HIF1/2 mediates hypoxia-induced LDHA expression in human pancreatic cancer cells

Subclassification of tumors based on molecular features may facilitate therapeutic choice and increase the response rate of cancer patients. However, the highly complex cell origin involved in osteosarcoma (OS) limits the utility of traditional bulk RNA sequencing for OS subclassification. Single-cell RNA sequencing (scRNA-seq) holds great promise for identifying cell heterogeneity. However, this technique has rarely been used in the study of tumor subclassification. By analyzing scRNA-seq data for six conventional OS and nine cancellous bone (CB) samples, we identified 29 clusters in OS and CB samples and discovered three differentiation trajectories from the cancer stem cell (CSC)-like subset, which allowed us to classify OS samples into three groups. The classification model was further examined using the TARGET dataset. Each subgroup of OS had different prognoses and possible drug sensitivities, and OS cells in the three differentiation branches showed distinct interactions with other clusters in the OS microenvironment. In addition, we verified the classification model through IHC staining in 138 OS samples, revealing a worse prognosis for Group B patients. Furthermore, we describe the novel transcriptional program of CSCs and highlight the activation of EZH2 in CSCs of OS. These findings provide a novel subclassification method based on scRNA-seq and shed new light on the molecular features of CSCs in OS and may serve as valuable references for precision treatment for and therapeutic development in OS.

Background: The extracellular matrix has been critically associated with the tumorigenesis and progression of Ewing sarcoma (ES). However, the regulatory and prognostic roles of tenascin-C (TNC) in ES remain unclear.Methods: TNC expression was examined in specimens by immunohistochemistry, and the association of TNC expression with ES patient survival was also analysed. TNC-knockout cell lines were constructed using CRISPR/Cas9 methods. In vitro experiments and in vivo bioluminescent imaging using BALB/c nude mice were conducted to evaluate the effect of TNC on ES tumour progression. RNA sequencing was performed, and the underlying mechanism of TNC was further explored.Results: TNC was overexpressed in ES tissue and cell lines, and TNC overexpression was associated with poor survival in ES patients. TNC enhanced cell proliferation, migration and angiogenesis in vitro and promoted ES metastasis in vivo. The oncoprotein EWS-FLI1 profoundly increased TNC expression by directly binding to the TNC promoter region. Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) upregulation induced by Yes-associated protein (YAP) activation was responsible for TNC-regulated ES tumour progression. Activated integrin α5β1 signalling might be correlated with YAP dephosphorylation and nuclear translocation.Conclusions: TNC may promote ES tumour progression by targeting MALAT1 through integrin α5β1-mediated YAP activation.

Chondrosarcoma (CS) is the second most common primary bone malignancy, known for its unique transcriptional landscape that renders most CS subtypes resistant to chemotherapy, including neoadjuvant chemotherapy commonly used in osteosarcoma (OS) treatment. Understanding the transcriptional landscape of CS and the mechanisms by which key genes contribute to chemotherapy resistance could be a crucial step in overcoming this challenge. To address this, we developed a single-cell transcriptional map of CS, comparing it with OS and normal cancellous bone. Our analysis revealed a specific increase in KDEL receptor 1 (KDELR1) expression in CS, which was closely associated with CS prognosis, tumor aggressiveness, and drug resistance. KDELR1 plays a key role in regulating membrane protein processing and secretion, as well as contributing to tumor extracellular matrix (ECM) formation and drug resistance. Further investigation using mass spectrometry proteomics and transcriptomics uncovered KDELR1’s involvement in modulating the Hippo-YAP pathway activity in CS cells. The KDELR1-Integrin-PLCγ-YAP1 axis emerges as a critical process mediating drug resistance and malignant behavior in CS, offering novel insights and potential therapeutic targets for CS treatment.

TGF-2-induced ANGPTL4 expression promotes tumor progression and osteoclast differentiation in giant cell tumor of bone TGF-β2-induced ANGPTL4 expression promotes tumor progression and osteoclast differentiation in giant cell tumor of bone