Biology subjects

Font, A.

Publications and source records attributed to Font, A..

5 recordsLinked to original sources

bioRxiv2026

RNA and protein are not interchangeable in single-cell spatial multi-omics

Spatial transcriptomics is increasingly used to infer cellular phenotypes, molecular interactions, and functional tissue organization from RNA, although most of these biological processes are ultimately mediated by proteins. Here, we directly tested the interchangeability of spatial RNA and protein measurements using paired Xenium profiling of 21 matched targets across ~1.8 million cells from primary lung adenocarcinoma and metastatic castration-resistant prostate cancer. After accounting for marker- and dataset-specific protein background, we quantified concordance at multiple levels, including single-cell detection, expression magnitude, cell-type distribution, patient-level abundance, and spatial organization. Agreement at single-cell level was strongly marker-dependent. Canonical lineage markers generally showed concordant RNA and protein patterns, whereas several molecules, including in our study PD-1, PD-L1, and LAG-3, showed little concordance across modalities. Importantly, spatial organization remained substantially more discordant between modalities than overall abundance, indicating that spatial biomarkers are not directly transferable across modalities. Together, our results show that spatial RNA and protein measurements provide largely overlapping information for lineage markers and overall abundance, but can diverse for specific molecules and for higher-order spatial features, where the two layers provide complementary rather than equivalent readouts. These findings provide practical guidance on when spatial transcriptomic readouts can be interpreted as proxies for protein and when orthogonal protein validation is advisable.

cancer biology↗

bioRxiv2020

Four novel Picornaviruses viruses detected in Magellanic Penguins (Spheniscus magellanicus) in Chile

Members of the Picornaviridae comprise a significant burden on the poultry industry, causing diseases such as gastroenteritis and hepatitis. However, with the advent of metagenomics, a number of picornaviruses have now been revealed in apparently healthy wild birds. In this study, we identified four novel viruses belonging to the family Picornaviridae in healthy Magellanic Penguins (Spheniscus magellanicus), a near threatened species found along the coastlines of temperate South America. We collected 107 faecal samples from 72 individual penguins. Twelve samples were initially sequenced by high throughout sequencing with metagenomics approach. All samples were subsequently screened by PCR for these new viruses, and approximately 20% of the penguins were infected with at least one of these viruses, and seven individuals were co-infected with two or more. The viruses were distantly related to members of the genera Hepatoviruses, Tremoviruses and unassigned viruses from Antarctic Penguins and Red-Crowned Cranes. Further, they had more than 60% amino acid divergence from other picornaviruses, and therefore likely constitute novel genera. That these four novel viruses were abundant among the sampled penguins, suggests Magellanic Penguins may be a reservoir for several picornaviruses belonging to different genera. Our results demonstrate the vast undersampling of wild birds for viruses, and we expect the discovery of numerous avian viruses that are related to Hepatoviruses and Tremoviruses in the future. ImportanceRecent work has demonstrated that Antarctic penguins of the genus Pygoscelis are hosts for an array of viral species. However, beyond these Antarctic penguin species, very little is known about the viral diversity or ecology in this highly charismatic avian order. Through metagenomics we identified four novel viruses belonging to the Picornaviridae family in faecal samples from Magellanic Penguins. These highly divergent viruses, each possibly representing novel genera, are related to members of the Hepatovirus, Tremovirus genera, and unassigned picornaviruses described from Antarctic Penguin and Red-crowned Cranes. By PCR these novel viruses were shown to be common in Magellanic Penguins, indicating that penguins may play a key role in their epidemiology and evolution. Overall, we encourage further sampling to reveal virus diversity, ecology, and evolution in these unique avian taxa.

ecology↗

bioRxiv2020

Taxane induces attenuation of the CXCR2/BCL-2 axis and sensitize prostate cancer to platinum-based treatments

BackgroundTaxanes are the most active chemotherapy agents in metastatic castration resistant prostate cancer (mCRPC) patients, yet resistance almost invariably occurs representing an important clinical challenge. Taxane-platinum combinations have shown clinical benefit in a subset of patients but the mechanistic basis and biomarkers remain elusive. ObjectiveTo identify mechanisms and response biomarkers for the antitumor efficacy of taxane-platinum combinations in mCRPC. Design, setting, and participantsTranscriptomic data from a publicly available mCRPC dataset of taxane-exposed and naive patients was analysed to identify response biomarkers and emerging vulnerabilities. Functional and preclinical validation was performed in taxane resistant mCRPC cell lines and genetically engineered mouse models (GEMM). InterventionmCRPC cells were treated with docetaxel, cisplatin, carboplatin and the CXCR2 inhibitor, SB265610. Gain and loss of function in culture of CXCR2 was achieved by overexpression or siRNA-silencing. Preclinical assays in GEMM mice tested the anti-tumor efficacy of taxane-platinum combinations. Outcome measurements and statistical analysisProliferation, apoptosis and colony assays measured drug activity in vitro. Preclinical endpoints in mice included growth, survival and histopathology. Changes in CXCR2, BCL-2 and chemokines were analysed by RT-qPCR and Western Blot. Human expression data was analyzed using GSEA, hierarchical clustering and correlation studies. GraphPad Prism software, R-studio, were used for statistical and data analyses. Results and limitationsTranscriptomic data from taxane-exposed human mCRPC tumors correlates with a marked negative enrichment of apoptosis and inflammatory response pathways accompanied by a marked downregulation of CXCR2 and BCL-2. Mechanistically, we show that docetaxel treatment inhibits CXCR2 and that BCL-2 downregulation occurs as a downstream effect. Further, we demonstrated that taxane resistance is directly associated to CXCR2 expression and that targeting of CXCR2 sensitizes prostate cancer (PC) cells to cisplatin. Finally, taxane-platinum combinations in vivo are highly synergistic and previous exposure to taxanes sensitizes mCRPC tumors to second line cisplatin treatment. ConclusionsTogether our data identifies an acquired vulnerability in taxane treated mCRPC patients with potential predictive activity for platinum-based treatments. Patient summaryA subset of patients with aggressive and therapy resistant PC benefits from taxane-platinum combination chemotherapy however, we lack biomarkers and mechanistic basis about how that synergistic effect occurs. Here, using patient data and preclinical models, we found that taxanes reduce cancer cell scape mechanisms to chemotherapy-induced cell death, hence turning these cells more vulnerable to additional platinum treatment.

cancer biology↗

bioRxiv2019

Immunohistochemistry-based taxonomical classification of bladder cancer predicts response to neoadjuvant chemotherapy

Platinum-based neoadjuvant chemotherapy (NAC) increases the survival of patients with organ-confined urothelial bladder cancer (UBC). Because not all patients benefit from treatment, NAC has not been widely applied in the clinical setting. There is strong evidence, based on retrospective studies, that patients with Basal/Squamous (BASQ)-like tumours present with more advanced disease and have worse prognosis; global transcriptomics can identify tumour subtypes associated with response to NAC. We aimed to investigate whether tumour immunohistochemical (IHC) subtyping predicts NAC response. Patients with muscle-invasive UBC having received platinum-based NAC were identified in two hospitals in Spain. Tissue microarrays were constructed; RNA and DNA were extracted from full sections. Nanostring analysis and immunohistochemistry to identify BASQ-like tumours and mutational analysis of UBC oncogenes. We used hierarchical clustering to classify 126 tumours and adjusted logistic regression to assess association with treatment response. Outcomes were progression-free survival and disease-specific survival; univariable and multivariate Cox regression models were applied. We found very high concordance between mRNA and protein for the 4 markers analyzed. We identified three main subgroups: BASQ-like (FOXA1/GATA3 low; KRT5/6/14 high), Luminal-like (FOXA1/GATA3 high; KRT5/6/14 low), and mixed-cluster (FOXA1/GATA3 high; KRT5/6 high; KRT14 low). Patients with BASQ-like tumours were more likely to achieve a pathological response to NAC, displaying a disease-specific survival similar to that of the remaining patients. In conclusion, patients with BASQ-like tumours - identified through simple and robust immunohistochemistry - have a higher likelihood of undergoing a pathological complete response to NAC. Prospective validation in independent series is required.\n\nNovelty and impactNeoadjuvant chemotherapy is an important component of the management of patietns with muscle-invasive bladder cancer but improved stratification is necessary. This retrospective study shows that patients with BASQ-like tumors can be identified using immunohistochemistry on paraffin-embedded tissue and are 4-fold more likely to achieve a pathological complete response to platinum-based NAC. The disease-specific survival of patients with BASQ-like tumours treated with NAC was not different from that of other tumour subtypes.

pathology↗

bioRxiv2018

Warm Temperatures, Cool Sponges: The Effect of Increased Temperatures on the Antarctic Sponge Isodictya sp.

Although the cellular and molecular responses to exposure to relatively high temperatures (acute thermal stress or heat shock) have been studied previously, only sparse empirical evidence of how it affects cold-water species is available. As climate change becomes more pronounced in areas such as the Western Antarctic Peninsula, it has become crucial to understand the capacity of these species to respond to thermal stress. Here we use the Antarctic sponge Isodictya sp. to investigate how sessile organisms (particularly Porifera) can adjust to acute short-term heat stress, by exposing this species to 3 and 5 {degrees}C for 4 hours, corresponding to predicted temperatures under high-end 2080 IPCC-SRES scenarios. Assembling a de novo reference transcriptome (90,188 contigs, >93.7% metazoan BUSCO genes) we have begun to discern the molecular componentry employed by Isodictya to adjust to environmental insult. Our initial analyses suggest that TGF-{beta}, ubiquitin and hedgehog cascades are involved, alongside other genes. However, the degree and type of response changed little from 3 to 5 {degrees}C, suggesting that even moderate rises in temperature could cause stress at the limits of this organisms capacity. Given the importance of sponges to Antarctic ecosystems, our findings are vital for discerning the consequences of increases in Antarctic ocean temperature on these and other species.

genomics↗