Objective:Pancreatic ductal adenocarcinoma(PDAC)is a highly malignant gastrointestinal cancer with a 5-year survival rate of only 9%.Of PDAC patients,15%-20%are eligible for radical surgery.Gemcitabine is an important...Objective:Pancreatic ductal adenocarcinoma(PDAC)is a highly malignant gastrointestinal cancer with a 5-year survival rate of only 9%.Of PDAC patients,15%-20%are eligible for radical surgery.Gemcitabine is an important chemotherapeutic agent for patients with PDAC;however,the efficacy of gemcitabine is limited due to resistance.Therefore,reducing gemcitabine resistance is essential for improving survival of patients with PDAC.Identifying the key target that determines gemcitabine resistance in PDAC and reversing gemcitabine resistance using target inhibitors in combination with gemcitabine are crucial steps in the quest to improve survival prognosis in patients with PDAC.Methods:We constructed a human genome-wide CRISPRa/dCas 9 overexpression library in PDAC cell lines to screen key targets of drug resistance based on sgRNA abundance and enrichment.Then,co-IP,ChIP,ChIP-seq,transcriptome sequencing,and qPCR were used to determine the specific mechanism by which phospholipase D1(PLD1)confers resistance to gemcitabine.Results:PLD1 combines with nucleophosmin 1(NPM1)and triggers NPM1 nuclear translocation,where NPM1 acts as a transcription factor to upregulate interleukin 7 receptor(IL7R)expression.Upon interleukin 7(IL-7)binding,IL7R activates the JAK1/STAT5 signaling pathway to increase the expression of the anti-apoptotic protein,BCL-2,and induce gemcitabine resistance.The PLD1 inhibitor,Vu0155069,targets PLD1 to induce apoptosis in gemcitabine-resistant PDAC cells.Conclusions:PLD1 is an enzyme that has a critical role in PDAC-associated gemcitabine resistance through a non-enzymatic interaction with NPM1,further promoting the downstream JAK1/STAT5/Bcl-2 pathway.Inhibiting any of the participants of this pathway can increase gemcitabine sensitivity.展开更多
Objective: Lymphovascular infiltration(LVI) is frequently detected in gastric cancer(GC) specimens. Studies have revealed that GC patients with LVI have a poorer prognosis than those without LVI.Methods: In total, 1,0...Objective: Lymphovascular infiltration(LVI) is frequently detected in gastric cancer(GC) specimens. Studies have revealed that GC patients with LVI have a poorer prognosis than those without LVI.Methods: In total, 1,007 patients with curatively resected GC at Department of Gastric Cancer, Tianjin Medical University Cancer Institute and Hospital were retrospectively enrolled. The patients were categorized into two groups based on the LVI status: a positive group(PG;presence of LVI) and a negative group(NG;absence of LVI). The clinicopathological factors corrected with LVI and prognostic variables were analyzed. Additionally, a pathological lymphovascular-node(lvN) classification system was proposed to evaluate the superiority of its prognostic prediction of GC patients compared with that of the eighth edition of the N staging system.Results: Two hundred twenty-four patients(22.2%) had LVI. The depth of invasion and lymph node metastasis were independently associated with the presence of LVI. GC patients with LVI demonstrated a significantly lower overall survival(OS) rate than those without LVI(42.8% vs. 68.9%, respectively;P<0.001). In multivariate analysis,LVI was identified as an independent prognostic factor for GC patients(hazard ratio: 1.370;95% confidence interval: 1.094-1.717;P=0.006). Using strata analysis, significant prognostic differences between the groups were only observed in patients at stage I-IIIa or N0-2. The lvN classification was found to be more appropriate to predict the OS of GC patients after curative surgery than the pN staging system. The-2 log-likelihood of lvN classification(4,746.922) was smaller than the value of pN(4,765.196), and the difference was statistically significant(χ^2=18.434, P<0.001).Conclusions: The presence of LVI influences the OS of GC patients at stage Ⅰ-Ⅲ a or N0-2. LVI should be incorporated into the pN staging system to enhance the accuracy of the prognostic prediction of GC patients.展开更多
Objective: Hypoxia is a significant feature of solid tumors, including pancreatic ductal adenocarcinoma(PDAC). It is associated with tumor invasion, metastasis, and drug resistance. However, the spatial distribution o...Objective: Hypoxia is a significant feature of solid tumors, including pancreatic ductal adenocarcinoma(PDAC). It is associated with tumor invasion, metastasis, and drug resistance. However, the spatial distribution of hypoxia-related heterogeneity in PDAC remains unclear.Methods: Spatial transcriptomics(STs), a new technique, was used to investigate the ST features of engrafted human PDAC in the ischemic hind limbs of nude mice. Transcriptomes from ST spots in the hypoxic tumor and the control were clustered using differentially-expressed genes. These data were compared to determine the spatial organization of hypoxia-induced heterogeneity in PDAC. Clinical relevance was validated using the Tumor Cancer Genome Atlas and KM-plotter databases. The CMAP website was used to identify molecules that may serve as therapeutic targets for PDAC.Results: ST showed that the tumor cell subgroups decreased to 7 subgroups in the hypoxia group, compared to 9 subgroups in the control group. Different subgroups showed positional characteristics and different gene signatures. Subgroup 6 located at the invasive front showed a higher proliferative ability under hypoxia. Subgroup 6 had active functions including cell proliferation, invasion, and response to stress. Expressions of hypoxia-related genes, LDHA, TPI1, and ENO1, induced changes. CMAP analysis indicated that ADZ-6482, a PI3 K inhibitor, was targeted by the invasive subgroup in hypoxic tumors.Conclusions: This study is the first to describe hypoxic microenvironment-induced spatial transcriptome changes in PDAC, and to identify potential treatment targets for PDAC. These data will provide the basis for further investigations of the prognoses and treatments of hypoxic tumors.展开更多
VEGF inhibitors are one of the most successful antiangiogenic drugs in the treatment of many solid tumors.Nevertheless,pancreatic adenocarcinoma(PAAD)cells can reinstate tumor angiogenesis via activation of VEGF-indep...VEGF inhibitors are one of the most successful antiangiogenic drugs in the treatment of many solid tumors.Nevertheless,pancreatic adenocarcinoma(PAAD)cells can reinstate tumor angiogenesis via activation of VEGF-independent pathways,thereby conferring resistance to VEGF inhibitors.Bioinformatic analysis showed that BICC1 was one of the top genes involved in the specific angiogenesis process of PAAD.The analysis of our own cohort confirmed that BICC1 was overexpressed in human PAAD tissues and was correlated to increased microvessel density and tumor growth,and worse prognosis.In cells and mice with xenograft tumors,BICC1 facilitated angiogenesis in pancreatic cancer in a VEGF-independent manner.Mechanistically,as an RNA binding protein,BICC1 bounds to the 3’UTR of Lipocalin-2(LCN2)mRNA and post-transcriptionally up-regulated LCN2 expression in PAAD cells.When its level is elevated,LCN2 binds to its receptor 24p3R,which directly phosphorylates JAK2 and activates JAK2/STAT3 signal,leading to increased production of an angiogenic factor CXCL1.Blocking of the BICC1/LCN2 signalling reduced the microvessel density and tumor volume of PAAD cell grafts in mice,and increased the tumor suppressive effect of gemcitabine.In conclusion,BICC1 plays a pivotal role in the process of VEGF-independent angiogenesis in pancreatic cancer,leading to resistance to VEGF inhibitors.BICC1/LCN2 signaling may serve as a promising anti-angiogenic therapeutic target for pancreatic cancer patients.展开更多
Metastases are the main cause of cancer-related mortality in breast cancer.Although significant progress has been made in the field of tumor metastasis,the exact molecular mechanisms involved in tumor metastasis are s...Metastases are the main cause of cancer-related mortality in breast cancer.Although significant progress has been made in the field of tumor metastasis,the exact molecular mechanisms involved in tumor metastasis are still unclear.Here,we report that ATOH8-V1,a novel isoform of ATOH8,is highly expressed in breast cancer and is a negative prognostic indicator of survival for patients.Forced expression of ATOH8-V1 dramatically enhances,while silencing of ATOH8-V1 decreases the metastasis of breast cancer cell lines.Moreover,ATOH8-V1 directly binds to the RhoC promoter and stimulates the expression of RhoC,which in turn enhances the metastasis of breast cancer.Altogether,our data demonstrate that ATOH8-V1 is a novel pro-metastatic factor that enhances cancer metastasis,suggesting that AT0H8-V1 is a potential therapeutic target for treatment of metastatic cancers.展开更多
基金supported by the National Key Research and Development Program of China(Grant No.2021YFA1201100)the National Natural Science Foundation of China(Grant Nos.82103006,82030092,81720108028,82072657,82072716,82103003,82173295,81871968,81871978,82072691,and 82103222)+1 种基金the Tianjin Hygiene Healthy Science and Technology Project(Grant No.TJWJ2022MS007)the Science&Technology Development Fund of Tianjin Education Commission for Higher Education(Grant No.2020KJ141).
文摘Objective:Pancreatic ductal adenocarcinoma(PDAC)is a highly malignant gastrointestinal cancer with a 5-year survival rate of only 9%.Of PDAC patients,15%-20%are eligible for radical surgery.Gemcitabine is an important chemotherapeutic agent for patients with PDAC;however,the efficacy of gemcitabine is limited due to resistance.Therefore,reducing gemcitabine resistance is essential for improving survival of patients with PDAC.Identifying the key target that determines gemcitabine resistance in PDAC and reversing gemcitabine resistance using target inhibitors in combination with gemcitabine are crucial steps in the quest to improve survival prognosis in patients with PDAC.Methods:We constructed a human genome-wide CRISPRa/dCas 9 overexpression library in PDAC cell lines to screen key targets of drug resistance based on sgRNA abundance and enrichment.Then,co-IP,ChIP,ChIP-seq,transcriptome sequencing,and qPCR were used to determine the specific mechanism by which phospholipase D1(PLD1)confers resistance to gemcitabine.Results:PLD1 combines with nucleophosmin 1(NPM1)and triggers NPM1 nuclear translocation,where NPM1 acts as a transcription factor to upregulate interleukin 7 receptor(IL7R)expression.Upon interleukin 7(IL-7)binding,IL7R activates the JAK1/STAT5 signaling pathway to increase the expression of the anti-apoptotic protein,BCL-2,and induce gemcitabine resistance.The PLD1 inhibitor,Vu0155069,targets PLD1 to induce apoptosis in gemcitabine-resistant PDAC cells.Conclusions:PLD1 is an enzyme that has a critical role in PDAC-associated gemcitabine resistance through a non-enzymatic interaction with NPM1,further promoting the downstream JAK1/STAT5/Bcl-2 pathway.Inhibiting any of the participants of this pathway can increase gemcitabine sensitivity.
基金supported in part by grants from the Program of National Natural Science Foundation of China (No. 81572372)National Key Research and Development Program of Major Chronic Non-infectious Disease Prevention and Control Research (No. 2016YFC1303202)+2 种基金National Key Research and Development Program “Precision Medicine Research” Program (No. 2017 YFC0908300)Application Foundation and Advanced Technology Program of Tianjin Municipal Science and Technology Commission (No. 15JCYBJC24800)Scientific Research Project of Tianjin Municipal Education Commission (No. 2018KJ015)
文摘Objective: Lymphovascular infiltration(LVI) is frequently detected in gastric cancer(GC) specimens. Studies have revealed that GC patients with LVI have a poorer prognosis than those without LVI.Methods: In total, 1,007 patients with curatively resected GC at Department of Gastric Cancer, Tianjin Medical University Cancer Institute and Hospital were retrospectively enrolled. The patients were categorized into two groups based on the LVI status: a positive group(PG;presence of LVI) and a negative group(NG;absence of LVI). The clinicopathological factors corrected with LVI and prognostic variables were analyzed. Additionally, a pathological lymphovascular-node(lvN) classification system was proposed to evaluate the superiority of its prognostic prediction of GC patients compared with that of the eighth edition of the N staging system.Results: Two hundred twenty-four patients(22.2%) had LVI. The depth of invasion and lymph node metastasis were independently associated with the presence of LVI. GC patients with LVI demonstrated a significantly lower overall survival(OS) rate than those without LVI(42.8% vs. 68.9%, respectively;P<0.001). In multivariate analysis,LVI was identified as an independent prognostic factor for GC patients(hazard ratio: 1.370;95% confidence interval: 1.094-1.717;P=0.006). Using strata analysis, significant prognostic differences between the groups were only observed in patients at stage I-IIIa or N0-2. The lvN classification was found to be more appropriate to predict the OS of GC patients after curative surgery than the pN staging system. The-2 log-likelihood of lvN classification(4,746.922) was smaller than the value of pN(4,765.196), and the difference was statistically significant(χ^2=18.434, P<0.001).Conclusions: The presence of LVI influences the OS of GC patients at stage Ⅰ-Ⅲ a or N0-2. LVI should be incorporated into the pN staging system to enhance the accuracy of the prognostic prediction of GC patients.
基金supported by grants from the National Natural Science Key Foundation of China (Grants Nos. 82030092 and 81230050)。
文摘Objective: Hypoxia is a significant feature of solid tumors, including pancreatic ductal adenocarcinoma(PDAC). It is associated with tumor invasion, metastasis, and drug resistance. However, the spatial distribution of hypoxia-related heterogeneity in PDAC remains unclear.Methods: Spatial transcriptomics(STs), a new technique, was used to investigate the ST features of engrafted human PDAC in the ischemic hind limbs of nude mice. Transcriptomes from ST spots in the hypoxic tumor and the control were clustered using differentially-expressed genes. These data were compared to determine the spatial organization of hypoxia-induced heterogeneity in PDAC. Clinical relevance was validated using the Tumor Cancer Genome Atlas and KM-plotter databases. The CMAP website was used to identify molecules that may serve as therapeutic targets for PDAC.Results: ST showed that the tumor cell subgroups decreased to 7 subgroups in the hypoxia group, compared to 9 subgroups in the control group. Different subgroups showed positional characteristics and different gene signatures. Subgroup 6 located at the invasive front showed a higher proliferative ability under hypoxia. Subgroup 6 had active functions including cell proliferation, invasion, and response to stress. Expressions of hypoxia-related genes, LDHA, TPI1, and ENO1, induced changes. CMAP analysis indicated that ADZ-6482, a PI3 K inhibitor, was targeted by the invasive subgroup in hypoxic tumors.Conclusions: This study is the first to describe hypoxic microenvironment-induced spatial transcriptome changes in PDAC, and to identify potential treatment targets for PDAC. These data will provide the basis for further investigations of the prognoses and treatments of hypoxic tumors.
基金National Natural Science Foundation of China(grants 82272680,82072659,81871978,81772633,82272799,81720108028,81525021,81502067,81302082,81272685,31301151,81172355,31471340,31470957,81472264,and 81401957)National Key R&D Program of China(grants 2020YFA0803704)+1 种基金Tianjin Science Foundation for Distinguished Young Scholars(grants 19JCJQJC63100)NIH grant R01CA233844,R01CA256911(to S.Y.).
文摘VEGF inhibitors are one of the most successful antiangiogenic drugs in the treatment of many solid tumors.Nevertheless,pancreatic adenocarcinoma(PAAD)cells can reinstate tumor angiogenesis via activation of VEGF-independent pathways,thereby conferring resistance to VEGF inhibitors.Bioinformatic analysis showed that BICC1 was one of the top genes involved in the specific angiogenesis process of PAAD.The analysis of our own cohort confirmed that BICC1 was overexpressed in human PAAD tissues and was correlated to increased microvessel density and tumor growth,and worse prognosis.In cells and mice with xenograft tumors,BICC1 facilitated angiogenesis in pancreatic cancer in a VEGF-independent manner.Mechanistically,as an RNA binding protein,BICC1 bounds to the 3’UTR of Lipocalin-2(LCN2)mRNA and post-transcriptionally up-regulated LCN2 expression in PAAD cells.When its level is elevated,LCN2 binds to its receptor 24p3R,which directly phosphorylates JAK2 and activates JAK2/STAT3 signal,leading to increased production of an angiogenic factor CXCL1.Blocking of the BICC1/LCN2 signalling reduced the microvessel density and tumor volume of PAAD cell grafts in mice,and increased the tumor suppressive effect of gemcitabine.In conclusion,BICC1 plays a pivotal role in the process of VEGF-independent angiogenesis in pancreatic cancer,leading to resistance to VEGF inhibitors.BICC1/LCN2 signaling may serve as a promising anti-angiogenic therapeutic target for pancreatic cancer patients.
基金This work was supported by the National Science Foundation for Young Scientists of China(81702994)International S&T Cooperation Program of China(2015DFA30420)We thank Dr Ralph A.Reisfeld from the Scripps Research In stitute for his valuable suggestions and for proof-readi ng this manuscript.
文摘Metastases are the main cause of cancer-related mortality in breast cancer.Although significant progress has been made in the field of tumor metastasis,the exact molecular mechanisms involved in tumor metastasis are still unclear.Here,we report that ATOH8-V1,a novel isoform of ATOH8,is highly expressed in breast cancer and is a negative prognostic indicator of survival for patients.Forced expression of ATOH8-V1 dramatically enhances,while silencing of ATOH8-V1 decreases the metastasis of breast cancer cell lines.Moreover,ATOH8-V1 directly binds to the RhoC promoter and stimulates the expression of RhoC,which in turn enhances the metastasis of breast cancer.Altogether,our data demonstrate that ATOH8-V1 is a novel pro-metastatic factor that enhances cancer metastasis,suggesting that AT0H8-V1 is a potential therapeutic target for treatment of metastatic cancers.
