Biology subjects

Serrano-Serrano, M. L.

Publications and source records attributed to Serrano-Serrano, M. L..

5 recordsLinked to original sources

bioRxiv2023

Tumor-agnostic transcriptome-based classifier identifies spatial infiltration patterns of CD8+ T cells in the tumor microenvironment and predicts clinical outcome in early- and late-phase clinical trials

BackgroundThe immune status of a patients tumor microenvironment (TME) may guide therapeutic interventions with cancer immunotherapy and help identify potential resistance mechanisms. Currently, patients immune status is mostly classified based on CD8+ tumor-infiltrating lymphocytes. An unmet need exists for comparable and reliable precision immunophenotyping tools that would facilitate clinical treatment-relevant decision-making and the understanding of how to overcome resistance mechanisms. MethodsWe systematically analyzed the CD8 immunophenotype of 2023 patients from 14 phase I-III clinical trials using immunohistochemistry (IHC) and additionally profiled gene expression by RNA-sequencing (RNA-seq). CD8 immunophenotypes were classified by pathologists into CD8-desert, CD8-excluded or CD8-inflamed tumors using CD8 IHC staining in epithelial and stromal areas of the tumor. Using regularized logistic regression, we developed an RNA-seq-based classifier as a surrogate to the IHC-based spatial classification of CD8+ tumor-infiltrating lymphocytes in the TME. ResultsThe CD8 immunophenotype and associated gene expression patterns varied across indications as well as across primary and metastatic lesions. Melanoma and kidney cancers were among the strongest inflamed indications, while CD8-desert phenotypes were most abundant in liver metastases across all tumor types. A good correspondence between the transcriptome and the IHC-based evaluation enabled us to develop a 92-gene classifier that accurately predicted the IHC-based CD8 immunophenotype in primary and metastatic samples (area under the curve (AUC) inflamed = 0.846; excluded = 0.712; desert = 0.855). The newly developed classifier was prognostic in The Cancer Genome Atlas (TCGA) data and predictive in lung cancer: patients with predicted CD8-inflamed tumors showed prolonged overall survival (OS) versus patients with CD8-desert tumors (hazard ratio [HR] 0.88; 95% confidence interval [CI]: 0.80-0.97) across TCGA, and longer OS upon immune checkpoint inhibitor administration (phase III OAK study) in non-small-cell lung cancer (HR 0.75; 95% CI: 0.58-0.97). ConclusionsWe provide a new precision immunophenotyping tool based on gene expression that reflects the spatial infiltration patterns of CD8+ lymphocytes in tumors. The classifier enables multiplex analyses and is easy to apply for retrospective, reverse translation approaches as well as for prospective patient enrichment to optimize the response to cancer immunotherapy. HIGHLIGHTSO_ST_ABSWhat is already known on this topicC_ST_ABST-cell infiltration, most commonly classified based on CD8+ T cell immunohistochemistry (IHC) staining, and various tumor microenvironment (TME)-specific resistance mechanisms, can impact response rates to cancer immunotherapy. What this study addsOur data provide new insights into the impact of tumor excision location and indication on the immune composition of the TME. We developed a transcriptome-based classifier that could accurately predict different spatial CD8+ T-cell infiltration patterns in the TME. We demonstrate the prognostic and predictive value of the classifier across independent patient cohorts (phase I to phase III trials). How this study might affect research, practice or policyOur new RNA-based tool provides a surrogate read-out for spatial IHC-based CD8 infiltration patterns, is easy to use and broadly applicable for both retrospective and prospective patient enrichment to enhance the effectiveness of cancer immunotherapy.

cancer biology↗

bioRxiv2020

Performance of a phylogenetic independent contrast method and an improved pairwise comparison under different scenarios of trait evolution after speciation and duplication

O_LIDespite the importance of gene function to evolutionary biology, the applicability of comparative methods to gene function is poorly known. A specific case which has crystalized methodological questions is the "ortholog conjecture", the hypothesis that function evolves faster after duplication (i.e., in paralogs), and conversely is conserved between orthologs. Since the mode of functional evolution after duplication is not well known, we investigate under which reasonable evolutionary scenarios phylogenetic independent contrasts or pairwise comparisons can recover a putative signal of different functional evolution between orthologs and paralogs. C_LIO_LIWe investigate three different simulation models, which represent reasonable but simplified hypotheses about the evolution of a gene function trait. These are time dependent trait acceleration, correlated changes in rates of both sequence and trait evolution, and asymmetric trait jump. For each model we tested phylogenetic independent contrasts and an improved pairwise comparison method which accounts for interactions between events and node age. C_LIO_LIBoth approaches lose power to detect the trend of functional evolution when the functional trait accelerates for a long time following duplication for trees with many duplications, with better power of phylogenetic contrasts under intermediate scenarios. Concomitant increase in evolutionary rates of sequence and of trait after duplication can lead to both an incorrect rejection of the null under null simulations of trait evolution, and a false rejection of the ortholog conjecture under ortholog conjecture simulations, by phylogenetic independent contrasts. Improved pairwise comparisons are robust to this bias. Both approaches perform equally well under rapid shifts in traits. C_LIO_LIConsidering our ignorance of gene function evolution, and the potential for bias under simple models, we recommend methodological pluralism in studying gene family evolution. Functional phylogenomics is complex and results supported by only one method should be treated with caution. C_LI

evolutionary biology↗

bioRxiv2019

Convergent changes in gene expression associated with repeated transitions between hummingbird and bee pollinated flowers

The repeated evolution of convergent floral shapes and colors in angiosperms has been largely interpreted as the response to pollinator-mediated selection to maximize attraction and efficiency of specific groups of pollinators. The genetic mechanisms contributing to certain flower traits have been studied in detail for model system species, but the extent by which flowers are free to vary and how predictable are the genetic changes underlying flower adaptation to pollinator shifts still remain largely unknown.\n\nHere, we aimed at detecting the genetic basis of the repeated evolution of flower phenotypes associated with pollinator shifts. We assembled and compared de novo transcriptomes of three phylogenetic independent pairs of Gesneriaceae species, each with contrasting flower phenotype adapted to either bee or hummingbird pollination. We assembled and analyzed a total of 14,059 genes and we showed that changes in expression in 550 of them was associated with the pollination syndromes. Among those, we observed genes with function linked to floral color, scent, shape and symmetry, as well as nectar composition. These genes represent candidates genes involved in the build-up of the convergent floral phenotypes.\n\nThis study provides the first insights into the molecular mechanisms underlying the repeated evolution of pollination syndromes. Although the presence of additional lineage-specific responses cannot be excluded, these results suggest that the convergent evolution of genes expression is involved in the convergent build-up of the pollination syndromes. Future studies aiming to directly manipulate certain genes will integrate our knowledge on the key genes for floral transitions and the pace of floral evolution.\n\nData availabilityRaw Illumina reads will be available in the Sequence Read Archive (SRA) in NCBI database. The assembled transcriptomes and their annotation will by available in DRYAD repository. Details and accession ID will be provided at the time of the manuscript acceptance.

evolutionary biology↗

bioRxiv2018

Genomic footprints of repeated evolution of CAM photosynthesis in tillandsioid bromeliads

The adaptive radiation of Bromeliaceae (pineapple family) is one of the most diverse among Neotropical flowering plants. Diversification in this group was facilitated by several key innovations including the transition from C3 to CAM photosynthesis. We used a phylogenomic approach complemented by differential gene expression (RNA-seq) and targeted metabolite profiling to address the patterns and mechanisms of C3/CAM evolution in the extremely species-rich bromeliad genus Tillandsia and related taxa. Evolutionary analyses at a range of different levels (selection on protein-coding genes, gene duplication and loss, regulatory evolution) revealed three common themes driving the evolution of CAM: response to heat and drought, alterations to basic carbohydrate metabolism, and regulation of organic acid storage. At the level of genes and their products, CAM/C3 shifts were accompanied by gene expansion of a circadian regulator, re-programming of ABA-related gene expression, and adaptive sequence evolution of an enolase, effectively linking carbohydrate metabolism to ABA-mediated stress response. These changes include several pleiotropic regulators, which facilitated the evolution of correlated adaptive traits during a textbook adaptive radiation.

genomics↗

bioRxiv2017

Evolutionary history of New World monkeys revealed by molecular and fossil data

New World monkeys (parvorder Platyrrhini) are one of the most diverse groups of primates, occupying today a wide range of ecosystems in the American tropics and exhibiting large variations in ecology, morphology, and behavior. Although the relationships among the almost 200 living species are relatively well understood, we lack robust estimates of the timing of origin, the ancestral morphology, and the evolution of the distribution of the clade. Here we integrate paleontological and molecular evidence to investigate the evolutionary dynamics of extinct and extant platyrrhines. We develop an analytical framework to infer ancestral states, the evolution of body mass, and changes in latitudinal ranges through time. Our results show that extant platyrrhines originated some 5-10 million years earlier than previously assumed, likely dating back to the Middle Eocene ([~] 43 million years ago, Ma). The estimated ancestral platyrrhine was strikingly small - weighing [~] 0.4 kg, as compared to the largest modern species over 10 kg - matching the size of their presumed Eocene North African ancestors. Small-sized callitrichines (marmosets and tamarins) retained a small body mass throughout their evolutionary history, thus challenging the hypothesis of phyletic dwarfism as an explanation to their adaptive traits. In contrast, a rapid change in body mass range took place as the three families diverged between the Late Oligocene and the Early Miocene. That period also marks a peak in diversity of fossil platyrrhines and is associated with their widest latitudinal range, expanding as far to the South as Patagonia. This geographic expansion is temporally coincident with a significant increase in platyrrhine population size inferred from genomic data, and with warm and humid climatic conditions linked to the Miocene Climatic Optimum and the lower elevation of the Andes. These results unveil the early evolution of an iconic group of monkeys and showcase the advantages of integrating fossil and molecular data for estimating evolutionary rates and trends.

evolutionary biology↗