Acute lymphoblastic leukemia and developmental biology: A crucial interrelationship

The latest scientific findings in the field of cancer research are redefining our understanding of the molecular and cellular basis of the disease, moving the emphasis toward the study of the mechanisms underlying the alteration of the normal processes of cellular differentiation. The concepts best exemplifying this new vision are those of cancer stem cells and tumoral reprogramming. The study of the biology of acute lymphoblastic leukemias (ALLs) has provided seminal experimental evidence supporting these new points of view. Furthermore, in the case of B cells, it has been shown that all the stages of their normal development show a tremendous degree of plasticity, allowing them to be reprogrammed to other cellular types, either normal or leukemic. Here we revise the most recent discoveries in the fields of B-cell developmental plasticity and B-ALL research and discuss their interrelationships and their implications for our understanding of the biology of the disease.Key words: leukemia, hematopoietic development, leukemic stem cells, lymphopoiesis, developmental plasticity, B cells, stem cells, cancer, B-ALL     

Cellular metabolism and disease: what do metabolic outliers teach us?

An understanding of metabolic pathways based solely on biochemistry textbooks would underestimate the pervasive role of metabolism in essentially every aspect of biology. It is evident from recent work that many human diseases involve abnormal metabolic states--often genetically programmed--that perturb normal physiology and lead to severe tissue dysfunction. Understanding these metabolic outliers is now a crucial frontier in disease-oriented research. This Review discusses the broad impact of metabolism in cellular function and how modern concepts of metabolism can inform our understanding of common diseases like cancer and also considers the prospects of developing new metabolic approaches to disease treatment.     

Impact of intercellular connectivity on epithelial mesenchymal transition plasticity

Epithelial mesenchymal transition (EMT) in development, tissue repair and carcinogenesis involves cellular plasticity with varying degrees of epithelial and mesenchymal properties. Several recent studies have focused on EMT phenotypic dynamism; however, information on cellular interaction in the context of EMT is inadequate. In our previous study, we investigated EMT phenotypic plasticity and anticipated it as a population driven interactive process. Present study has characterized cellular connectivity as a representative of interactivity during EMT in epithelial normal and cancer cell. It has also explored dynamism of connectivity and phenotype employing Markov model. Further, plasticity was substantiated with cell surface microvilli and molecular marker. The study unveiled interplay between phenotype and connectivity too. Findings have revealed that intercellular connectivity fueled EMT plasticity and its dynamism was more prominent in cancer population. However, normal cells are more vibrant in transition and phenotypic plasticity. We have proposed connectivity plasticity as a hallmark of EMT and needs to be studied in depth. Present study also paves the way in translating in vitro EMT findings in histopathological practices.     

Cellular mechanobiology and cancer metastasis

The primary cause of cancer treatment failure is invasion and metastasis, and invading tumor cells utilize many of the motility patterns that have been documented for normal morphogenesis. Recently, the role of mechanical forces in guiding various tissue and cell movements in embryonic development has been systematically analyzed with new experimental and computational methods. The tissue and cellular mechanobiology approach also holds promise for increasing the understanding of tumor invasion. In fact, the mechanical stiffness of tumors has correlated with invasiveness, and manipulation of extracellular matrix (ECM) stiffness in vitro has suppressed the cancer phenotype. Several important signaling molecules reside on the cytoskeleton, which is affected by external stress imparted by the ECM, and deformation of the nucleus can trigger the activation of certain genes. All these observations suggest that a synthesis of the biology of cancer cell invasion and cellular mechanobiology may offer new targets for the treatment of malignant disease. Accordingly, sensitive and relevant in vivo models and methods to study cancer mechanobiology are needed.     

Adipose tissue stem cells meet preadipocyte commitment: going back to the future

White adipose tissue (WAT) is perhaps the most plastic organ in the body, capable of regeneration following surgical removal and massive expansion or contraction in response to altered energy balance. Research conducted for over 70 years has investigated adipose tissue plasticity on a cellular level, spurred on by the increasing burden that obesity and associated diseases are placing on public health globally. This work has identified committed preadipocytes in the stromal vascular fraction of adipose tissue and led to our current understanding that adipogenesis is important not only for WAT expansion, but also for maintenance of adipocyte numbers under normal metabolic states. At the turn of the millenium, studies investigating preadipocyte differentiation collided with developments in stem cell research, leading to the discovery of multipotent stem cells within WAT. Such adipose tissue-derived stem cells (ASCs) are capable of differentiating into numerous cell types of both mesodermal and nonmesodermal origin, leading to their extensive investigation from a therapeutic and tissue engineering perspective. However, the insights gained through studying ASCs have also contributed to more-recent progress in attempts to better characterize committed preadipocytes in adipose tissue. Thus, ASC research has gone back to its roots, thereby expanding our knowledge of preadipocyte commitment and adipose tissue biology.     

Why should cell biologists study microbial pathogens?

One quarter of all deaths worldwide each year result from infectious diseases caused by microbial pathogens. Pathogens infect and cause disease by producing virulence factors that target host cell molecules. Studying how virulence factors target host cells has revealed fundamental principles of cell biology. These include important advances in our understanding of the cytoskeleton, organelles and membrane-trafficking intermediates, signal transduction pathways, cell cycle regulators, the organelle/protein recycling machinery, and cell-death pathways. Such studies have also revealed cellular pathways crucial for the immune response. Discoveries from basic research on the cell biology of pathogenesis are actively being translated into the development of host-targeted therapies to treat infectious diseases. Thus there are many reasons for cell biologists to incorporate the study of microbial pathogens into their research programs.     

Implications of autophagy for vascular smooth muscle cell function and plasticity

Vascular smooth muscle cells (VSMCs) are fundamental in regulating blood pressure and distributing oxygen and nutrients to peripheral tissues. They also possess remarkable plasticity, with the capacity to switch to synthetic, macrophage-like, or osteochondrogenic phenotypes when cued by external stimuli. In arterial diseases such as atherosclerosis and restenosis, this plasticity seems to be critical and, depending on the disease context, can be deleterious or beneficial. Therefore, understanding the mechanisms regulating VSMC phenotype and survival is essential for developing new therapies for vascular disease as well as understanding how secondary complications due to surgical interventions develop. In this regard, the cellular process of autophagy is increasingly being recognized as a major player in vascular biology and a critical determinant of VSMC phenotype and survival. Although autophagy was identified in lesional VSMCs in the 1960s, our understanding of the implications of autophagy in arterial diseases and the stimuli promoting its activation in VSMCs is only now being elucidated. In this review, we highlight the evidence for autophagy occurring in VSMCs in vivo, elaborate on the stimuli and processes regulating autophagy, and discuss the current understanding of the role of autophagy in vascular disease.     

The best of both worlds- bringing together cell biology and infection at the Institut Pasteur

Only a profound understanding of the structure and function of cells - either as single units or in the context of tissues and whole organisms - will allow a comprehension of what happens in pathological conditions and provides the means to fight disease. The Cell Biology and Infection (BCI for Biologie Cellulaire et Infection) department was created in 2002 at the Institut Pasteur in Paris to develop a research program under the umbrella of cell biology, infection biology and microbiology. Its visionary ambition was to shape a common framework for cellular microbiology, and to interface the latter with hard sciences like physics and mathematics and cutting-edge technology. This concept, ahead of time, has given high visibility to the field of cellular microbiology and quantitative cell biology, and it has allowed the successful execution of highly interdisciplinary research programs linking a molecular understanding of cellular events with disease. Now, the BCI department embraces additional pathologies, namely cancer and neurodegenerative diseases. Here, we will portray how the integrative research approach of BCI has led to major scientific breakthroughs during the last ten years, and where we see scientific opportunities for the near future.     

Cancer stem cell biology: from leukemia to solid tumors

The biology of stem cells and their intrinsic properties are now recognized as integral to tumor pathogenesis in several types of cancer. This observation has broad ramifications in the cancer research field and is likely to impact our understanding of the basic mechanisms of tumor formation and the strategies we use to treat cancers. A role for stem cells has been demonstrated for cancers of the hematopoietic system, breast and brain. Going forward it is likely that stem cells will also be implicated in other malignancies. Hence, a detailed understanding of stem cells and how they mediate tumor pathogenesis will be critical in developing more effective cancer therapies.     

DNA微阵列技术及其在肿瘤生物学中的应用

人类基因组测序工作的完成使人们可以方便地调用任何基因序列,但仅有基因序列并不能解释众多的生物学问题,这要求发展一种高通量的技术用于研究基因的生物学功能以及基因的相互作用。DNA微阵列技术以其高通量的特点,已经在肿瘤生物学的研究中逐渐被采用。由于癌症是源于基因表达谱改变的基因疾病,通过DNA微阵列技术研究癌症细胞和对应的正常细胞的基因表达差异,将会使人们更好地了解肿瘤的形成和发展过程。     

Inhibitor of DNA Binding 4 (ID4) Is Highly Expressed in Human Melanoma Tissues and May Function to Restrict Normal Differentiation of Melanoma Cells

Melanoma tissues and cell lines are heterogeneous, and include cells with invasive, proliferative, stem cell-like, and differentiated properties. Such heterogeneity likely contributes to the aggressiveness of the disease and resistance to therapy. One model suggests that heterogeneity arises from rare cancer stem cells (CSCs) that produce distinct cancer cell lineages. Another model suggests that heterogeneity arises through reversible cellular plasticity, or phenotype-switching. Recent work indicates that phenotype-switching may include the ability of cancer cells to dedifferentiate to a stem cell-like state. We set out to investigate the phenotype-switching capabilities of melanoma cells, and used unbiased methods to identify genes that may control such switching. We developed a system to reversibly synchronize melanoma cells between 2D-monolayer and 3D-stem cell-like growth states. Melanoma cells maintained in the stem cell-like state showed a striking upregulation of a gene set related to development and neural stem cell biology, which included SRY-box 2 (SOX2) and Inhibitor of DNA Binding 4 (ID4). A gene set related to cancer cell motility and invasiveness was concomitantly downregulated. Intense and pervasive ID4 protein expression was detected in human melanoma tissue samples, suggesting disease relevance for this protein. SiRNA knockdown of ID4 inhibited switching from monolayer to 3D-stem cell-like growth, and instead promoted switching to a highly differentiated, neuronal-like morphology. We suggest that ID4 is upregulated in melanoma as part of a stem cell-like program that facilitates further adaptive plasticity. ID4 may contribute to disease by preventing stem cell-like melanoma cells from progressing to a normal differentiated state. This interpretation is guided by the known role of ID4 as a differentiation inhibitor during normal development. The melanoma stem cell-like state may be protected by factors such as ID4, thereby potentially identifying a new therapeutic vulnerability to drive differentiation to the normal cell phenotype.     

Why modules matter

The serendipitous discovery of the SH2 domain unleashed a sea-change in our conceptual molecular understanding of protein function. The reductionist approaches that followed from the recognition of modular protein interaction domains transformed our understanding of cellular signal transduction systems, how they evolve and how they may be manipulated. We now recognize thousands of conserved protein modules - many of which have been described in structure and function, implicated in disease, or underlie targeted therapeutics. The reductionist study of isolated protein modules has enabled the reconstruction of the protein interaction networks that underlie cellular signalling. Protein modules themselves are becoming tools to probe cellular activation states and identify key interactions hubs in both normal and diseased cells and the concept of protein modularity is central to the field of synthetic biology. This brief word of introduction serves to highlight the historical impact of the very powerful idea of protein modules and sets the stage for the exciting on-going discoveries discussed in this issue.     

Role of long interspersed nuclear element-1 in the regulation of chromatin landscapes and genome dynamics

LINE-1 retrotransposon, the most active mobile element of the human genome, is subject to tight regulatory control. Stressful environments and disease modify the recruitment of regulatory proteins leading to unregulated activation of LINE-1. The activation of LINE-1 influences genome dynamics through altered chromatin landscapes, insertion mutations, deletions, and modulation of cellular plasticity. To date, LINE-1 retrotransposition has been linked to various cancer types and may in fact underwrite the genetic basis of various other forms of chronic human illness. The occurrence of LINE-1 polymorphisms in the human population may define inter-individual differences in susceptibility to disease. This review is written in honor of Dr Peter Stambrook, a friend and colleague who carried out highly impactful cancer research over many years of professional practice. Dr Stambrook devoted considerable energy to helping others live up to their full potential and to navigate the complexities of professional life. He was an inspirational leader, a strong advocate, a kind mentor, a vocal supporter and cheerleader, and yes, a hard critic and tough friend when needed. His passionate stand on issues, his witty sense of humor, and his love for humanity have left a huge mark in our lives. We hope that that the knowledge summarized here will advance our understanding of the role of LINE-1 in cancer biology and expedite the development of innovative cancer diagnostics and treatments in the ways that Dr Stambrook himself had so passionately envisioned.     

植物养分捕获的菌根塑性——外生菌根的塑性

植物根资源捕获塑性是地下生态学研究的重点之一, 在过去二三十年间有长足的进步。菌根塑性是根资源捕获塑性的重要方面, 但由于研究手段的限制, 目前仅有概念上的探讨。缺乏菌根塑性的根塑性研究至少是不全面的。菌根生物学的迅速发展, 尤其是分子生物学手段的介入, 使对菌根塑性进行深入研究成为可能。该文对外生菌根塑性进行讨论, 在简要介绍了外生菌根的生物学基本知识后, 着重讨论了外生菌根形态塑性和生理塑性的定义与内涵。通过文献综述, 分析讨论了外生菌根塑性的研究现状: 很少有研究聚焦在菌根塑性本身, 现有的材料多为其他研究的隐示或研究结果的引申, 并多在形态塑性方面。外生菌根的生理塑性未见有直接的实验数据。该文还对外生菌根研究中发展的、可用于菌根塑性研究的方法进行了综述。由于外生菌根塑性的复杂性, 对菌根塑性的研究会较植物根本身塑性的研究复杂得多, 问题也会相对复杂, 比如植物和外生菌根菌之间的营养需求关系、植物外生菌根塑性的生态意义、实验方法的缺陷等等。对今后外生菌根塑性研究的方向进行了探讨。     

From teratocarcinomas to embryonic stem cells

The recent derivation of human embryonic stem (ES) cell lines, together with results suggesting an unexpected degree of plasticity in later, seemingly more restricted, stem cells (so-called adult stem cells), have combined to focus attention on new opportunities for regenerative medicine, as well as for understanding basic aspects of embryonic development and diseases such as cancer. Many of the ideas that are now discussed have a long history and much has been underpinned by the earlier studies of teratocarcinomas, and their embryonal carcinoma (EC) stem cells, which present a malignant surrogate for the normal stem cells of the early embryo. Nevertheless, although the potential of EC and ES cells to differentiate into a wide range of tissues is now well attested, little is understood of the key regulatory mechanisms that control their differentiation. Apart from the intrinsic biological interest in elucidating these mechanisms, a clear understanding of the molecular process involved will be essential if the clinical potential of these cells is to be realized. The recent observations of stem-cell plasticity suggest that perhaps our current concepts about the operation of cell regulatory pathways are inadequate, and that new approaches for analysing complex regulatory networks will be essential.     

Autophagy in stem cells

Autophagy is a highly conserved cellular process by which cytoplasmic components are sequestered in autophagosomes and delivered to lysosomes for degradation. As a major intracellular degradation and recycling pathway, autophagy is crucial for maintaining cellular homeostasis as well as remodeling during normal development, and dysfunctions in autophagy have been associated with a variety of pathologies including cancer, inflammatory bowel disease and neurodegenerative disease. Stem cells are unique in their ability to self-renew and differentiate into various cells in the body, which are important in development, tissue renewal and a range of disease processes. Therefore, it is predicted that autophagy would be crucial for the quality control mechanisms and maintenance of cellular homeostasis in various stem cells given their relatively long life in the organisms. In contrast to the extensive body of knowledge available for somatic cells, the role of autophagy in the maintenance and function of stem cells is only beginning to be revealed as a result of recent studies. Here we provide a comprehensive review of the current understanding of the mechanisms and regulation of autophagy in embryonic stem cells, several tissue stem cells (particularly hematopoietic stem cells), as well as a number of cancer stem cells. We discuss how recent studies of different knockout mice models have defined the roles of various autophagy genes and related pathways in the regulation of the maintenance, expansion and differentiation of various stem cells. We also highlight the many unanswered questions that will help to drive further research at the intersection of autophagy and stem cell biology in the near future.     

The malignant social network: Cell-cell adhesion and communication in cancer stem cells

Tumors contain a vastly complicated cellular network that relies on local communication to execute malignant programs. The molecular cues that are involved in cell-cell adhesion orchestrate large-scale tumor behaviors such as proliferation and invasion. We have recently begun to appreciate that many tumors contain a high degree of cellular heterogeneity and are organized in a cellular hierarchy, with a cancer stem cell (CSC) population identified at the apex in multiple cancer types. CSCs reside in unique microenvironments or niches that are responsible for directing their behavior through cellular interactions between CSCs and stromal cells, generating a malignant social network. Identifying cell-cell adhesion mechanisms in this network has implications for the basic understanding of tumorigenesis and the development of more effective therapies. In this review, we will discuss our current understanding of cell-cell adhesion mechanisms used by CSCs and how these local interactions have global consequences for tumor biology.