Basal-like breast cancers: from pathology to biology and back again

Human breast cancers referred to as "basal-like" are of interest because they lack effective therapies and their biology is poorly understood. The term basal-like derives from studies demonstrating tumor gene expression profiles that include some transcripts characteristic of the basal cells of the normal adult human mammary gland and others associated with a subset of normal luminal cells. Elucidating the mechanisms responsible for the profiles of basal-like tumors is an active area of investigation. More refined molecular analysis of patients' samples and genetic strategies to produce breast cancers de novo from defined populations of normal mouse mammary cells have served as complementary approaches to identify relevant pathway alterations. However, both also have limitations. Here, we review some of the underlying reasons, including the unifying concept that some normal luminal cells have both luminal and basal features, as well as some emerging new avenues of investigation

p53: A New Kingpin in the Stem Cell Arena

Identifying new regulators of the stem cell state offers potential for future gains in biomedicine. Evidence that the tumor suppressor p53 is a key regulator of the stem cell state (Cicalese et al., 2009) suggests a broad role for this protein and its pathways in the control of normal tissue homeostasis and tumor formation

Tipping the Balance: MTDH-SND1 Curbs Oncogene-Induced Apoptosis and Promotes Tumorigenesis

Tumorigenesis is a complex and poorly understood process in which oncogenes can activate competing proapoptotic and proneoplastic programs. A recent paper in Cancer Cell demonstrates a dual role of the MTDH-SND1 complex in suppressing the apoptotic response and promoting breast cancer development, suggesting a new therapeutic avenue

Cancer Stem Cells: Notes for Authors.

Stem Cell Reports frequently receives manuscripts dealing with the topic of cancer stem cells. Many of the submissions on this topic have major shortcomings in their content or limits to the conclusions that can be drawn from the results presented. The purpose of this Commentary is to highlight some of the underlying issues so that authors can enhance the strength of their research contributions

Expression of the leukemic prognostic marker CD7 is linked to epigenetic modifications in chronic myeloid leukemia

<p>Abstract</p> <p>Background</p> <p>Expression levels of the cell surface glycoprotein, CD7, and the serine protease, elastase 2 (ELA2), in the leukemic cells of patients with chronic myeloid leukemia (CML) have been associated with clinical outcome. However, little is known about the mechanisms that underlie the variable expression of these genes in the leukemic cells.</p> <p>Results</p> <p>To address this question, we compared the level of their expression with the DNA methylation and histone acetylation status of 5' sequences of both genes in leukemic cell lines and primitive (lin^-CD34⁺) leukemic cells from chronic phase CML patients. DNA methylation of the <it>ELA2 </it>gene promoter did not correlate with its expression pattern in lin^-CD34⁺cells from chronic phase CML patient samples even though there was clear differential DNA methylation of this locus in <it>ELA2</it>-expressing and non-expressing cell lines. In contrast, we found a strong relation between CD7 expression and transcription-permissive chromatin modifications, both at the level of DNA methylation and histone acetylation with evidence of hypomethylation of the <it>CD7 </it>promoter region in the lin^-CD34⁺cells from CML patients with high CD7 expression.</p> <p>Conclusion</p> <p>These findings indicate a link between epigenetic modifications and CD7 expression in primitive CML cells.</p

Distinct Stromal Cell Factor Combinations Can Separately Control Hematopoietic Stem Cell Survival, Proliferation, and Self-Renewal

SummaryHematopoietic stem cells (HSCs) are identified by their ability to sustain prolonged blood cell production in vivo, although recent evidence suggests that durable self-renewal (DSR) is shared by HSC subtypes with distinct self-perpetuating differentiation programs. Net expansions of DSR-HSCs occur in vivo, but molecularly defined conditions that support similar responses in vitro are lacking. We hypothesized that this might require a combination of factors that differentially promote HSC viability, proliferation, and self-renewal. We now demonstrate that HSC survival and maintenance of DSR potential are variably supported by different Steel factor (SF)-containing cocktails with similar HSC-mitogenic activities. In addition, stromal cells produce other factors, including nerve growth factor and collagen 1, that can antagonize the apoptosis of initially quiescent adult HSCs and, in combination with SF and interleukin-11, produce >15-fold net expansions of DSR-HSCs ex vivo within 7 days. These findings point to the molecular basis of HSC control and expansion

The future of mammary stem cell biology: the power of in vivo transplants

The recent review by Smith and Medina [1] of in vivo transplantation models and their role in investigating mammary stem cell (MaSC) biology provides comprehensive coverage of the history and complexity of the ‘gold standard ’ MaSC assay in mice. This includes a description of the pioneering studies that showed that mammary epithelial outgrowths can be generated in cleared mammary fat pads transplanted with explants or admixtures of mammary cells [2]. However, this approach clearly does not lend itself to prospective analysis of isolated subpopulations in order to identify which cells possess in vivo regenerative activity. More recently, success in obtaining complex mammary gland structures from transplanted suspensions of single cells has now made this possible [3-7]. Moreover, the regenerated structures have been shown to contain daughter cells with the same in viv

Analysis of parameters that affect human hematopoietic cell outputs in mutant c-kit-immunodeficient mice.

Xenograft models are transforming our understanding of the output capabilities of primitive human hematopoietic cells in vivo. However, many variables that affect posttransplantation reconstitution dynamics remain poorly understood. Here, we show that an equivalent level of human chimerism can be regenerated from human CD34(+) cord blood cells transplanted intravenously either with or without additional radiation-inactivated cells into 2- to 6-month-old NOD-Rag1(-/-)-IL2Rγc(-/-) (NRG) mice given a more radioprotective conditioning regimen than is possible in conventionally used, repair-deficient NOD-Prkdc(scid/scid)-IL2Rγc(-/-) (NSG) hosts. Comparison of sublethally irradiated and non-irradiated NRG mice and W(41)/W(41) derivatives showed superior chimerism in the W(41)-deficient recipients, with some differential effects on different lineage outputs. Consistently superior outputs were observed in female recipients regardless of their genotype, age, or pretransplantation conditioning, with greater differences apparent later after transplantation. These results define key parameters for optimizing the sensitivity and minimizing the intraexperimental variability of human hematopoietic xenografts generated in increasingly supportive immunodeficient host mice. Exp Hematol 2017 Apr; 48:41-49

Hematopoietic Stem Cells Are the Major Source of Multilineage Hematopoiesis in Adult Animals

Hematopoietic stem cells (HSCs) sustain long-term reconstitution of hematopoiesis in transplantation recipients, yet their role in the endogenous steady-state hematopoiesis remains unclear. In particular, recent studies suggested that HSCs provide a relatively minor contribution to immune cell development in adults. We directed transgene expression in a fraction of HSCs that maintained reconstituting activity during serial transplantations. Inducible genetic labeling showed that transgene-expressing HSCs gave rise to other phenotypic HSCs, confirming their top position in the differentiation hierarchy. The labeled HSCs rapidly contributed to committed progenitors of all lineages and to mature myeloid cells and lymphocytes, but not to B-1a cells or tissue macrophages. Importantly, labeled HSCs gave rise to more than two-thirds of all myeloid cells and platelets in adult mice, and this contribution could be accelerated by an induced interferon response. Thus, classically defined HSCs maintain immune cell development in the steady state and during systemic cytokine responses

GateFinder: projection-based gating strategy optimization for flow and mass cytometry

Motivation: High-parameter single-cell technologies can reveal novel cell populations of interest, but studying or validating these populations using lower-parameter methods remains challenging.Results: Here, we present GateFinder, an algorithm that enriches high-dimensional cell types with simple, stepwise polygon gates requiring only two markers at a time. A series of case studies of complex cell types illustrates how simplified enrichment strategies can enable more efficient assays, reveal novel biomarkers and clarify underlying biology