Evolutionary Processes in Cancer

Cancer develops through the evolution of somatic cells in multicellular bodies. The familiar dynamics of organismal evolution, including mutations, natural selection, genetic drift, and migration, also occur among the cells of multicellular organisms. In some cases, but not all, these evolutionary processes lead to cancer. This has profound implications for both our understanding of cancer and our treatment of the disease, as well as its prevention. All of our medical interventions impose selective pressures on the heterogeneous populations of billions of cells in tumors, and tend to select for mutant cells that are resistant to the intervention, regardless of whether the intervention is a drug, radiation, the immune system, or anything else that has been tried. We will likely need evolutionary and ecological approaches to cancer to manage its evolution in response to our interventions. The field of the evolutionary biology and ecology of cancer is still young and relatively small. We are in the early stages of translating ideas and tools from evolutionary biology and ecology to study and manage cancers. There is a desperate need for more researchers with expertise in evolutionary biology and ecology to apply their skills and ideas to cancer. Currently, there are far more important questions that need to be addressed than there are people to address them.

Mammalian tumor-like organs. 1. The role of tumor-like normal organs and atypical tumor organs in the evolution of development (carcino-evo-devo)

Background Earlier I hypothesized that hereditary tumors might participate in the evolution of multicellular organisms. I formulated the hypothesis of evolution by tumor neofunctionalization, which suggested that the evolutionary role of hereditary tumors might consist in supplying evolving multicellular organisms with extra cell masses for the expression of evolutionarily novel genes and the origin of new cell types, tissues, and organs. A new theory—the carcino-evo-devo theory—has been developed based on this hypothesis. Main text My lab has confirmed several non-trivial predictions of this theory. Another non-trivial prediction is that evolutionarily new organs if they originated from hereditary tumors or tumor-like structures, should recapitulate some tumor features in their development. This paper reviews the tumor-like features of evolutionarily novel organs. It turns out that evolutionarily new organs such as the eutherian placenta, mammary gland, prostate, the infantile human brain, and hoods of goldfishes indeed have many features of tumors. I suggested calling normal organs, which have many tumor features, the tumor-like organs. Conclusion Tumor-like organs might originate from hereditary atypical tumor organs and represent the part of carcino-evo-devo relationships, i.e., coevolution of normal and neoplastic development. During subsequent evolution, tumor-like organs may lose the features of tumors and the high incidence of cancer and become normal organs without (or with almost no) tumor features.

Jack of all trades, master of each: the diversity of fibroblast growth factor signalling in eye development

A central question in development biology is how a limited set of signalling pathways can instruct unlimited diversity of multicellular organisms. In this review, we use three ocular tissues as models of increasing complexity to present the astounding versatility of fibroblast growth factor (FGF) signalling. In the lacrimal gland, we highlight the specificity of FGF signalling in a one-dimensional model of budding morphogenesis. In the lens, we showcase the dynamics of FGF signalling in altering functional outcomes in a two-dimensional space. In the retina, we present the prolific utilization of FGF signalling from three-dimensional development to homeostasis. These examples not only shed light on the cellular basis for the perfection and complexity of ocular development, but also serve as paradigms for the diversity of FGF signalling.

FlyPhoneDB: An integrated web-based resource for cell-cell communication prediction in Drosophila

Multicellular organisms rely on cell-cell communication to exchange information necessary for developmental processes and metabolic homeostasis. Cell-cell communication pathways can be inferred from transcriptomic datasets based on ligand-receptor (L-R) expression. Recently, data generated from single cell RNA sequencing (scRNA-seq) have enabled L-R interaction predictions at an unprecedented resolution. While computational methods are available to infer cell-cell communication in vertebrates such a tool does not yet exist for Drosophila. Here, we generated a high confidence list of L-R pairs for the major fly signaling pathways and developed FlyPhoneDB, a quantification algorithm that calculates interaction scores to predict L-R interactions between cells. At the FlyPhoneDB user interface, results are presented in a variety of tabular and graphical formats to facilitate biological interpretation. To demonstrate that FlyPhoneDB can effectively identify active ligands and receptors to uncover cell-cell communication events, we applied FlyPhoneDB to Drosophila scRNA-seq data sets from adult midgut, abdomen, and blood, and demonstrate that FlyPhoneDB can readily identify previously characterized cell-cell communication pathways. Altogether, FlyPhoneDB is an easy-to-use framework that can be used to predict cell-cell communication between cell types from scRNA-seq data in Drosophila.

Towards Self-organized Control: Using Neural Cellular Automata to Robustly Control a Cart-pole Agent

Neural cellular automata (Neural CA) are a recent framework used to model biological phenomena emerging from multicellular organisms. In these systems, artificial neural networks are used as update rules for cellular automata. Neural CA are end-to-end differentiable systems where the parameters of the neural network can be learned to achieve a particular task. In this work, we used neural CA to control a cart-pole agent. The observations of the environment are transmitted in input cells while the values of output cells are used as a readout of the system. We trained the model using deep-Q learning where the states of the output cells were used as the Q-value estimates to be optimized. We found that the computing abilities of the cellular automata were maintained over several hundreds of thousands of iterations, producing an emergent stable behavior in the environment it controls for thousands of steps. Moreover, the system demonstrated life-like phenomena such as a developmental phase, regeneration after damage, stability despite a noisy environment, and robustness to unseen disruption such as input deletion.

The Expansion of Life

The story of life tells of relentless expansion from obscure beginnings to smother the earth in organized biochemistry. First came the prokaryotes, Bacteria and Archaea, followed some two billion years later by eukaryotic microbes. The latter pattern of organization underpins the rise of multicellular organisms, and their spectacular proliferation over the past 600 million years. There have been no fundamentally new kinds of organisms since, but the rise of mind culminating in humanity may signal a new phase in life’s history. Life has expanded in both quantity and quality, a gyre of mounting size, complexity, and functional capacity; in some elusive sense evolution is progressive. Multicellularity, the key invention, is not singular but happened multiple times in several eukaryotic lineages. The proliferation of higher organisms was probably enabled by increased energy flow, and dependent on the increase in atmospheric oxygen. It is studded with innovations in structure, physiology, and behavior, whose origin is a recurrent theme in evolutionary biology. Novelty is rooted in mutational events at the gene level, supplemented by the acquisition of genes from the outside by both gene transfer and symbiosis, and possibly by other avenues. Chance events were scrutinized and culled by natural selection. There appears to be no intrinsic progressive drive, but natural selection generally favors the more functional and better organized.

A novel role of PRL in regulating epithelial cell density by inducing apoptosis at confluence

Maintaining proper epithelial cell density is essential for the survival of multicellular organisms. While regulation of cell density through apoptosis is well known, its mechanistic details remain elusive. Here, we report the involvement of membrane-anchored phosphatase of regenerating liver (PRL), originally known for its role in cancer malignancy, in this process. In epithelial MDCK cells, upon confluence, doxycycline-induced expression of PRL upregulated apoptosis, reducing the cell density. This could be circumvented by artificially reducing the cell density via stretching the cell-seeded silicon chamber. Moreover, siRNA-mediated knockdown of endogenous PRL blocked apoptosis, leading to greater cell density. Mechanistically, PRL promoted apoptosis by upregulating the translation of E-cadherin and activating TGF-β pathway. Morpholino-mediated inhibition of PRL expression in zebrafish embryos caused developmental defect with reduced apoptosis and increased epithelial cell density during convergent extension. This study revealed a novel role of PRL in regulating density-dependent apoptosis in vertebrate epithelium.

A biodiversity survey on the planktonic protistan grazers of the Gulf of Naples (Italy)

Plankton communities include both unicellular and multicellular organisms. An important unicellular component is represented by those protists (i.e., unicellular eukaryotes) that are non-strictly autotrophic organisms and consume bacteria and other protists. These organisms are an important link between primary producers and metazoans and are usually known as microzooplankton, protozooplankton, or mixoplankton, as many of them couple phagotrophic and photoautotrophic behaviours. Herein we report on the diversity of these organisms sampled at two sampling sites (coastal and offshore stations), at two depths (0 and 10 m), in the Gulf of Naples during the early autumn of 2020. Despite efforts to list plankton biodiversity of primary producers and metazoan grazers made in this area so far, protistan grazers are still poorly investigated and previous information date back to decades ago. Our survey identified dinoflagellates and oligotrich ciliates as the most abundant groups, while tintinnids were less quantitatively relevant. The taxonomic composition in samples investigated herein remarked that reported by previous studies, with the sole exception of the tintinnid Ascampbeliella armilla, which was never reported before. A coastal-offshore gradient in the taxonomical composition of protistan grazers was also observed, with some species more abundant within coastal waters and other better thriving in offshore ones. Surface and sub-surface communities also differed in terms of species composition, with the deeper communities in the two sites being more similar reciprocally than with communities at the surface. These differences were associated with distinct environmental conditions, such as light availability, as well with the standing feeding environment, arising potential implications in the functioning of the planktonic food web at the local scale.

Flv3A facilitates O2 photoreduction and affects H2 photoproduction independently of Flv1A in diazotrophic Anabaena filaments

The model heterocyst-forming filamentous cyanobacterium, Anabaena sp. PCC 7120 (Anabaena) represents multicellular organisms capable of simultaneously performing oxygenic photosynthesis in vegetative cells and the O2-sensitive N2-fixation inside the heterocysts. The flavodiiron proteins (FDPs) have been shown to participate in photoprotection of photosynthesis by driving excess electrons to O2 (Mehler-like reaction). Here, we addressed the physiological relevance of the vegetative cell-specific Flv1A and Flv3A on the bioenergetic processes occurring in the diazotrophic Anabaena under variable CO2. We demonstrate that both Flv1A and Flv3A are required for proper induction of the Mehler-like reaction upon a sudden change in light intensity, which is likely important for the activation of carbon-concentrating mechanisms (CCM) and CO2 fixation. Nevertheless, Flv3A showed a more important role in photoprotection than Flv1A. Under low CO2 diazotrophic conditions, Flv3A is capable of mediating moderate O2 photoreduction, independently of Flv1A, but in coordination with Flv2 and Flv4. Strikingly, the lack of Flv3A resulted in strong downregulation of the heterocyst-specific uptake hydrogenase, which led to enhanced H2 photoproduction under both oxic and micro-oxic conditions. These results reveal a novel regulatory network between the Mehler-like reaction and the H2 metabolism, which is of great interest for future photobiological production of H2 in Anabaena.

An Evolutionary Perspective on Hox Binding Site Preferences in Two Different Tissues

Transcription factor (TF) networks define the precise development of multicellular organisms. While many studies focused on TFs expressed in specific cell types to elucidate their contribution to cell specification and differentiation, it is less understood how broadly expressed TFs perform their precise functions in the different cellular contexts. To uncover differences that could explain tissue-specific functions of such TFs, we analyzed here genomic chromatin interactions of the broadly expressed Drosophila Hox TF Ultrabithorax (Ubx) in the mesodermal and neuronal tissues using bioinformatics. Our investigations showed that Ubx preferentially interacts with multiple yet tissue-specific chromatin sites in putative regulatory regions of genes in both tissues. Importantly, we found the classical Hox/Ubx DNA binding motif to be enriched only among the neuronal Ubx chromatin interactions, whereas a novel Ubx-like motif with rather low predicted Hox affinities was identified among the regions bound by Ubx in the mesoderm. Finally, our analysis revealed that tissues-specific Ubx chromatin sites are also different with regards to the distribution of active and repressive histone marks. Based on our data, we propose that the tissue-related differences in Ubx binding behavior could be a result of the emergence of the mesoderm as a new germ layer in triploblastic animals, which might have required the Hox TFs to relax their binding specificity.