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...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(sc RNA-seq)holds great promise for identifying cell heterogeneity.However,this technique has rarely been used in the study of tumor subclassification.By analyzing sc RNA-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 sc RNA-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.展开更多
The vicious cycle between tumor cell proliferation and bone resorption remarkably elevates the progression and metastasis of bone tumors.Here,we fabricated polyethylene glycol-conjugated alendronate-functionalized and...The vicious cycle between tumor cell proliferation and bone resorption remarkably elevates the progression and metastasis of bone tumors.Here,we fabricated polyethylene glycol-conjugated alendronate-functionalized and chloroquine(CQ)-loaded polydopamine nanoparticles(PPA/CQ)for efficient treatment of bone tumors via breaking the vicious cycle.The nanoparticles were efficiently accumulated to the bone tissues,especially the osteolytic lesions around tumors.CQ released from PPA/CQ inhibited osteoclastogenesis via preventing the degradation of tumor necrosis factor(TNF)receptor-associated receptor 3 to attenuate the osteolysis in bone tumors.On the other hand,CQ blocked the autophagy in cancer cells,resulting in improved photothermal killing of cancer cells.Finally,the in vivo experiment revealed that PPA/CQ-associated treatment efficiently inhibited both tumor growth and osteolysis.This work suggests that autophagy inhibition-associated photothermal therapy could be a promising strategy for treating malignant bone tumors.展开更多
基金National Natural Science Foundation of China(Nos.31970663 and 82173028 to J.X.,No.81874180 to T.W.,No.81201556 to W.Z.,No.82072971 to H.W.and No.81972505 to Z.W.)。
文摘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(sc RNA-seq)holds great promise for identifying cell heterogeneity.However,this technique has rarely been used in the study of tumor subclassification.By analyzing sc RNA-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 sc RNA-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.
基金the National Natural Science Foundation of China(21725402,31871010,81971735,81871470 and 81901867)Shanghai Municipal Science and Technology Commission(17XD1401600)+1 种基金the Fok Ying Tong Education Foundation(151036)Guangdong Innovative and Entrepreneurial Research Team Program(2016ZT06C322)。
文摘The vicious cycle between tumor cell proliferation and bone resorption remarkably elevates the progression and metastasis of bone tumors.Here,we fabricated polyethylene glycol-conjugated alendronate-functionalized and chloroquine(CQ)-loaded polydopamine nanoparticles(PPA/CQ)for efficient treatment of bone tumors via breaking the vicious cycle.The nanoparticles were efficiently accumulated to the bone tissues,especially the osteolytic lesions around tumors.CQ released from PPA/CQ inhibited osteoclastogenesis via preventing the degradation of tumor necrosis factor(TNF)receptor-associated receptor 3 to attenuate the osteolysis in bone tumors.On the other hand,CQ blocked the autophagy in cancer cells,resulting in improved photothermal killing of cancer cells.Finally,the in vivo experiment revealed that PPA/CQ-associated treatment efficiently inhibited both tumor growth and osteolysis.This work suggests that autophagy inhibition-associated photothermal therapy could be a promising strategy for treating malignant bone tumors.