Applying multilevel selection to understand cancer evolution and progression.

Natural selection occurs at multiple levels of organization in cancer. At an organismal level, natural selection has led to the evolution of diverse tumor suppression mechanisms, while at a cellular level, it favors traits that promote cellular proliferation, survival and cancer. Natural selection also occurs at a subcellular level, among collections of cells and even among collections of organisms; selection at these levels could influence the evolution of cancer and cancer suppression mechanisms, affecting cancer risk and treatment strategies.

Epistemic limitations of measurable residual disease in haematological malignancies.

The growing use of measurable residual disease (MRD) assays across haematology-oncology creates an urgent need for clinicians and researchers to reflect on the biological and clinical rationale of this class of biomarkers. In this Viewpoint, we critically examine two premises behind MRD's use in haematology-oncology, focusing on its biological plausibility as a predictive biomarker and surrogate endpoint, and the evidence needed for it to influence decision making in haematological cancers. Examining these premises leads us to advocate for the establishment of more robust biological and clinical evidence to ensure the clinically useful and safe application of MRD.

Monocytes generated by interleukin-6-treated human hematopoietic stem and progenitor cells secrete calprotectin that inhibits erythropoiesis.

Elevated circulating levels of calprotectin (CAL), the S100A8/A9 heterodimer, are biomarkers of severe systemic inflammation. Here, we investigate the effects of CAL on early human hematopoiesis. CAL demonstrates limited impact on gene expression in stem and progenitor cells, in contrast with interleukin-6 (IL6), which promotes the expression of the and genes in hematopoietic progenitors and the generation of monocytes that release CAL.

Targeting heterochromatin eliminates chronic myelomonocytic leukemia malignant stem cells through reactivation of retroelements and immune pathways.

Chronic myelomonocytic leukemia (CMML) is a severe myeloid malignancy affecting the elderly, for which therapeutic options are limited. DNA hypomethylating agents (HMAs) provide transient responses, failing to eradicate the malignant clone. Hematopoietic stem cell (HSC) aging involves heterochromatin reorganization, evidenced by alterations in histone marks H3K9me2 and H3K9me3.

CXCL8 secreted by immature granulocytes inhibits WT hematopoiesis in chronic myelomonocytic leukemia.

Chronic myelomonocytic leukemia (CMML) is a severe myeloid malignancy with limited therapeutic options. Single-cell analysis of clonal architecture demonstrates early clonal dominance with few residual WT hematopoietic stem cells. Circulating myeloid cells of the leukemic clone and the cytokines they produce generate a deleterious inflammatory climate.

The evolutionary theory of cancer: challenges and potential solutions.

The clonal evolution model of cancer was developed in the 1950s-1970s and became central to cancer biology in the twenty-first century, largely through studies of cancer genetics. Although it has proven its worth, its structure has been challenged by observations of phenotypic plasticity, non-genetic forms of inheritance, non-genetic determinants of clone fitness and non-tree-like transmission of genes. There is even confusion about the definition of a clone, which we aim to resolve.

Transcriptomic landscape of posterior regeneration in the annelid Platynereis dumerilii.

Background: Restorative regeneration, the capacity to reform a lost body part following amputation or injury, is an important and still poorly understood process in animals. Annelids, or segmented worms, show amazing regenerative capabilities, and as such are a crucial group to investigate. Elucidating the molecular mechanisms that underpin regeneration in this major group remains a key goal.

Reuniting philosophy and science to advance cancer research.

Cancers rely on multiple, heterogeneous processes at different scales, pertaining to many biomedical fields. Therefore, understanding cancer is necessarily an interdisciplinary task that requires placing specialised experimental and clinical research into a broader conceptual, theoretical, and methodological framework. Without such a framework, oncology will collect piecemeal results, with scant dialogue between the different scientific communities studying cancer.

SRSF2-P95H decreases JAK/STAT signaling in hematopoietic cells and delays myelofibrosis development in mice.

Heterozygous mutation targeting proline 95 in Serine/Arginine-rich Splicing Factor 2 (SRSF2) is associated with V617F mutation in Janus Activated Kinase 2 (JAK2) in some myeloproliferative neoplasms (MPNs), most commonly primary myelofibrosis. To explore the interaction of Srsf2 with Jak2, we generated Cre-inducible knock-in mice expressing these mutants under control of the stem cell leukemia (Scl) gene promoter. In transplantation experiments, Srsf2 unexpectedly delayed myelofibrosis induced by Jak2 and decreased TGFβ1 serum level.

Cancer's second genome: Microbial cancer diagnostics and redefining clonal evolution as a multispecies process: Humans and their tumors are not aseptic, and the multispecies nature of cancer modulates clinical care and clonal evolution: Humans and their tumors are not aseptic, and the multispecies nature of cancer modulates clinical care and clonal evolution.

The presence and role of microbes in human cancers has come full circle in the last century. Tumors are no longer considered aseptic, but implications for cancer biology and oncology remain underappreciated. Opportunities to identify and build translational diagnostics, prognostics, and therapeutics that exploit cancer's second genome-the metagenome-are manifold, but require careful consideration of microbial experimental idiosyncrasies that are distinct from host-centric methods.

Reprogramming monocyte-derived macrophages through caspase inhibition.

Macrophages are widely distributed innate immune cells that play an indispensable role in a variety of physiologic and pathologic processes, including organ development, host defense, acute and chronic inflammation, solid and hematopoietic cancers. Beyond their inextricable role as conveyors of programmed cell death, we have previously highlighted that caspases exert non-apoptotic functions, especially during the differentiation of monocyte-derived cells in response to CSF-1. Here, we found that non-canonic cleavages of caspases, reflecting their activation, are maintained during IL-4-induced monocyte-derived macrophages polarization.

Clonal Architecture and Evolutionary Dynamics in Acute Myeloid Leukemias.

Acute myeloid leukemias (AML) results from the accumulation of genetic and epigenetic alterations, often in the context of an aging hematopoietic environment. The development of high-throughput sequencing-and more recently, of single-cell technologies-has shed light on the intratumoral diversity of leukemic cells. Taking AML as a model disease, we review the multiple sources of genetic, epigenetic, and functional heterogeneity of leukemic cells and discuss the definition of a leukemic clone extending its definition beyond genetics.

On the origins and conceptual frameworks of natural plasticity-Lessons from single-cell models in C. elegans.

How flexible are cell identities? This problem has fascinated developmental biologists for several centuries and can be traced back to Abraham Trembley's pioneering manipulations of Hydra to test its regeneration abilities in the 1700s. Since the cell theory in the mid-19th century, developmental biology has been dominated by a single framework in which embryonic cells are committed to specific cell fates, progressively and irreversibly acquiring their differentiated identities. This hierarchical, unidirectional and irreversible view of cell identity has been challenged in the past decades through accumulative evidence that many cell types are more plastic than previously thought, even in intact organisms.

To portray clonal evolution in blood cancer, count your stem cells.

Clonal evolution, the process of expansion and diversification of mutated cells, plays an important role in cancer development, resistance, and relapse. Although clonal evolution is most often conceived of as driven by natural selection, recent studies uncovered that neutral evolution shapes clonal evolution in a significant proportion of solid cancers. In hematological malignancies, the interplay between neutral evolution and natural selection is also disputed.

Multilayer intraclonal heterogeneity in chronic myelomonocytic leukemia.

The functional diversity of cells that compose myeloid malignancies, i.e., the respective roles of genetic and epigenetic heterogeneity in this diversity, remains poorly understood.

Beyond the tumour microenvironment.

In contrast to the once dominant tumour-centric view of cancer, increasing attention is now being paid to the tumour microenvironment (TME), generally understood as the elements spatially located in the vicinity of the tumour. Thinking in terms of TME has proven extremely useful, in particular because it has helped identify and comprehend the role of nongenetic and noncell-intrinsic factors in cancer development. Yet some current approaches have led to a TME-centric view, which is no less problematic than the former tumour-centric vision of cancer, insofar as it tends to overlook the role of components located beyond the TME, in the 'tumour organismal environment' (TOE).

Towards a classification of stem cells.

The characteristic properties of stem cells - notably their ability to self-renew and to differentiate - have meant that they have traditionally been viewed as distinct from most other types of cells. However, recent research has blurred the line between stem cells and other cells by showing that the former display a range of behaviors in different tissues and at different stages of development. Here, we use the tools of metaphysics to describe a classification scheme for stem cells, and to highlight what their inherent diversity means for cancer treatment.

The Multiple Layers of the Tumor Environment.

The notion of tumor microenvironment (TME) has been brought to the forefront of recent scientific literature on cancer. However, there is no consensus on how to define and spatially delineate the TME. We propose that the time is ripe to go beyond an all-encompassing list of the components of the TME, and to construct a multilayered view of cancer.

[The identity of normal and cancer stem cells].

What is a stem cell? Is stemness an intrinsic or extrinsic property? What role does the microenvironment play in the stemness identity? We distinguish four identities for normal and cancerous stem cells and explore their consequences for therapeutic strategy choice in the oncology setting. Acquisition of genetic and epigenetic alterations during cell transformation and disease progression questions the stability of the stemness property's identity in cancers.

Defining "Development".

Is it possible, and in the first place is it even desirable, to define what "development" means and to determine the scope of the field called "developmental biology"? Though these questions appeared crucial for the founders of "developmental biology" in the 1950s, there seems to be no consensus today about the need to address them. Here, in a combined biological, philosophical, and historical approach, we ask whether it is possible and useful to define biological development, and, if such a definition is indeed possible and useful, which definition(s) can be considered as the most satisfactory.

Reprogramming and Stemness.

Reprogramming technologies show that cellular identity can be reprogrammed, challenging the classical conception of cell differentiation as an irreversible process. If non-stem cells can be reprogrammed into stem cells, then what is it to be a stem cell, and what kind of property is stemness? This article addresses this question both philosophically and biologically, states the different possibilities, and illustrates their potential consequences for science with the example of anti-cancer therapies.

The guardians of inherited oncogenic vulnerabilities.

Similar to seemingly maladaptive genes in general, the persistence of inherited cancer-causing mutant alleles in populations remains a challenging question for evolutionary biologists. In addition to traditional explanations such as senescence or antagonistic pleiotropy, here we put forward a new hypothesis to explain the retention of oncogenic mutations. We propose that although natural defenses evolve to prevent neoplasm formation and progression thus increasing organismal fitness, they also conceal the effects of cancer-causing mutant alleles on fitness and concomitantly protect inherited ones from purging by purifying selection.

Concise Review: Induced Pluripotent Stem Cells as New Model Systems in Oncology.

The demonstration that pluripotent stem cells could be generated by somatic cell reprogramming led to wonder if these so-called induced pluripotent stem (iPS) cells would extend our investigation capabilities in the cancer research field. The first iPS cells derived from cancer cells have now revealed the benefits and potential pitfalls of this new model. iPS cells appear to be an innovative approach to decipher the steps of cell transformation as well as to screen the activity and toxicity of anticancer drugs.