Mardiyyah/TAPT_data_V2_split · Datasets at Hugging Face

PMCID stringclasses 24 values	Title stringclasses 24 values	Sentences stringlengths 2 40.7k
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	Similarly, no association was detected between SLFN12 mRNA expression and male gender (Kruskal–Wallis test, p = 0.880).
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	Finally, we examined whether PDE3A modulators may have efficacy in treating LPS.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	PDE3A and SLFN12 protein expression were first evaluated in eight LPS cell lines (Figure 4A).
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	PDE3A- and SLFN12-coexpression was detected in two of the eight LPS cell lines, SA4 and GOT3, and in the GIST882 control cell line.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	We then measured, with CellTiterGlo, the effect of three PDE3A modulators (anagrelide, BAY 2666605, and DNMDP) and one PDE3A enzyme inhibitor (cilostazol) on cell viability in these cell lines.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	Cell viabilities decreased with all PDE3A modulators in all three cell lines (two-tailed unpaired t-test, p < 0.001) (Figure 4B).
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	No response was observed with cilostazol, indicating that PDE3A-and SLFN12-positive LPS cell lines are affected via the PDE3A–SLFN12 complex and not by enzyme inhibition.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	Efficacious subtype-specific targeted therapies are currently not available for LPSs.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	In this study, we sought to discover novel genes that are specifically overexpressed in LPS subtypes, via a large-scale transcriptome analysis.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	We identified 381 genes, many of which may have a role in tumorigenesis or cancer biology pathways and, therefore, may serve as therapeutic targets in LPSs.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	As expected, the analysis yielded some known LPS-subtype-specific genes, but also revealed multiple genes that are linked to other cancer types.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	As many of these genes have been described as possibly targetable—for example PAPPA in breast cancer and TROAP in glioma —the discovery of their LPS-subtype-specificity is worth considering for further investigation.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	In addition to identifying individual therapeutic targets, we were interested in examining signaling pathways associated with the overexpressed genes to describe the LPS subtypes and to understand the possible mechanisms of tumorigenesis.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	The emerging hedgehog signaling in the DDLPS-specific pathway analysis is a compelling discovery, as targeting sonic hedgehog signaling and its key factor, GLI1, has been studied in other sarcomas .
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	Moreover, we identified GLI1 as the most upregulated gene in DDLPS, and previous studies have also shown high expression of two GLI homologs, GLI1 and GLI2, in DDLPS .
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	MLPS tumors have frequently been described as having an activated IGF1R/PI3K/Akt signaling pathway that is induced by the FUS-DDIT3 oncoprotein .
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	Interestingly, a highly homologous pathway, the insulin signaling pathway, was observed as the second-most-upregulated pathway in our analysis, after the phospholipase C-mediated cascade.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	Almost all of the upregulated pathways in PLPS were involved in DNA replication and cell proliferation.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	Aberrations in cell-division-associated pathways aligns with morphological features of PLPS, which frequently exhibit a high number of mitoses and multinucleated giant cells .
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	Further studies should be conducted to investigate whether these pathways can be targeted—for example, with cyclin-dependent kinase inhibitors.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	Although PDE3A was only ranked 124th on the MLPS DEG list, it caught our attention because it has been recognized in GISTs and described as potentially targetable with drugs, called PDE3A modulators, that are cytotoxic to PDE3A- and SLFN12-coexpressing cell lines .
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	The high PDE3A expression in GISTs and cardiovascular tissue might explain why it ranked relatively low in our analysis.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	In addition to confirming the association between PDE3A expression and the myxoid subtype, via IHC staining, high and frequent PDE3A expression was specifically seen in the high-grade MLPS samples with a round cell phenotype.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	High PDE3A expression, in protein level, was also associated with male gender, but no other connections with clinical factors were observed.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	Our pathway analysis identified PDE3A as part of the insulin signaling pathway, which shares significant similarities with the IGF1R/PI3K/Akt pathway, driven by the commonly observed FUS-DDIT3 fusion protein in MLPS .
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	However, further research is needed to determine if elevated PDE3A expression is associated with the fusion oncogene-driven pathway alterations.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	The MLPS samples also exhibited higher SLFN12 mRNA expression levels than those of the DDLPS and PLPS samples.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	Interestingly, most of the samples that presented PDE3A and SLFN12 mRNA expression levels that were higher than those of the GIST882 cell line belonged to the myxoid subtype.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	This finding is intriguing and warrants further efficacy studies of PDE3A modulators in LPS in vivo models, as these compounds may lead to an MLPS-specific targeted therapy.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	The study had certain limitations.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	As frozen tissue samples for RNA extraction were not available, we used RNA isolated from FFPE samples, in which RNA is known to be degraded.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	However, in a previous study, we demonstrated that the transcriptomic data derived from FFPE provide profiles that are similar to those of RNA data from fresh-frozen tissue in Merkel cell carcinoma .
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	We were unable to find any PDE3A-positive MLPS cell lines for the study.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	Instead, we used two PDE3A- and SLFN12-positive LPS cell lines, GOT3 classified as a WDLPS, and SA4 with unspecified histology, which showed responses to PDE3A modulators.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	Therefore, an association of frequent and high PDE3A expression and the efficacy of PDE3A modulators in MLPS was not confirmed in vitro.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	However, other studies have shown that PDE3A- and SLFN12-expressing cell lines and xenografts of various cancer types are sensitive to PDE3A modulators, suggesting that the mechanism behind the cytotoxic effect is universal and not cell-type dependent .
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	In conclusion, our findings suggest that LPSs, specifically MLPS tumors that coexpress PDE3A and SLFN12, may be candidates for PDE3A modulator treatment.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	Further in vivo experiments and optimization of PDE3A and SLFN12 diagnostics should be conducted to identify suitable patients for therapy, ultimately enabling efficient patient stratification and precision medicine in the future.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	In summary, we identified LPS-subtype-specific highly expressed genes, which could potentially be targeted with precision medicine.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	These genes are associated with the hedgehog signaling pathway in DDLPS, phospholipase C, and insulin signaling pathways in MLPS and cell proliferation pathways in PLPS.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	Through in vitro experiments, we observed elevated PDE3A expression correlating with high-grade myxoid samples and discovered that two LPS cell lines were responsive to PDE3A modulators.
PMC10669966	PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma	Further research is required to determine whether PDE3A modulators could potentially be used as precision medicine in treating MLPS—specifically, in high-grade tumors.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	The immune–epithelial–stromal interactions underpinning intestinal damage in celiac disease (CD) are incompletely understood.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	To address this, we performed single-cell transcriptomics (RNA sequencing; 86,442 immune, parenchymal and epithelial cells; 35 participants) and spatial transcriptomics (20 participants) on CD intestinal biopsy samples.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Here we show that in CD, epithelial populations shifted toward a progenitor state, with interferon-driven transcriptional responses, and perturbation of secretory and enteroendocrine populations.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Mucosal T cells showed numeric and functional changes in regulatory and follicular helper-like CD4 T cells, intraepithelial lymphocytes, CD8 and γδ T cell subsets, with skewed T cell antigen receptor repertoires.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Mucosal changes remained detectable despite treatment, representing a persistent immune–epithelial ‘scar’.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Spatial transcriptomics defined transcriptional niches beyond those captured in conventional histological scores, including CD-specific lymphoid aggregates containing T cell–B cell interactions.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Receptor–ligand spatial analyses integrated with disease susceptibility gene expression defined networks of altered chemokine and morphogen signaling, and provide potential therapeutic targets for CD prevention and treatment.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Celiac disease (CD) is a common gastrointestinal disorder affecting 1–2% of European and North American populations, in which small intestinal inflammation and damage are driven by aberrant adaptive immune responses to gluten.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	The only treatment is a lifelong gluten-free diet (GFD).
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	There is an unmet therapeutic need for those living with CD, including refractory CD, where ongoing tissue damage occurs despite a GFD.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	A strong genetic component drives CD, dominated by HLA-DQ2 and HLA-DQ8 (ref. ),
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	with association studies identifying over 40 non-HLA genomic loci, implicating over 100 candidate genes and a role for immunoregulatory mechanisms.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Murine models implicate viral infection as a trigger of loss of tolerance driving CD pathogenesis, a hypothesis supported by epidemiological studies.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	CD pathophysiology is multifactorial with several cell types implicated.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Dietary gluten is deamidated by tissue transglutaminase 2, and deamidated gluten peptides presented via HLA-DQ2/HLA-DQ8 to CD4 T cells.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Gluten-specific CD4 T cells possess a distinct type 1 helper T (TH1)/follicular helper T (TFH) cell phenotype, emphasizing the importance of T cell–B cell interactions.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Tissue plasma and B cells may present gluten peptides via HLA-DQ.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Subsequent stimulation of disease-specific plasma cells drives anti-tissue transglutaminase and anti-deamidated gliadin peptide antibody production.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Gluten-specific T cells are necessary but not sufficient to generate mucosal damage.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	The mechanisms by which this response leads to tissue architectural change are incompletely understood.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Intraepithelial lymphocytes (IELs), mainly CD8 T IELs, are highly enriched in CD, likely driven by epithelial and myeloid-derived interleukin (IL)-15, in combination with CD4 T cell-derived IL-2, IL-21 and interferon gamma (IFNγ).
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	IELs may be directly involved in EC killing in a T cell antigen receptor (TCR)-independent manner, via NKG2C and NKG2D and their epithelial ligands MICA and HLA-E. However, the transcriptional state and involvement of TCR signaling in these CD8 T cell populations remains unclear.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	While novel treatments are under development, recent therapeutic trials targeting gluten degradation, gluten-specific CD4 T cell tolerance and IL-15 have been unsuccessful.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	However, therapies including tissue transglutaminase inhibitors and inducers of immune tolerance have shown promise.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Single-cell transcriptomics have redefined cellular landscapes in the gastrointestinal tract, offering insights into CD immunopathology.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Recent studies have sought to understand the cellular basis of CD using mass cytometry, including studies of refractory CD, gluten-specific T cells, and mucosal and circulating T cells.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Single-cell RNA sequencing (scRNA-seq) has been used to study mucosal immune cells, T cells, circulating immune cells and mucosal plasma cells.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Here, we combined single-cell and spatial transcriptomics to define the network of intestinal immune, epithelial and parenchymal cell populations in adults and children with CD.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Our description of spatially localized immune–parenchymal interactions driving inflammation and remodeling of the mucosa, and with specific disease-associated T cell subsets occupying distinct mucosal niches, will facilitate identification of therapeutic targets.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	We generated scRNA-seq profiles of duodenal epithelial, immune and parenchymal populations from 35 participants: 21 with CD (16 children, 5 adults) and 14 controls (5 children, 9 adults; Fig. 1 and Supplementary Table 1).
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	We used complementary single-cell techniques for adult and pediatric datasets, with 86,442 cells sequenced.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	In adults (datasets 1 and 3), we performed scRNA-seq (10x Genomics) on epithelial, immune (Supplementary Fig. 1a,b), stromal and endothelial cells.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	In children (dataset 2), we performed targeted scRNA-seq (BD Rhapsody; 504 targeted gene primer pairs) and surface protein expression (79 oligonucleotide-conjugated antibodies) on intestinal immune cells (Supplementary Fig. 1c,d and Supplementary Tables 2 and 3).Fig.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	1Study schematic.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Schematic of scRNA-seq, RNA-seq, TCR-seq, spatial transcriptomics, and flow cytometry experiments and datasets.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Dataset 1: ECs and total mucosal CD45 cells were isolated from intestinal biopsy samples before scRNA-seq library preparation using the 10x Genomics platform.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Dataset 2: total mucosal CD45 cells were isolated from intestinal biopsy samples before combined targeted scRNA-seq and multiplex surface antibody characterization using the BD Rhapsody platform.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Dataset 3: scRNA-seq (10x Genomics) was performed on intestinal stromal and endothelial cells.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Datasets 4 and 5: OCT-embedded frozen duodenal biopsy samples were sectioned and used for spatial transcriptomics (10x Visium).
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Datasets 6 and 7: mucosal CD8 T cells were isolated before bulk RNA-seq and TCR-seq.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Dataset 8: mucosal CD8 and γδ T cells were isolated before scRNA-seq library preparation using the 10x Genomics platform.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Dataset 9: flow cytometry of circulating CD8 T cells.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Study participant numbers and disease characteristics, as well as cell numbers after the quality-control pipeline, are indicated.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	ILC, innate lymphoid cell; HC, healthy controls; ACD, active celiac disease; TCD, treated celiac disease.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Schematic of scRNA-seq, RNA-seq, TCR-seq, spatial transcriptomics, and flow cytometry experiments and datasets.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Dataset 1: ECs and total mucosal CD45 cells were isolated from intestinal biopsy samples before scRNA-seq library preparation using the 10x Genomics platform.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Dataset 2: total mucosal CD45 cells were isolated from intestinal biopsy samples before combined targeted scRNA-seq and multiplex surface antibody characterization using the BD Rhapsody platform.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Dataset 3: scRNA-seq (10x Genomics) was performed on intestinal stromal and endothelial cells.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Datasets 4 and 5: OCT-embedded frozen duodenal biopsy samples were sectioned and used for spatial transcriptomics (10x Visium).
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Datasets 6 and 7: mucosal CD8 T cells were isolated before bulk RNA-seq and TCR-seq.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Dataset 8: mucosal CD8 and γδ T cells were isolated before scRNA-seq library preparation using the 10x Genomics platform.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Dataset 9: flow cytometry of circulating CD8 T cells.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Study participant numbers and disease characteristics, as well as cell numbers after the quality-control pipeline, are indicated.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	ILC, innate lymphoid cell; HC, healthy controls; ACD, active celiac disease; TCD, treated celiac disease.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	We analyzed EPCAM epithelial populations from dataset 1.
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Nine transcriptionally distinct epithelial cell (EC) clusters were identified, representing progenitor, secretory and absorptive lineages along the developmental progression of the crypt–villus axis (Fig. 2a,b, Extended Data Fig. 1a and Supplementary Table 4).
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	BEST4 enterocytes (BEST4CA7CPA2), first identified in the colon, were seen, expressing CFTR and showing chloride channel activity (Fig. 2b and Extended Data Fig. 1a).
PMC12133578	Immune-epithelial-stromal networks define the cellular ecosystem of the small intestine in celiac disease.	Goblet cells (ITLN1MUC2SPINK4) and tuft cells (PLCG2TRPM5IRAG2) were also identified.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

Similarly, no association was detected between SLFN12 mRNA expression and male gender (Kruskal–Wallis test, p = 0.880).

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

Finally, we examined whether PDE3A modulators may have efficacy in treating LPS.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

PDE3A and SLFN12 protein expression were first evaluated in eight LPS cell lines (Figure 4A).

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

PDE3A- and SLFN12-coexpression was detected in two of the eight LPS cell lines, SA4 and GOT3, and in the GIST882 control cell line.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

We then measured, with CellTiterGlo, the effect of three PDE3A modulators (anagrelide, BAY 2666605, and DNMDP) and one PDE3A enzyme inhibitor (cilostazol) on cell viability in these cell lines.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

Cell viabilities decreased with all PDE3A modulators in all three cell lines (two-tailed unpaired t-test, p < 0.001) (Figure 4B).

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

No response was observed with cilostazol, indicating that PDE3A-and SLFN12-positive LPS cell lines are affected via the PDE3A–SLFN12 complex and not by enzyme inhibition.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

Efficacious subtype-specific targeted therapies are currently not available for LPSs.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

In this study, we sought to discover novel genes that are specifically overexpressed in LPS subtypes, via a large-scale transcriptome analysis.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

We identified 381 genes, many of which may have a role in tumorigenesis or cancer biology pathways and, therefore, may serve as therapeutic targets in LPSs.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

As expected, the analysis yielded some known LPS-subtype-specific genes, but also revealed multiple genes that are linked to other cancer types.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

As many of these genes have been described as possibly targetable—for example PAPPA in breast cancer and TROAP in glioma —the discovery of their LPS-subtype-specificity is worth considering for further investigation.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

In addition to identifying individual therapeutic targets, we were interested in examining signaling pathways associated with the overexpressed genes to describe the LPS subtypes and to understand the possible mechanisms of tumorigenesis.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

The emerging hedgehog signaling in the DDLPS-specific pathway analysis is a compelling discovery, as targeting sonic hedgehog signaling and its key factor, GLI1, has been studied in other sarcomas .

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

Moreover, we identified GLI1 as the most upregulated gene in DDLPS, and previous studies have also shown high expression of two GLI homologs, GLI1 and GLI2, in DDLPS .

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

MLPS tumors have frequently been described as having an activated IGF1R/PI3K/Akt signaling pathway that is induced by the FUS-DDIT3 oncoprotein .

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

Interestingly, a highly homologous pathway, the insulin signaling pathway, was observed as the second-most-upregulated pathway in our analysis, after the phospholipase C-mediated cascade.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

Almost all of the upregulated pathways in PLPS were involved in DNA replication and cell proliferation.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

Aberrations in cell-division-associated pathways aligns with morphological features of PLPS, which frequently exhibit a high number of mitoses and multinucleated giant cells .

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

Further studies should be conducted to investigate whether these pathways can be targeted—for example, with cyclin-dependent kinase inhibitors.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

Although PDE3A was only ranked 124th on the MLPS DEG list, it caught our attention because it has been recognized in GISTs and described as potentially targetable with drugs, called PDE3A modulators, that are cytotoxic to PDE3A- and SLFN12-coexpressing cell lines .

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

The high PDE3A expression in GISTs and cardiovascular tissue might explain why it ranked relatively low in our analysis.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

In addition to confirming the association between PDE3A expression and the myxoid subtype, via IHC staining, high and frequent PDE3A expression was specifically seen in the high-grade MLPS samples with a round cell phenotype.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

High PDE3A expression, in protein level, was also associated with male gender, but no other connections with clinical factors were observed.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

Our pathway analysis identified PDE3A as part of the insulin signaling pathway, which shares significant similarities with the IGF1R/PI3K/Akt pathway, driven by the commonly observed FUS-DDIT3 fusion protein in MLPS .

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

However, further research is needed to determine if elevated PDE3A expression is associated with the fusion oncogene-driven pathway alterations.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

The MLPS samples also exhibited higher SLFN12 mRNA expression levels than those of the DDLPS and PLPS samples.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

Interestingly, most of the samples that presented PDE3A and SLFN12 mRNA expression levels that were higher than those of the GIST882 cell line belonged to the myxoid subtype.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

This finding is intriguing and warrants further efficacy studies of PDE3A modulators in LPS in vivo models, as these compounds may lead to an MLPS-specific targeted therapy.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

The study had certain limitations.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

As frozen tissue samples for RNA extraction were not available, we used RNA isolated from FFPE samples, in which RNA is known to be degraded.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

However, in a previous study, we demonstrated that the transcriptomic data derived from FFPE provide profiles that are similar to those of RNA data from fresh-frozen tissue in Merkel cell carcinoma .

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

We were unable to find any PDE3A-positive MLPS cell lines for the study.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

Instead, we used two PDE3A- and SLFN12-positive LPS cell lines, GOT3 classified as a WDLPS, and SA4 with unspecified histology, which showed responses to PDE3A modulators.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

Therefore, an association of frequent and high PDE3A expression and the efficacy of PDE3A modulators in MLPS was not confirmed in vitro.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

However, other studies have shown that PDE3A- and SLFN12-expressing cell lines and xenografts of various cancer types are sensitive to PDE3A modulators, suggesting that the mechanism behind the cytotoxic effect is universal and not cell-type dependent .

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

In conclusion, our findings suggest that LPSs, specifically MLPS tumors that coexpress PDE3A and SLFN12, may be candidates for PDE3A modulator treatment.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

Further in vivo experiments and optimization of PDE3A and SLFN12 diagnostics should be conducted to identify suitable patients for therapy, ultimately enabling efficient patient stratification and precision medicine in the future.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

In summary, we identified LPS-subtype-specific highly expressed genes, which could potentially be targeted with precision medicine.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

These genes are associated with the hedgehog signaling pathway in DDLPS, phospholipase C, and insulin signaling pathways in MLPS and cell proliferation pathways in PLPS.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

Through in vitro experiments, we observed elevated PDE3A expression correlating with high-grade myxoid samples and discovered that two LPS cell lines were responsive to PDE3A modulators.

PMC10669966

PDE3A Is a Highly Expressed Therapy Target in Myxoid Liposarcoma

Further research is required to determine whether PDE3A modulators could potentially be used as precision medicine in treating MLPS—specifically, in high-grade tumors.

PMC12133578