Biology subjects

Wagner, G.

Publications and source records attributed to Wagner, G..

At least 37 records · Page 2Linked to original sources

bioRxiv2022

Is short sleep bad for the brain? Brain structure and cognitive function in short sleepers

Many sleep less than recommended without experiencing daytime tiredness. According to prevailing views, short sleep increases risk of lower brain health and cognitive function. Chronic mild sleep deprivation could cause undetected sleep debt, negatively affecting cognitive function and brain health. However, it is possible that some have less sleep need and are more resistant to negative effects of sleep loss. We investigated this question using a combined cross-sectional and longitudinal sample of 47,029 participants (age 20-89 years) with measures of self-reported sleep, including 51,295 MRIs of the brain and cognitive tests. 701 participants who reported to sleep < 6 hours did not experience daytime tiredness or sleep problems. These short sleepers showed significantly larger regional brain volumes than both short sleepers with daytime tiredness and sleep problems (n = 1619) and participants sleeping the recommended 7-8 hours (n = 3754). However, both groups of short sleepers showed slightly lower general cognitive function, 0.16 and 0.19 standard deviations, respectively. Analyses using acelerometer-estimated sleep duration confirmed the findings, and the associations remained after controlling for body mass index, depression symptoms, income and education. The results suggest that some people can cope with less sleep without obvious negative consequences for brain morphometry, in line with a view on sleep need as individualized. Tiredness and sleep problems seem to be more relevant for brain structural differences than sleep duration per se. However, the slightly lower performance on tests of general cognitive function warrants closer examination by experimental designs in natural settings. Significance statementShort habitual sleep is prevalent, with unknown consequences for brain health and cognitive performance. Here we show that daytime tiredness and sleep problems are more important variables for regional brain volumes than sleep duration. However, participants sleeping < 6 hours had slightly lower scores on tests of general cognitive function. This indicates that sleep need is individual, and that sleep duration per se may be a less relevant variable for brain health than daytime tiredness and sleep problems. The association between habitual short sleep and lower scores on tests of general cogntitive function must be further scrutinized in natural settings.

neuroscience↗

bioRxiv2022

A SNP affects Wnt4 expression in endometrial stroma, with antagonistic implications for pregnancy, endometriosis and reproductive cancers

The common human single nucleotide polymorphism rs3820282 is associated with multiple phenotypes ranging from gestational length to likelihood of endometriosis and ovarian cancer and can thus serve as a paradigm for a highly pleiotropic genetic variant. Pleiotropy makes it challenging to assign specific causal roles to particular genetic variants. Deleterious mutations in multifunctional genes may cause either the co-occurrence of multiple disorders in the same individuals (i.e., syndromes), or be repeatedly associated with a variety of disorders in a population. Moreover, the adverse effects can occur in combination with advantages in other traits, maintaining high frequencies of deleterious alleles in the population. To reveal the causal role of this specific SNP, we investigated the molecular mechanisms affected by rs3820282 in mice. We have shown previously that rs3820282 introduces a high affinity estrogen receptor 1 binding site at the Wnt4 locus. Having introduced this nucleotide substitution into the homologous site of the mouse genome by CRISPR/Cas 9 we show that this change causes a specific upregulation of Wnt4 transcription in the endometrial stromal cells during the preovulatory estrogen peak in late proestrus. Transcriptomic analysis of the whole uterus reveals broad systemic effects on uterine gene expression, including downregulation of proliferation and induction of many progesterone-regulated pro-implantation genes. The effect on proliferation is limited to the luminal epithelium, whereas other effects involve the uterine stromal compartment. We suggest that in the uterus, these changes could contribute to increased permissiveness to embryo invasion. Yet in other estrogen-responsive tissues, the same changes potentially lead to decreased resistance to invasion by cancer cells and endometriotic foci. A single molecular effect of rs3820282 on Wnt4 expression may thus underlie the various associated phenotypic effects.

genetics↗

bioRxiv2022

Cytocapsular cancer evolution analyses of 311 kinds of cancers

Cancer is a leading cause of human lethality. Cytocapsular tube, a newly discovered cancer cell specific organelle in vivo, plays pleiotropic biological functions and its generation distinguishes incomplete from complete cancer cells. It is essential for complete malignant tumor growth, cancer metastasis, conventional cancer drug pan-resistance, and cancer relapse. However, mechanisms of cytocapsular cancer evolution are still elusive. Here, we investigated cytocapsular cancer evolution in 311 kinds/subtype of cancers, including 265 types/subtypes of solid cancers and 46 types/subtypes of liquid/hematological cancers. We analyzed 9,856 pieces of annotated clinical tissue samples from 9,682 cancer patients in the asymptotic early stage, Stages I-IV, and before, during and after cancer treatments. We discovered that cytocapsular cancer evolution in solid cancers includes: transformation, formation of incomplete cancer cells, transition to complete cancer cells surrounded by cytocapsulae (CC), merging of complete cancer cells by devolution, formation of cytocapsular tubes (CCTs) and complete malignant tumors in superlarge CC. This is followed by generation of CCT networks, cancer metastasis, CCT network-tumor system (CNTS), CCT degradation and decomposition, and spatiotemporal moving CNTS. In addition, cytocapsular cancer evolution related to liquid (hematological) cancers including bone marrow, thymus, lymph nodes, and spleen, mirrors the process in solid cancers, except that cancer cells in the blood only form CCs but not CCTs. In summary, our study established a cytocapsular cancer evolution atlas, which may pave an avenue for the research on therapy of both solid and liquid cancers.

cancer biology↗

bioRxiv2022

Molecular evolution of IRG1 shapes itaconate production in metazoans and alleviates the 'double-edged dilemma' of innate immune defense

Itaconate is an innate immune metabolite specifically produced in activated immune cells via the decarboxylation of cis-aconitate, an intermediate of the TCA cycle. By inhibiting succinate-related metabolism, itaconate exerts antimicrobial properties at the expense of potentially disrupting the hosts own central energy metabolism, a double-edged dilemma of immunometabolism. To explore the evolutionary logic of itaconate biosynthesis, we investigated the evolutionary trajectory of IRG1, which encodes for cis-aconitate decarboxylase (CAD), the enzyme responsible for itaconate production. Phylogenetic analysis reveals a putative independent acquisition of metazoan and fungal IRG1 from prokaryotic sources. In metazoans, IRG1 underwent gene duplication and subsequently lost the mitochondrial targeting sequence (MTS), relocating CAD outside the mitochondrial matrix and therefore preventing direct inhibition of energy metabolism. In basal metazoans that contain IRG1, oysters and amphioxus, primitive IRG1 expression is also induced by innate immune stimuli, suggesting an already specialized role of itaconate for innate immune defense in early bilaterians. Our integrated in silico and experimental analysis highlight the molecular adaptations in IRG1, including subcellular relocation, that optimize itaconate production for innate immunity in resolving a fundamental trade-off in immunometabolism.

evolutionary biology↗

bioRxiv2022

Proteotype Co-evolution and Diversity in Mammals

Evolutionary profiling has been largely limited to the nucleotide level. Using consistent proteomic methods, we quantified proteomic and phosphoproteomic layers in fibroblasts from 11 common mammalian species, with transcriptomic variability as reference. The co-variation analysis indicates that transcript and protein expression robustness across mammals remarkably follows functional role, with extracellular matrix-associated expressions being most variable, demonstrating strong transcriptome-proteome co-evolution. Interestingly, the variability control of gene expression is universal at both inter-individual and inter-species scales, but of different extent. RNA metabolism processes particularly show the higher inter-species versus inter-individual variations. Our results further uncover that while ubiquitin-proteasome system is extremely conserved in mammals, the lysosome-mediated protein degradation exhibits a remarkable variation between mammalian lineages. Additionally, the phosphosite profiles reveals phosphorylation co-evolution network independent of protein abundance.

systems biology↗

bioRxiv2022

Normalizing need not be the norm: count-based math for analyzing single-cell data

Counting transcripts of mRNA is a key method of observation in modern biology. With advances in counting transcripts in single cells (single-cell RNA sequencing or scRNA-seq), these data are routinely used to identify cells by their transcriptional profile, and to identify genes with differential cellular expression. Because the total number of transcripts counted per cell can vary for technical reasons, the first step of standard scRNA-seq workflows is to normalize by sequencing depth, transforming counts into proportional abundances. The primary objective of this step is to reshape the data such that cells with similar biological proportions of transcripts end up with similar transformed measurements. But there is growing concern that normalization and other transformations result in unintended distortions that hinder both analyses and the interpretation of results. This has led to an intense focus on optimizing methods for normalization and transformation of scRNA-seq data. Here we take an alternative approach, by avoiding normalization altogether. We abandon the use of distances to compare cells, and instead use a restricted algebra, motivated by measurement theory and abstract algebra, that preserves the count nature of the data. We demonstrate that this restricted algebra is sufficient to draw meaningful and practical comparisons of gene expression through the use of the dot product and other elementary operations. This approach sidesteps many of the problems with common transformations, and has the added benefit of being simpler and more intuitive. We implement our approach in the package countland, available in python and R. By explicitly considering counts in terms of their measurement process, we avoid and overcome many challenges in modern RNA-seq and open new avenues for the analysis of these data.

cell biology↗

bioRxiv2022

Sleep duration and brain structure - phenotypic associations and genotypic covariance

The question of how much sleep is best for the brain attracts scientific and public interest, and there is concern that insuficient sleep leads to poorer brain health. However, it is unknown how much sleep is sufficient and how much is too much. We analyzed 51,295 brain magnetic resonnance images from 47,039 participants, and calculated the self-reported sleep duration associated with the largest regional volumes and smallest ventricles relative to intracranial volume (ICV) and thickest cortex. 6.8 hours of sleep was associated with the most favorable brain outcome overall. Critical values, defined by 95% confidence intervals, were 5.7 and 7.9 hours. There was regional variation, with for instance the hippocampus showing largest volume at 6.3 hours. Moderately long sleep (> 8 hours) was more strongly associated with smaller relative volumes, thinner cortex and larger ventricles than even very short sleep (< 5 hours), but effect sizes were modest. People with larger ICV reported longer sleep (7.5 hours), so not correcting for ICV yielded longer durations associated with maximal volume. Controlling for socioeconomic status, body mass index and depression symptoms did not alter the associations. Genetic analyses showed that genes related to longer sleep in short sleepers were related to shorter sleep in long sleepers. This may indicate a genetically controlled homeostatic regulation of sleep duration. Mendelian randomization analyses did not suggest sleep duration to have a causal impact on brain structure in the analyzed datasets. The findings challenge the notion that habitual short sleep is negatively related to brain structure. Significance statementAccording to consensus recommendations, adults should sleep between 7 and 9 hours to optimize their health. We found that sleeping less than the recommended amount was associated with greater regional brain volumes relative to intracranial volume, and very short sleep was only weakly related to smaller volumes. Genetic analyses did not show causal effects of sleep duration on brain structure. Taken together, the results suggest that habitual short sleep is not an important contributor to lower brain volumes in adults on a group level, and that large individual dfferences in sleep need likely exist.

neuroscience↗

bioRxiv2022

Cytocapsulae and cytocapsular tubes are golden targets for precise, effective and efficient cancer diagnosis and therapy in 307 kinds of liquid and solid cancers

Cancer is a leading cause of human lethality worldwide. A cancer cell is not only the cytoplasm and nucleus enclosed in the cell membrane. A malignant tumor is not only a mass of cancer cells. Cancer in a patient is not only isolated tumors distributed in tissues and organs. The comprehensive understanding of the complete structural compartments and their biological functions of cancer cells, malignant tumors and tumor systems in patients in vivo is an indispensable prerequisite for effective drug development and efficient clinical cancer pharmacotherapies. However, there remains an open question for a long time: what are the complete structural compartments of cancer cells, malignant tumors and tumor systems in the patient body? Here, we comprehensively and systematically investigated the complete structural compartments of cancer cells, malignant tumors and cytocapsular tube (CCT) network-tumor system (CNTS) of 307 types/subtypes of cancers in 33 kinds of tissues and organs by biochemistry and molecular biology assays with 9,811 clinical cancer tissue specimens from 9,637 cancer patients and >110,000 immunohistochemistry (IHC) fluorescence staining images. We discovered the complete structural compartments of cancer cells, malignant tumors and CNTSs in 307 kinds of cancers, elucidated mechanisms of cytocapsular growth and CCT elongation, and identified the comprehensive procedures of cancer evolution in patients. This study paves avenues for curing all kinds of cancers.

cancer biology↗

bioRxiv2022

Cytocapsular tube network-tumor system is an integrated physical target for the highly effective and efficient pharmacotherapy of solid cancers

Cancer is a leading cause of human lethality and cancer drug pan-resistant tumor metastasis (cdp-rtm) is a major source of cancer death. The integrated cytocapsular tube (CCT) networktumor system (CNTS) is essential for cancer evolution procedures including cancer cell proliferation, migration and dissemination in CCT networks, new tumor growth in CCT terminals, conventional cancer drug pan-resistance, and tumor relapse. The preclinical screening experimentations with CCTs and networks are necessary prerequisites for the discovery and development of cancer drug candidates for efficient clinical trials, and effective and precise clinical cancer pharmacotherapy. However, it is unknown whether the popularly employed conventional mouse experimentations for preclinical therapeutic development generate CCTs and networks. Here, we comprehensively investigated the cancer cell line derived xenografts (CDX) of 8 kinds of cancer cell lines, and patient cancer cells derived-xenografts (PDX) with 16 kinds of clinical primary and metastatic malignant tumor cells in multiple cancer stages by immunohistochemistry staining assays with CCT marker protein antibodies of anti-CM-01 antibodies. We found that there are no CCTs or CCT networks in all these examined 16 CDX and 22 PDX transplanted tumors. Our data evidenced that the conventional transplantation tumors for preclinical therapeutic development do not engender CCTs or CNTS, which is consistent with and provides an explanation of the poor clinical outcomes of the marketed cancer drugs. This study demonstrated that CCT network-tumor system (CNTS) is an integrated physical target for pharmacotherapy, and that preclinical experimentations engendering CNTS (such as CCT xenograft, CCTX) should be employed for the discovery and development of highly effective and efficient cancer drugs aimed for cure of solid cancers.

cancer biology↗

bioRxiv2022

Cytocapsular tubes and networks function as physical superdefence freeway systems conducting conventional cancer drug pan-resistant tumor metastasis

Cancer drug pan-resistant tumor metastasis (cdp-rtm) is a major source of cancer lethality. Cytocapsular tubes (CCTs) and their networks are physical membrane-enclosed freeway systems for cancer cell dissemination across tissues and organs in vivo. Whether cytocapsular tube superlarge biomembranes function as superdenfence and conduct cdp-rtm is unknown. It is also unknown whether conventional cancer drug development methods, including cancer cell line derived xenograft (CDX) and patient cancer cell derived xenograft (PDX), generate cytocapsular tubes (CCTs). It is also unclear whether xenografts can be created that contain CCTs for efficient cancer drug development. Here, we investigated CCT functions related to cancer drug resistance, CCTs in CDX and PDX and CCT xenograft (CCTX). Using clinical cancer tissues, we discovered that CCTs potently shielded against multiple chemotherapy treatments with diverse conventional cancer drugs. Next, our quantitative analyses show that CCT biomembrane drug barriers significantly increase cancer drug resistance by 6.6-folds to14-folds. We found that conventional CDX and PDX animal models do not generate CCTs in these xenografts. By mimicking in vivo cancer cell environments for cancer patient cancer cell culturing, we have successfully isolated CH-5high/CH-6high subpopulations of patient breast cancer cells and pancreas cancer cells that are propertied with cytocapsular tube generation capacities and engender large quantities of CCTs in mouse xenografts. Biochemical and immunohistochemistry analyses demonstrated that CCTs in these xenografts are similar to those in clinical cancer tissues. In summary, our research has identified that CCTs and networks function as physical superdefence freeway systems conducting conventional cancer drug pan-resistant tumor metastasis, and developed a CCTX platform for highly efficient cancer drug development, which pave avenues for more efficient development of effective and precise cancer drugs for tumor cure at both personal and broad-spectrum levels.

cancer biology↗

bioRxiv2021

Cohort Profile: Genetic data in the German Socio-Economic Panel Innovation Sample (Gene-SOEP)

The German Socio-Economic Panel (SOEP) serves a global research community by providing representative annual longitudinal data of private households in Germany. The sample provides a detailed life course perspective based on a rich collection of information about living conditions, socio-economic status, family relationships, personality, values, preferences, and health. We collected genetic data from 2,598 individuals in the SOEP Innovation Sample, yielding the first genotyped sample that is representative of the entire German population (Gene-SOEP). The Gene-SOEP sample is a longitudinal study that includes 107 full-sibling pairs, 501 parent-offspring pairs, and 152 parent-offspring trios that are overlapping with the parent-offspring pairs. We constructed a repository of 66 polygenic indices in the Gene-SOEP sample based on results from well-powered genome-wide association studies. The Gene-SOEP data provides a valuable resource to study individual differences, inequalities, life-course development, health, and interactions between genetic predispositions and environment.

genetics↗

bioRxiv2021

Cancer Metastases of 202 Kinds of Cancers via Cytocapsular Tubes

BACKGROUNDCancer metastasis is the primary source of solid cancer lethality, but the underlying mechanisms have essentially remained elusive. Recently, we found that cytocapsular tubes, a newly discovered organelle of mammalian cells, conduct cell translocation, suggesting an efficient pathway for cancer cell metastases. METHODSWe performed immunohistochemistry staining and fluorescence microscope imaging analyses of 6 kinds of normal organs (n=14 patients), 38 subtypes of benign tumors (n= 126 patients), and 8,061 clinical solid cancer tissue samples (covering 202 types and subtypes of cancers, and including cancers, paracancer tissues and metastatic cancers) taken from 7,125 cancer patients. These solid cancers cover 30 types of organs. We characterized cytocapsular tubes (CTs), cell migration in CTs, and CT quantity, density, network, superstructures and lifecycle in clinical samples of normal tissues, benign tumors, cancers, paracancer tissues, and metastatic cancers. RESULTSThere is no cytocapsular tubes (CTs) in normal organ tissues. Among the 126 benign tumor samples (covering 38 subtypes) from 126 patients, 86.6% do not have CTs and the other 13.4% show benign-to-malignancy transitions with CTs. Of the 8,061 solid cancer tissue and paracancer samples from 7,125 patients, 100% of cancers (including carcinomas in situ), 100% of paracancer tissues, and 100% of metastatic cancer tissues/organs, harbor large quantities (from thousands to hundreds of thousands) of CTs with many cancer cells in migration inside. CONCLUSIONCytocapsular tubes and networks provide membrane-enclosed physical freeway systems for clinical cancer cell metastasis to neighboring and far-distance tissues and organs.

cancer biology↗

bioRxiv2021

A nascent polypeptide sequence modulates DnaA translation elongation in response to nutrient availability

The ability to regulate DNA replication initiation in response to changing nutrient conditions is an important feature of most cell types. In bacteria, DNA replication is triggered by the initiator protein DnaA, which has long been suggested to respond to nutritional changes, nevertheless the underlying mechanisms remain poorly understood. Here, we report a novel mechanism that adjusts DnaA synthesis in response to nutrient availability in Caulobacter crescentus. By performing a detailed biochemical and genetic analysis of the dnaA mRNA we identified a sequence downstream of the dnaA start codon that inhibits DnaA translation elongation upon carbon exhaustion. Our data show that the corresponding peptide sequence, but not the mRNA secondary structure or the codon choice, are critical for this response, suggesting that specific amino acids in the growing DnaA nascent chain tune translational efficiency. Our study provides new insights into DnaA regulation and highlights the importance of translation elongation as a regulatory target. We propose that nascent chain sequences, like the one described, might constitute a general strategy for modulating the synthesis rate of specific proteins under changing conditions.

microbiology↗

bioRxiv2020

Decidual cell differentiation is evolutionarily derived from fibroblast activation

What the molecular mechanisms underlying the evolutionary origin of novel cell types are is a major unresolved question in biology. The uterine decidual cell is a novel cell type of placental mammals which serves as the interface between maternal and fetal tissues during pregnancy. In this paper, we investigate two models for the nature of the differentiation of decidual cells: first, that it represents a mesenchymal-epithelial transition (MET), and second, that it evolved from wound-induced fibroblast activation (WIFA). Immunocytochemistry and RNA-seq analysis of decidualizing human endometrial fibroblasts cast doubt on the MET hypothesis and instead demonstrate a similarity between decidualization and fibroblast activation, including a central role for TGFB1. Through single-cell RNA-seq, we found a transient myofibroblast-like cell population in the in vitro differentiation trajectory of human decidual cells and found that these cells represent a pre-decidual state approaching the inferred transcriptomic transition to decidual cells. We propose an evolutionary developmental model wherein the decidual cell is a novel cell type not equivalent to the myofibroblast, but the process of decidual differentiation itself evolved as an endometrial-specific modification to fibroblast activation in response to the wound caused by embryo implantation.

evolutionary biology↗

bioRxiv2020

Hidden limbs in the limbless skink Brachymeles lukbani: developmental observations

Reduced limbs and limblessness have evolved independently in many lizard clades. Skinks exhibit a wide range of limb-reduced morphologies, but only some species have been used to study the embryology of limb reduction (i.g., digit reduction in Chalcides and limb reduction in Scelotes). The genus Brachymeles, a Southeast Asian clade of skinks, includes species with a range of limb morphologies, from pentadactyl to functionally as well as structurally limbless species. Adults of the small, snake-like species Brachymeles lukbani show no sign of external limbs in the adult except for small depressions where they might be expected to occur. Embryos of B. lukbani in early stages of development, on the other hand, show a truncated but well-developed limb with a stylopod and a zeugopod, but no signs of an autopod. As development proceeds, the limbs small size persists even while the embryo elongates. These observations are made based on external morphology. We used florescent whole-mount immunofluorescence to visualize the morphology of skeletal elements and muscles within the embryonic limb of B. lukabni. Early stages have a humerus and separated ulna and radius cartilages; associated with these structures are dorsal and ventral muscle masses as those found in the embryos of other limbed species. While the limb remains small, the pectoral girdle grows in proportion to the rest of the body, with well-developed skeletal elements and their associated muscles. In later stages of development, the small limb is still present under the skin but there are few indications of its presence, save for the morphology of the scale covering it. The adult morphology consists of a well-developed pectoral girdle, small humerus, extremely reduced ulna and radius, and well-developed limb musculature connected to the pectoral girdle. These muscles form in association with a developing limb during embryonic stages, a hint that "limbless" lizards that possesses these muscles may have or have had at least transient developing limbs, as we find in B. lukbani. Overall, the observed pattern of ontogenetic reduction, leading to an externally limbless adult in which a limb rudiment is hidden and covered under the trunk skin, is a situation called cryptomelia. The results of this work add to our growing understanding of clade-specific patterns of limb reduction and the convergent evolution of limbless phenotypes through different developmental processes.

evolutionary biology↗

bioRxiv2020

Deep computational analysis of human cancer and non-cancer tissues details dysregulation of eIF4F components and their interactions in human cancers

Eukaryotic translation initiation complex (eIF4F) plays roles so diverse in human cancers as to complicate development of an overarching understanding of eIF4Fs functional and regulatory impacts across tumor types. Our analysis of large public data sets yielded several useful findings. EIF4G1 frequently gains gene copies and is overexpressed to achieve characteristic stoichiometries with EIF4E and EIF4A1 in cancers. Varied expressions among EIF4F components distinguish malignant from healthy tissues, regardless of tissue or cancer types. EIF4G1 expression in particular correlates with poor prognosis. Tumors dysregulate biological "house-keeping" pathways typically regulated by cap-dependent initiation in healthy tissues, yet strengthen regulation of cancer-specific pathways in cap-independent contexts. In lung adenocarcinoma, altered interactions among eIF4F subunits are mechanistically linked to eIF4G1 phosphorylation. Tumors may select between cap-dependent and -independent mechanisms, through eIF4G1s adaptable interactions with eIF4F subunits. Collectively, these results are an important advance towards a general model of translation initiation in cancer.

cancer biology↗

bioRxiv2020

Cis-Regulatory Differences Explaining Evolved Levels of Endometrial Invasibility in Eutherian Mammals

Eutherian (placental) mammals exhibit great differences in the degree of placental invasion into the maternal endometrium, with humans being on the most invasive end. Previously, we have shown that these differences in invasiveness is largely controlled by the stromal fibroblasts of the maternal endometrium, with secondary effect on stroma of other tissues resulting in correlated differences in cancer malignancy. Here, we present a statistical investigation of the second dogma linking the phenotypic and transcriptional differences to the genomic changes across species, revealing the regulatory genomic sequence differences underlying these inter-species differences. We show that gain or loss of specific transcription factor binding site sequences are connected to the inter-species gene-expression differences in a statistically significant manner, with a particularly larger effect on stromal genes related to invasibility. We also uncover transcriptional factors differentially regulating genes related to pro- and anti- invasible property of stroma. This work extends the understanding of inter-species differences in stromal invasion to the causal genomic sequence differences paving new avenues to target stromal characteristics to regulate placental, or cancer invasion.

evolutionary biology↗

bioRxiv2020

Human vulnerability to cancer malignancy is enhanced by evolution of higher mesenchymal CD44 expression compared to other mammals

CD44 is a membrane-bound extracellular matrix (ECM) receptor interacting, among others, with hyaluronic acid (HA) and osteopontin (OPN). Cancer progression and metastasis are greatly influenced by the cancer micro-environment, consisting of ECM, immune cells and cancer-associated fibroblasts (CAF). Recruitment of fibroblasts (FB) into the role as CAFs is caused by paracrine signals from the tumor, including TGFb1, PDGF and OPN. The effect of OPN on the transformation of FB into CAF is mediated by CD44. CD44 expression in human skin and endometrial stromal fibroblasts (SF and ESF, respectively) also enhances invasibility of stroma by trophoblast as well as cancer cells. Here we study the evolution of CD44 expression in therian mammals in both SF as well as ESF and demonstrate that the human lineage has experienced a concerted evolutionary enhancement of CD44 expression in SF and ESF, correlating with an increase in human vulnerability to cancer malignancy. In both human and cattle (Bos taurus), the dominant isoforms are CD44s and CD44v10 with 9 and 10 exons, respectively. CD44s is an isoform strongly associated with malignancy. In humans, an additional isoform is expressed: HsaCD44-205 with 8 exons not found in cattle. We show that the concerted increase of CD44 expression in SF and ESF is largely due to cis-regulatory effects in the proximal promoter of CD44. We identify a primate specific acquisition of CEBPB binding sites in the CD44 promoter. Recruitment of CEBPB into CD44 regulation explains almost 50% of the lineage-specific increased CD44 expression in primate skin fibroblasts but is not necessary for high CD44 expression in ESF. All these results suggest that selective modulation of CD44 expression in skin fibroblasts could attenuate the cancer-promoting effect of CAF recruitment in the skin with minimal side effects on other cell types. Additional experimental data is needed to explore this possibility.

evolutionary biology↗