War and peace in the tumor microenvironment : tumor-associated cells as facilitators or adversaries during tumor development

The tumor microenvironment, including immune cells, fibroblasts and vasculature, profoundly affects tumor development by initially opposing, but eventually facilitating tumor growth, vascularization and spread. Though corrupted by the growing tumor, such cells remain non-transformed and thus, with proper cues, are possible to direct toward their physiological anti-tumor function. Understanding the mechanisms by which the tumor microenvironment is shaped, before and during tumor growth, has been the principal aim of this thesis. In paper I, we demonstrate that the composition of tumor-associated macrophages (TAMs) can be modulated by selective proliferation of TAM subsets. We identify SEMA3A as a factor potentiating such selective proliferation of anti-tumor TAMs. In paper II we extend the study of SEMA3A’s effect on tumor immunity by showing that it can functionally alter the phenotype of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC). As a consequence of its effects on TAMs and PMN-MDSCs, the tumor microenvironment is infiltrated by activated cytotoxic lymphocytes which act to obstruct tumor growth. In paper III we show that regulation of mRNA translation shapes the phenotype of TAMs as they become increasingly pro-tumor during tumor growth. We further show that transcripts translationally activated during tumor growth in TAMs were regulated similarly upon M2- polarization of macrophages in vitro. Selective inhibition of the MNK2/phospho-eIF4E pathway, which impinges on mRNA translation, functionally altered in vitro M2-polarized macrophages toward a pro-inflammatory phenotype. This suggests that modulation of mRNA translation is a potential target in TAM-based anti-tumor therapies. We further emphasize the importance of mRNA translation in regulating gene expression in the microenvironment in paper IV, where we show changes in its efficiency to drive cancer- associated gene expression alterations in the stroma of patients with chronic obstructive pulmonary disease (COPD). Depending on the lung function, two distinct gene expression programs were discovered. These were enriched for proteins previously identified in fibroblast secretomes that promoted cancer initiation in animal models, highlighting the involvement of non-transformed cells in neoplastic transformation. In paper V, we show that class switch junctions in B cells from patients with BRCA1 mutations display decreased use of non-homologous end joining pathway in favor of the alternative end-joining pathway. This implicates a role for BRCA1 in maintaining genome stability and tumor suppression outside of its recognized role in mediating homologous recombination during cell division

Climatic Changes and Orogeneses in the Late Miocene of Eurasia: The Main Triggers of an Expansion at a Continental Scale?

Migrations from the Qinghai-Tibetan Plateau (QTP) to other temperate regions represent one of the main biogeographical patterns for the Northern Hemisphere. However, the ages and routes of these migrations are largely not known. We aimed to reconstruct a well-resolved and dated phylogeny of Hippophae L. (Elaeagnaceae) and test hypothesis of a westward migration of this plant out of the QTP across Eurasian mountains in the Miocene. We produced two data matrices of five chloroplast DNA (cpDNA) and five nuclear DNA markers for all distinct taxa of Hippophae. These matrices were used to reconstruct phylogenetic relationships in the genus. In dating analyses, we first estimated the stem node age of Elaeagnaceae using five fossil records evenly distributed across a tree of Rosales. We used this estimate and two fossil records to calibrate the cpDNA and nDNA phylogenies of Hippophae. The same phylogenies were used to reconstruct ancestral areas within the genus. The monophyly of Hippophae, all five species, and most of subspecies was strongly supported by both plastid and nuclear data sets. Diversification of Hippophae likely started in central Himalayas/southern Tibet in the early Miocene and all extant distinct species had probably originated by the middle Miocene. Diversification of Hippophae rhamnoides likely started in the late Miocene east of the QTP from where this species rapidly expanded to central and western Eurasia. Our findings highlight the impact of different stages in uplift of the QTP and Eurasian mountains and climatic changes in the Neogene on diversification and range shifts in the highland flora on the continent. The results provide support to the idea of an immigration route for some European highland plants from their ancestral areas on the QTP across central and western mountain ranges of Eurasia in the late Miocene

Andean orogeny and the diversification of lowland neotropical rain forest trees:A case study in Sapotaceae

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordUnderstanding how species diversify and evolve in species-rich areas like the lowland rain forest in the Neotropics is critical for conservation in times of unprecedented threats. To determine how the Andean uplift, the formation of the Panama land bridge, and Pleistocene climatic fluctuations affected dispersal and diversification in the Sapotaceae subfamily Chrysophylloideae, we collected 146 Chrysophylloideae accessions in previously under-explored areas, generating one of the most geographically complete data sets for neotropical Sapotaceae. Sapotaceae is a good model to test diversification hypotheses in lowland neotropical rain forests as it predominantly occurs <1000 m altitude, and it is an abundant and species-rich group in this biome. We generated a time calibrated phylogeny of 123 Sapotaceae species based upon the nuclear ribosomal internal transcribed spacer region that suggests migration between lineages to the east and the west Andean Cordilleras occurred before and after periods of major uplift, indicating that the Andes did not represent a significant barrier to dispersal for Sapotaceae, although it may have promoted vicariance in some cases. Dispersal between South and Central America occurred mainly prior to the formation of the Panama land bridge, suggesting that this event did not affect migration patterns in Chrysophylloideae. We inferred diversification rates and detected three shifts in the phylogeny, but they are not congruent with tectonic movements during the middle Miocene and climatic changes during the Pleistocene. Finally, some species with restricted distributions appear to be phylogenetically nested within species with broader ranges, suggesting ancestor descendent relationships and insights into patterns of speciation in rain forest trees.Natural Environment Research Council (NERC)National Science Foundation (NSF)Geological Society of Americ

Significance of Photosynthetic Characters in the Evolution of Asian Gnetum (Gnetales)

Gnetum is a genus in the Gnetales that has a unique but ambiguous placement within seed plant phylogeny. Previous studies have shown that Gnetum has lower values of photosynthetic characters than those of other seed plants, but few Gnetum species have been studied, and those that have been studied are restricted to narrow taxonomic and geographic ranges. In addition, the mechanism underlying the lower values of photosynthetic characters in Gnetum remains poorly understood. Here, we investigated the photosynthetic characters of a Chinese lianoid species, i.e., Gnetum parvifolium, and co-occurring woody angiosperms growing in the wild, as well as seedlings of five Chinese Gnetum species cultivated in a greenhouse. The five Gnetum species had considerably lower values for photosynthesis parameters (net photosynthetic rate, transpiration rate, intercellular CO2 concentration, and stomatal conductance) than those of other seed plant representatives. Interrelated analyses revealed that the low photosynthetic capacity may be an intrinsic property of Gnetum, and may be associated with its evolutionary history. Comparison of the chloroplast genomes (cpDNAs) of Gnetum with those of other seed plant representatives revealed that 17 coding genes are absent from the cpDNAs of all species of Gnetum. This lack of multiple functional genes from the cpDNAs probably leads to the low photosynthetic rates of Gnetum. Our results provide a new perspective on the evolutionary history of the Gnetales, and on the ecophysiological and genomic attributes of tropical biomes in general. These results could also be useful for the breeding and cultivation of Gnetum

Diversity dynamics in New Caledonia: towards the end of the museum model?

<p>Abstract</p> <p>Background</p> <p>The high diversity of New Caledonia has traditionally been seen as a result of its Gondwanan origin, old age and long isolation under stable climatic conditions (the museum model). Under this scenario, we would expect species diversification to follow a constant rate model. Alternatively, if New Caledonia was completely submerged after its breakup from Gondwana, as geological evidence indicates, we would expect species diversification to show a characteristic slowdown over time according to a diversity-dependent model where species accumulation decreases as space is filled.</p> <p>Results</p> <p>We reanalyze available datasets for New Caledonia and reconstruct the phylogenies using standardized methodologies; we use two ultrametrization alternatives; and we take into account phylogenetic uncertainty as well as incomplete taxon sampling when conducting diversification rate constancy tests. Our results indicate that for 8 of the 9 available phylogenies, there is significant evidence for a diversification slowdown. For the youngest group under investigation, the apparent lack of evidence of a significant slowdown could be because we are still observing the early phase of a logistic growth (i.e. the clade may be too young to exhibit a change in diversification rates).</p> <p>Conclusions</p> <p>Our results are consistent with a diversity-dependent model of diversification in New Caledonia. In opposition to the museum model, our results provide additional evidence that original New Caledonian biodiversity was wiped out during the episode of submersion, providing an open and empty space facilitating evolutionary radiations.</p