characterization of these new mouse models would clearly benefit many cancer research areas.

Image of a mouse mammary duct (adult, virgin mouse). GFP+ cells are stained with a K14 antibody