Biology subjects

Elias, R.

Publications and source records attributed to Elias, R..

6 recordsLinked to original sources

bioRxiv2026

Epithelial to mesenchymal transition and M2 macrophages drive aggressiveness in murine and human sarcomatoid urothelial carcinoma.

Patients with majority variant subtype histology including sarcomatoid urothelial carcinoma (SUC) have poor outcomes and limited treatment options, and there are few preclinical resources to investigate rare histologic subtypes. We developed three novel variant subtype histology bladder cancer (BC) cell lines by finding that basal BC tumor cells derived from mice treated with N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) were initially not competent to grow in immune competent mice, but then acquired tumorigenicity following passaging (recycling) in mice lacking mature B and T cells. Three genitourinary oncology pathologists identified BBN966 as SUC, BBN964 as a hybrid between SUC and squamous, and BBN975 as squamous, and each had unique growth characteristics. Using a publicly available dataset and our spatial transcriptomics analysis of a cohort of human tumors with mixed SUC and UC as comparators, we found that consistent with human SUC, BBN966 lack expression of basal and luminal genes. Consistent with human SUC and spatial transcriptomics analysis of canine SUC, BBN966 had the highest epithelial to mesenchymal transition (EMT) upregulation, and all three recycled tumor cells had increased EMT pathway expression in recycled tumor cells. Moreover, increased expression of genes upregulated in all three recycled tumor cells associated with worse overall survival in patients with muscle invasive UC. Similar to human SUC, BBN966 tumors had higher proportion of M2 macrophage gene expression. Finally, we found in the largest cohort of PD-L1 IHC to date that 20 of 38 (52.6%) human SUC had CPS > 50, which was driven mostly by tumor proportion score. Consistent with this, we found anti-PD1 immune checkpoint inhibitor (ICI) significantly inhibited BBN966 tumor growth, while the hybrid BBN964 tumors had mixed response to ICI. Thus, the murine BBN966 tumors exhibited similarities to human SUC, and can be used to examine novel therapies for translation into future SUC clinical studies.

cancer biology↗

bioRxiv2026

TFE3 fusions drive expression of CD44 and SPP1 in Translocation Renal Cell Carcinoma

Xp11.2 translocation RCC [Xp11.2 tRCC]) is an underdiagnosed and aggressive subtype of RCC with few specific or targeted therapies. The transmembrane glycoprotein CD44 is an emerging target in many advanced malignancies, and with its ligand OPN (SPP1), is a crucial driver of cancer progression, stemness, metastasis, and immune suppression. Here we show that common TFE3-fusions [ including SFPQ-TFE3, PRCC-TFE3, ASPSCR1-TFE3, and NONO-TFE3] are associated with upregulated expression of CD44 and SPP1, as observed in multiple human and murine bulk transcriptomic studies and a murine tRCC snRNA-Seq dataset. CD44 and/or SPP1 protein expression were also upregulated in murine models of transgenic tRCC kidneys and urine specimens, patient-derived cell lines and human tRCC cases, by immunoblotting and/or IHC. Transient deletion of CD44 was associated with profound and specific suppression of tRCC cell line growth, with decreased mTOR signaling. These data suggest that CD44 and/or SPP1 may potentially drive tumorigenesis in tRCC.

cancer biology↗

bioRxiv2026

Clear cell renal cell carcinoma consensus transcriptomic programs reveal converging trajectories towards aggressive disease

Clear cell renal cell carcinoma (ccRCC) is characterized by a branching genomic trajectory in which early biallelic VHL inactivation splits into PBRM1- and BAP1-mutant lineages. However, driver mutations alone do not account for the molecular and phenotypic heterogeneity. To dissect this heterogeneity, we developed a non-negative matrix factorization (NMF)-based gene expression analytical framework for identifying recurrent transcriptional programs across factorization dimensionalities and across datasets. We applied it to three curated datasets (IMmotion151, n = 823; JAVELIN Renal 101, n = 726; TCGA, n = 614) to define 17 consensus transcriptomic programs (CTPs). Mapping CTPs onto single-cell RNAseq (scRNAseq) of human ccRCC tumors and patient-derived tumorgraft models linked these programs to their cellular sources, distinguishing RCC-intrinsic, tumor-cell-extrinsic, and mixed programs. RCC-intrinsic CTPs associated with canonical drivers, including VHL (R1), PBRM1 (R2), BAP1 (R4), PTEN/TSC1 (R3), TFE3/TFEB fusions (R5), NF2 (R6), and CDKN2A/TP53 (MP-Prolif). Additional CTPs captured tumor microenvironment (TME) composition (TME-Tcell, TME-Myelo, TME-Endo, TME-Stroma) and biological processes active across multiple cellular compartments, including proliferation, Y-chromosome-linked expression in male tumors, ciliary biology, and translation. Trajectory inference methods revealed PBRM1-like and BAP1-like branches that converged on a shared aggressive late transcriptomic stage (TS) associated with higher nuclear grade, additional driver alterations, myeloid/stromal infiltration, and poor clinical outcomes. Spatial transcriptomics (and multiregional sequencing) of paired conventional ccRCC and sarcomatoid regions linked TS advancement with morphological progression and clonal evolution. After adjusting for stage, grade, and BAP1/PBRM1 status, TS remained independently prognostic. Furthermore, our data suggest that immune checkpoint inhibitor combinations are particularly beneficial for MP-Prolif and not R1 utilizing specimens. In summary, we present an atlas of recurring transcriptomic programs in RCC and an ontological framework bridging genotype, tumor-cell-intrinsic gene expression, and microenvironment remodeling, with implications for risk stratification and treatment selection in ccRCC.

Cancer Biology↗

bioRxiv2025

tRNA Modification Landscapes in Streptococci: Shared Losses and Clade-Specific Adaptations

tRNA modifications are central to bacterial translational control. Here, we integrated genetics, mass spectrometry, epitranscriptomics, and comparative genomics to map the tRNA modification genes of the Gram-positive pathogens Streptococcus mutans and Streptococcus pneumoniae. Both species show a marked loss of modifications dependent on Fe-S enzymes, consistent with a broader trend of Fe-S enzyme reduction in Streptococcus central metabolism. In addition, the D, m1A, m7G, t6A, and i6A modifications were mapped in S. pneumoniae tRNAs, and we confirmed that a unique DusB1 enzyme is responsible for the insertion of all the detectable D modifications. We uncovered differences in queuosine (Q) metabolism: while S. mutans synthesizes Q de novo, S. pneumoniae instead salvages preQ and accumulates the epoxy-Q precursor, a strategy shared with multiple other Streptococci as revealed by analysis of Q pathways in 1,599 sequenced streptococcal genomes. Comparative essentiality profiling of modification genes revealed notable differences, including the essentiality of the NLJ-threonylcarbamoyladenosine (tLJA) synthesis enzyme TsaE in S. pneumoniae but not in S. mutans, which was confirmed by genetic studies. We found that suppressor mutations in asnS encoding asparaginyl-tRNA synthetase (AsnRS) restored viability to {Delta}tsaE mutants, albeit with reduced growth. Our finding highlights the functional importance of modifications in the recognition of tRNAs by aminoacyl-tRNA synthetases.

microbiology↗

bioRxiv2025

Strain, procedures, and tools for reproducible genetic transformation and genome editing of Spirodela polyrhiza (L.) Schleid.

Duckweeds (Lemnaceae) have excellent potential for fundamental and applied research due to ease of cultivation, small size, and continuous fast clonal growth. However, their usage as model organisms and platforms for biotechnological applications is often limited by the lack of universal genetic manipulation methods necessary for transgene expression, gene editing, and other methods to modify gene expression. To identify suitable strains for genetic manipulation of the giant duckweed, Spirodela polyrhiza, we screened several genotypes for callus induction and regeneration and established genetic transformation. We have identified SP162 to be amenable to Agrobacterium-mediated transformation via tissue culture. The procedure is robust and reproducible across laboratories, allowing stable expression of different reporter genes and selectable markers, enabling CRISPR/Cas9-mediated genome editing. In addition, due to a weak small RNA-based silencing response, S. polyrhiza sustains prolonged periods of transgene activity in transient expression assays. To promote duckweed research and encourage the adoption of S. polyrhiza, we have made SP162 (ID#: 5676) and its genome publicly available and provide here detailed procedures for its cultivation and transformation. Furthermore, we created a web server to explore its genome, retrieve gene sequences, and implemented orthologous gene search and a gRNA design function for diverse CRISPR/Cas-based applications (https://agxu.uni-mainz.de/SP162/).

plant biology↗

bioRxiv2024

Atypical epigenetic and small RNA control of transposons in clonally reproducing Spirodela polyrhiza.

A handful of model plants have provided insight into silencing of transposable elements (TEs) through RNA-directed DNA methylation (RdDM). Guided by 24-nt long small-interfering RNAs (siRNAs), this epigenetic regulation installs DNA methylation and histone modifications like H3K9me2, which can be subsequently maintained independently of siRNAs. However, the genome of the clonally propagating duckweed Spirodela polyrhiza (Lemnaceae) has low levels of DNA methylation, very low expression of RdDM components, and near absence of 24-nt siRNAs. Moreover, some genes encoding RdDM factors, DNA methylation maintenance, and RNA silencing mechanisms are missing from the genome. Here, we investigated the distribution of TEs and their epigenetic marks in the Spirodela genome. While abundant degenerated TEs have largely lost DNA methylation and H3K9me2 is low, they remain marked by the heterochromatin associated H3K9me1 and H3K27me1 modifications. By contrast, we found high levels of DNA methylation and H3K9me2 in the relatively few intact TEs which are source of 24-nt siRNAs like RdDM-controlled TEs in other angiosperms. The data suggest that, potentially as adaptation to vegetative propagation, RdDM extent, silencing components, and targets are different from other angiosperms, preferentially focused on potentially intact TEs. It also provides evidence for heterochromatin maintenance independently of DNA methylation in flowering plants. These discoveries highlight the diversity of silencing mechanisms that exist in plants and the importance of using disparate model species to discover these mechanisms.

plant biology↗