Biology subjects

Roma, L.

Publications and source records attributed to Roma, L..

4 recordsLinked to original sources

bioRxiv2026

MTAP deficiency is a novel biomarker in neuroendocrine neoplasms of the lung

IntroductionMTAP emerges as potential predictive biomarker for MTA-cooperative PRMT5-inhibitors. Although MTAP attracts increasing attention in non-small cell lung cancer, its role in pulmonary neuroendocrine neoplasms (NENs) remains largely unexplored. MethodsHere, we assessed the prevalence of MTAP deficiency in 209 pulmonary NENs using immunohistochemistry (IHC). Additionally, we performed fluorescence in situ hybridization (FISH), whole exome sequencing (WES), deep proteomic profiling, transcriptomic, and methylation analyses of selected MTAP deficient and proficient carcinoids to further elucidate the underlying mechanisms of MTAP expression pattern. ResultsMTAP deficiency by IHC was detected in all neuroendocrine precursor lesions (n=17), 92% of typical carcinoids (n=51), 86% of atypical carcinoids (n=21), and 10% of large cell neuroendocrine carcinomas (LCNEC) (n=30). In contrast, all small cell lung cancers (SCLC) were MTAP proficient (n=90). In MTAP deficient carcinoids, FISH and WES did not detect homozygous 9p21 deletions, and methylation analysis showed no evidence of MTAP promoter hypermethylation. Comparing MTAP deficient and MTAP proficient carcinoids, proteomic data showed a clear separation between the two groups. Further, there was an inverse correlation between the expression of MTAP and OTP (orthopedia homeobox protein), which is known as a strong prognostic marker in pulmonary carcinoids. DiscussionMTAP deficiency is a novel hallmark of neuroendocrine precursors and most pulmonary carcinoids, clearly distinguishing the latter from SCLC and most LCNEC. It is neither caused by 9p21 deletion, nor by MTAP promoter hypermethylation. MTAP deficiency is a group-defining feature of carcinoids that might pave the way for new therapeutic approaches.

pathology↗

bioRxiv2026

A modular patient-derived organoid-xenograft platform reveals molecular and clinical trajectories of prostate cancer progression

Patient-derived organoids (PDOs) are becoming increasingly important in prostate cancer (PCa) translational research. However, direct proof-of-concept studies demonstrating their ability to model disease evolution, identify relevant biomarkers, and accurately predict treatment response in PCa patients, remain scarce. Here, we report the establishment of serially transplantable xenografts series derived from two advanced PCa PDO lines, which can be further re-cultured as organoids. Newly-generated model series maintain key phenotypic, genomic, and functional characteristics of the original patient tumors, and emulate relevant molecular subtypes of advanced PCa. Single-cell RNA sequencing (scRNA-seq) analysis uncovers transcriptomic differences between xenograft and organoid models, as well as signaling pathways which are largely preserved and can be targeted ex vivo. Functional drug profiles correlate with molecular and clinical attributes, as exemplified by response to androgen receptor (AR) pathway inhibitors and glucocorticoid-mediated AR signaling activation. Longitudinal scRNA-seq analysis of perturbed PDOs identifies a rare PROX1+/ALDH1A1+ cell population, which pre-exist in the treatment-naive setting and is significantly enriched upon androgen deprivation. Notably, this cell population is similarly enriched in post-treatment samples of the original patient and is associated with aggressive AR-negative PCa molecular subtypes, suggesting a potential link with PCa progression. Our study provides proof-of-concept evidence that organoids can mirror PCa patient-specific drug sensitivity profiles and molecular paths of disease progression, uncovering pertinent biomarkers. Ultimately, our organoid-xenograft model series provide a modular and scalable platform that can readily be used for mechanistic and translational studies.

cancer biology↗

bioRxiv2023

Patient-derived organoids identify tailored therapeutic options and determinants of plasticity in sarcomatoid urothelial bladder cancer

Sarcomatoid Urothelial Bladder Cancer (SARC) is a rare and aggressive histological subtype of bladder cancer for which therapeutic options are limited and experimental models are lacking. Here, we report the establishment of the first long-term 3D organoid-like model derived from a SARC patient (SarBC-01). SarBC-01 emulates aggressive morphological and phenotypical features of SARC and harbor somatic mutations in genes frequently altered in sarcomatoid tumors such as TP53, RB1, and KRAS. High-throughput drug screening, using a library comprising 1567 compounds in SarBC-01 and organoids derived from a patient with conventional urothelial carcinoma (UroCa), identified drug candidates active against SARC cells exclusively, or UroCa cells exclusively, or both. Among those, standard-of-care chemotherapeutic drugs inhibited both SARC and UroCa cells, while a subset of targeted drugs was specifically effective in SARC cells, such as agents targeting the Glucocorticoid Receptor (GR) pathway. In two independent patient cohorts, GR was found to be significantly more expressed, at mRNA and protein level, in SARC as compared to UroCa tumor samples. Further, glucocorticoid treatment impaired the mesenchymal morphology, abrogated the invasive ability of SARC cells, and led to transcriptomic changes associated with reversion of epithelial-to-mesenchymal transition, at single-cell level. Altogether, our study highlights the power of organoids for precision oncology and for providing key insights into factors driving rare tumor entities.

cancer biology↗

bioRxiv2021

Minor intron splicing efficiency increases with the development of lethal prostate cancer

Here we explored the role of minor spliceosome (MiS) function and minor intron-containing gene (MIG) expression in prostate cancer (PCa). We show MIGs are enriched as direct interactors of cancer-causing genes and their expression discriminates PCa progression. Increased expression of MiS U6atac snRNA, including others, and 6x more efficient minor intron splicing was observed in castration-resistant PCa (CRPC) versus primary PCa. Notably, androgen receptor signalling influenced MiS activity. Inhibition of MiS through siU6atac in PCa caused minor intron mis-splicing and aberrant expression of MIG transcripts and encoded proteins, which enriched for MAPK activity, DNA repair and cell cycle. Single cell-RNAseq confirmed cell cycle defects and lineage dependency on the MiS from primary to CRPC and neuroendocrine PCa. siU6atac was [~]50% more efficient in lowering tumor burden of CRPC cells and organoids versus current state-of-the-art combination therapy. In all, MiS is a strong therapeutic target for lethal PCa and potentially other cancers. Graphical AbstractU6atac expression, MiS activity, and minor intron splicing correlate with PCa therapy resistance and PCa progression to CRPC-adeno and transdifferentiation to CRPC-NE. One major MiS regulator during that process is the AR-axis, which is re-activated during CRPC-adeno and blocked in CRPC-NE. Molecularly, an increase in MiS dependent splicing promotes changes of transcriptome and proteome. This results in cell cycle activation, increased MAPK signalling and increased DNA repair. U6atac mediated MiS inhibition renders MiS splicing error-prone through increased intron retention and alternative splicing events, which results in cell cycle block and decreased MAPK signalling and DNA repair. MiS inhibition blocks all stages of PCa. Figure created with BioRender.com. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=154 SRC="FIGDIR/small/471104v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@1c1c296org.highwire.dtl.DTLVardef@1ce1416org.highwire.dtl.DTLVardef@88d842org.highwire.dtl.DTLVardef@2ddf96_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗