scholarly journals The mammary stem cell hierarchy: a looking glass into heterogeneous breast cancer landscapes

2015 ◽  
Vol 22 (6) ◽  
pp. T161-T176 ◽  
Author(s):  
Amulya Sreekumar ◽  
Kevin Roarty ◽  
Jeffrey M Rosen
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Drug Targets ◽  
Cell Types ◽  
Mammary Development ◽  
Lineage Tracing ◽  
Mammary Epithelial ◽  
Cancer Drug ◽  
Mammary Stem ◽  
Stem Cell Hierarchy

The mammary gland is a dynamic organ that undergoes extensive morphogenesis during the different stages of embryonic development, puberty, estrus, pregnancy, lactation and involution. Systemic and local cues underlie this constant tissue remodeling and act by eliciting an intricate pattern of responses in the mammary epithelial and stromal cells. Decades of studies utilizing methods such as transplantation and lineage-tracing have identified a complex hierarchy of mammary stem cells, progenitors and differentiated epithelial cells that fuel mammary epithelial development. Importantly, these studies have extended our understanding of the molecular crosstalk between cell types and the signaling pathways maintaining normal homeostasis that often are deregulated during tumorigenesis. While several questions remain, this research has many implications for breast cancer. Fundamental among these are the identification of the cells of origin for the multiple subtypes of breast cancer and the understanding of tumor heterogeneity. A deeper understanding of these critical questions will unveil novel breast cancer drug targets and treatment paradigms. In this review, we provide a current overview of normal mammary development and tumorigenesis from a stem cell perspective.

A small molecule LN435a targeting TGFβR1 exerts promising antitumor effects on breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15069-e15069
Author(s):  
Yuzhu Zhang ◽  
Huachao Li ◽  
Hongyan Zhang ◽  
Xiaoyuan Liu ◽  
Tianyu Luo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cell ◽  
Anticancer Activity ◽  
Multiple Drug Resistance ◽  
Cancer Drug ◽  
Her2 Status ◽  
Stem Cell Markers ◽  
Antitumor Effects ◽  
Cell Markers ◽  
Anti Cancer

e15069 Background: Breast cancer has overtaken lung cancer as the most diagnosed cancer. Despite conventional treatment, metastases occur in 20-30% of patients, resulting in death. This study aims to screen of effective drugs by metastatic patient-derived organoid and the potential molecular mechanism. Methods: Breast Cancer patient-derived organoid (PDO) model was established from the patient who have multiple drug resistance, multiple visceral and contralateral breast metastases. The organoid morphologies was tested by hematoxylin-eosin (HE) staining and immunohistochemistry (IHC). Then, pharmacological activity assay of 2370 natural product monomer (from Selleck) was performed with organoids. we modified the structure of harmine(HM) and screened the best active drugs. Cell proliferation assay and wound healing assay were used to detect LN435a anticancer activity in vitro. Orthotopic, Metastatic Xenograft and Patient-Derived tumor Xenograft(PDX) model of Breast Cancer were used to detect LN435a anticancer activity in vivo. In order to explore the anti-cancer target of LN435a, we used RNA transcriptome and proteomics sequencing. To further validate anti-cancer targets,TGFβ receptor 1 (TGFβR1), we used real-time quantitative qPCR, western blot, lentiviral packing and biolayer interferometry assay. To investigate whether LN435a inhabition of EMT and stem cell markers, we performed flow cytometry, immunohistochemistry and fluorescence. Results: We observe that organoid morphologies typically matched the histopathology, hormone receptor status, and HER2 status of the original tumor. In the first anti-cancer drug screening, HM showes the best effect on PDO. Because HM contains β-carbine alkaloids as the structural units, we designe a series of active drugs based on this and did anticancer screening. We find LN435a as one of the lead compounds exerting anti-metastatic activity in the nanomolar range in PDO and breast cancer cells. Proteomic and biochemical studies identify TGFβR1 as the direct target of LN435a. And then it inhibits EMT and stem cell markers. In parallel, loss of TGFβR1 or pharmacological inhibition of TGFβR1 by LN435a reduces breast cancer extravasation into the lung in an experimental metastasis mouse model, which reveals an essential role of TGFβR1 in breast cancer progression. Conclusions: Altogether, LN435a is a novel inhibitor of promising anti-tumor effects on breast cancer that works by blocking TGFβ signaling pathways.

scholarly journals Profiling proliferative cells and their progeny in damaged murine hearts

2018 ◽  
Vol 115 (52) ◽  
pp. E12245-E12254 ◽  
Author(s):  
Kai Kretzschmar ◽  
Yorick Post ◽  
Marie Bannier-Hélaouët ◽  
Andrea Mattiotti ◽  
Jarno Drost ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Function ◽  
Cardiac Fibroblasts ◽  
Cardiac Injury ◽  
Cardiac Regeneration ◽  
Cell Types ◽  
Postnatal Growth ◽  
Lineage Tracing ◽  
Genetic Lineage ◽  
Proliferating Cells

The significance of cardiac stem cell (CSC) populations for cardiac regeneration remains disputed. Here, we apply the most direct definition of stem cell function (the ability to replace lost tissue through cell division) to interrogate the existence of CSCs. By single-cell mRNA sequencing and genetic lineage tracing using two Ki67 knockin mouse models, we map all proliferating cells and their progeny in homoeostatic and regenerating murine hearts. Cycling cardiomyocytes were only robustly observed in the early postnatal growth phase, while cycling cells in homoeostatic and damaged adult myocardium represented various noncardiomyocyte cell types. Proliferative postdamage fibroblasts expressing follistatin-like protein 1 (FSTL1) closely resemble neonatal cardiac fibroblasts and form the fibrotic scar. Genetic deletion of Fstl1 in cardiac fibroblasts results in postdamage cardiac rupture. We find no evidence for the existence of a quiescent CSC population, for transdifferentiation of other cell types toward cardiomyocytes, or for proliferation of significant numbers of cardiomyocytes in response to cardiac injury.

scholarly journals Plasticity and Potency of Mammary Stem Cell Subsets During Mammary Gland Development

2019 ◽  
Vol 20 (9) ◽  
pp. 2357 ◽  
Author(s):  
Eunmi Lee ◽  
Raziye Piranlioglu ◽  
Max S. Wicha ◽  
Hasan Korkaya
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Mammary Gland ◽  
Mammary Gland Development ◽  
Mammary Epithelial ◽  
Stem Cell Markers ◽  
Quiescent State ◽  
Mammary Stem Cells ◽  
Mammary Stem ◽  
Gland Development

It is now widely believed that mammary epithelial cell plasticity, an important physiological process during the stages of mammary gland development, is exploited by the malignant cells for their successful disease progression. Normal mammary epithelial cells are heterogeneous and organized in hierarchical fashion, in which the mammary stem cells (MaSC) lie at the apex with regenerative capacity as well as plasticity. Despite the fact that the majority of studies supported the existence of multipotent MaSCs giving rise to both basal and luminal lineages, others proposed lineage restricted unipotent MaSCs. Consistent with the notion, the latest research has suggested that although normal MaSC subsets mainly stay in a quiescent state, they differ in their reconstituting ability, spatial localization, and molecular and epigenetic signatures in response to physiological stimuli within the respective microenvironment during the stages of mammary gland development. In this review, we will focus on current research on the biology of normal mammary stem cells with an emphasis on properties of cellular plasticity, self-renewal and quiescence, as well as the role of the microenvironment in regulating these processes. This will include a discussion of normal breast stem cell heterogeneity, stem cell markers, and lineage tracing studies.

scholarly journals Evidence for a stem cell hierarchy in the adult human breast

2007 ◽  
Vol 177 (1) ◽  
pp. 87-101 ◽  
Author(s):  
René Villadsen ◽  
Agla J. Fridriksdottir ◽  
Lone Rønnov-Jessen ◽  
Thorarinn Gudjonsson ◽  
Fritz Rank ◽  
...  
Keyword(s):  
Stem Cell ◽  
Progenitor Cells ◽  
Functional Characterization ◽  
Cell Activity ◽  
Cell Types ◽  
Human Breast ◽  
Mammosphere Formation ◽  
Adult Human ◽  
Dividing Cells ◽  
Stem Cell Hierarchy

Cellular pathways that contribute to adult human mammary gland architecture and lineages have not been previously described. In this study, we identify a candidate stem cell niche in ducts and zones containing progenitor cells in lobules. Putative stem cells residing in ducts were essentially quiescent, whereas the progenitor cells in the lobules were more likely to be actively dividing. Cells from ducts and lobules collected under the microscope were functionally characterized by colony formation on tissue culture plastic, mammosphere formation in suspension culture, and morphogenesis in laminin-rich extracellular matrix gels. Staining for the lineage markers keratins K14 and K19 further revealed multipotent cells in the stem cell zone and three lineage-restricted cell types outside this zone. Multiparameter cell sorting and functional characterization with reference to anatomical sites in situ confirmed this pattern. The proposal that the four cell types are indeed constituents of an as of yet undescribed stem cell hierarchy was assessed in long-term cultures in which senescence was bypassed. These findings identify an adult human breast ductal stem cell activity and its earliest descendants.

scholarly journals scRNA-seq in medulloblastoma shows cellular heterogeneity and lineage expansion support resistance to SHH inhibitor therapy

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Jennifer Ocasio ◽  
Benjamin Babcock ◽  
Daniel Malawsky ◽  
Seth J. Weir ◽  
Lipin Loo ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cell Types ◽  
Lineage Tracing ◽  
Inhibitor Therapy ◽  
Cellular Heterogeneity ◽  
Specific Cell ◽  
Stem Cell Markers ◽  
Shh Pathway ◽  
Oncogenic Pathways ◽  
Support Resistance

AbstractTargeting oncogenic pathways holds promise for brain tumor treatment, but inhibition of Sonic Hedgehog (SHH) signaling has failed in SHH-driven medulloblastoma. Cellular diversity within tumors and reduced lineage commitment can undermine targeted therapy by increasing the probability of treatment-resistant populations. Using single-cell RNA-seq and lineage tracing, we analyzed cellular diversity in medulloblastomas in transgenic, medulloblastoma-prone mice, and responses to the SHH-pathway inhibitor vismodegib. In untreated tumors, we find expected stromal cells and tumor-derived cells showing either a spectrum of neural progenitor-differentiation states or glial and stem cell markers. Vismodegib reduces the proliferative population and increases differentiation. However, specific cell types in vismodegib-treated tumors remain proliferative, showing either persistent SHH-pathway activation or stem cell characteristics. Our data show that even in tumors with a single pathway-activating mutation, diverse mechanisms drive tumor growth. This diversity confers early resistance to targeted inhibitor therapy, demonstrating the need to target multiple pathways simultaneously.

Sign in / Sign up

Export Citation Format

Share Document