Triple negative breast cancer is a highly aggressive subtype of breast cancer with 9000-14000 new cases in Germany each year and is characterized by a significant higher frequency of visceral as well as central nervous system metastases than the other subtypes. Due to this clinical behaviour TNBC shows a poor prognosis profile with significant lower recurrence free and overall survival rates, respectively. Breast cancer stem cells (BCSCs) are hypothesized to play a crucial role for the tumorbiological behavior of TNBC with the high metastatic potential as well as the observed metastatic pattern. We established a method to isolate and propagate BCSC from individual triple-negative tumors resected from patients after neoadjuvant chemotherapy and characterized the cells in vitro and in vivo. We utilize BCSCs in analyzing basic tumorbiology and try to model the interaction of different cell types in tumor tissue. Since already a few of these cells are capable of recapitulating the patient tumor with matching histology and gene expression in immunocompromised animals, we can use the cells also for screening and testing novel therapeutics. As a proof-of-concept we describe an orally available, selective and potent KDM4 inhibitor (QC6352) with unique preclinical characteristics. QC6352 blocked BCSC proliferation, sphere formation and xenograft tumor formation. QC6352 also abrogated expression of EGFR which drives the growth of therapy-resistant triple-negative breast cancer cells.
The activity of thymidylate synthase shapes the de-differentiated phenotype of aggressive breast cancers
Triple negative breast cancer is a highly aggressive subtype of breast cancer with 9000-14000 new cases in Germany each year and is characterized by a significant higher frequency of visceral as well as central nervous system metastases than the other subtypes. Due to this clinical behaviour TNBC shows a poor prognosis profile with significant lower recurrence free and overall survival rates, respectively. Breast cancer stem cells (BCSCs) are hypothesized to play a crucial role for the tumorbiological behavior of TNBC with the high metastatic potential as well as the observed metastatic pattern. We established a method to isolate and propagate BCSC from individual triple-negative tumors resected from patients after neoadjuvant chemotherapy and characterized the cells in vitro and in vivo. We utilize BCSCs in analyzing basic tumorbiology and try to model the interaction of different cell types in tumor tissue. Since already a few of these cells are capable of recapitulating the patient tumor with matching histology and gene expression in immunocompromised animals, we can use the cells also for screening and testing novel therapeutics. As a proof-of-concept we describe an orally available, selective and potent KDM4 inhibitor (QC6352) with unique preclinical characteristics. QC6352 blocked BCSC proliferation, sphere formation and xenograft tumor formation. QC6352 also abrogated expression of EGFR which drives the growth of therapy-resistant triple-negative breast cancer cells.
Cytokine regulation of stem cell activity, endocrine resistance and metastasis
Metastatic ER+ breast cancer is treated with endocrine therapies, and more recently CDK4/6 inhibitors. In order to discover resistance mechanisms contributing to growth in metastatic sites and progression, we studied the tumour cells that survive anti-estrogen therapies such as tamoxifen and fulvestrant.
We found that tamoxifen and fulvestrant therapy-resistant cells have cancer stem cell (CSC) attributes such as aldehyde dehydrogenase (ALDH) enzyme activity, mammosphere colony formation ex vivo and tumour initiation in vivo. We established that these CSC activities are regulated by pathways downstream of the interleukin (IL) 1beta/IL1 receptor, and IL6/STAT3 signalling. These cytokine signalling pathways contribute to both metastatic progression and endocrine and CDK4/6 inhibitor therapy resistance. Targeting them in combination with current therapies has the potential to improve clinical outcomes.
An integrative single-cell transcriptomic atlas of the post-natal mouse mammary gland allows discovery of new developmental trajectories in the luminal compartment.
The mammary gland (MG) is a highly dynamic organ which undergoes periods of expansion, differentiation and cell death in each reproductive cycle. In agreement with the dynamic nature of the gland, mammary epithelial cells (MECs) are extraordinarily heterogeneous. Single cell RNA-seq (scRNA-seq) analyses have contributed to understand the cellular and transcriptional heterogeneity of this complex tissue. Here, we integrate scRNA-seq data from three foundational reports that have explored the MG cell populations throughout development at single-cell level. We focused our analysis on MG post-natal development. This new integrated study corresponds to RNA sequences from a total of 53,686 individual cells. The large volume of information provides new insights, as a better resolution of the previously detected Procr+ stem-like cell subpopulation. Moreover, our study proposes new pseudo-temporal trajectories of MEC populations at two resolution levels, either considering all mammary cell subtypes or focusing specifically on the luminal lineages. Interestingly, the luminal-restricted analysis reveals distinct expression patterns for different millk-protein genes, suggesting specific and non-redundant roles for each of these proteins. In summary, our data show that the application of bioinformatic tools to integrate multiple scRNA-seq data-sets helps to describe and interpret the high level of plasticity involved in gene expression regulation throughout MG post-natal development.
