Prostate cancer is a clinically heterogeneous disease, with some men having indolent disease that can safely be observed, while others have aggressive, lethal disease. Over the past decade, researchers have begun to u...Prostate cancer is a clinically heterogeneous disease, with some men having indolent disease that can safely be observed, while others have aggressive, lethal disease. Over the past decade, researchers have begun to unravel some of the genomic heterogeneity that contributes to these varying clinical phenotypes. Distinct molecular sub-classes of prostate cancer have been identified, and the uniqueness of these sub-classes has been leveraged to predict clinical outcomes, design novel biomarkers for prostate cancer diagnosis, and develop novel therapeutics. Recent work has also elucidated the temporal and spatial heterogeneity of prostate cancer, helping us understand disease pathogenesis, response to therapy, and progression. New genomic techniques have provided us with a window into the remarkable clinical and genomic heterogeneity of prostate cancer, and this new perspective will increasingly impact patient care.展开更多
Integrin β4 (ITGB4) is emerging as a pivotal player in breast cancer progression, particularly in aggressive and invasive subtypes such as triple-negative breast cancer (TNBC). This review broadly summarizes current ...Integrin β4 (ITGB4) is emerging as a pivotal player in breast cancer progression, particularly in aggressive and invasive subtypes such as triple-negative breast cancer (TNBC). This review broadly summarizes current research on ITGB4’s involvement in breast cancer, focusing on its role in metastasis, metabolic reprogramming, drug resistance, and immunoregulation that collectively influence tumor behavior with implications for the development of innovative and more efficacious therapeutic modalities.展开更多
Background:Cholangiocarcinoma(CCA)is one of the primary hepatobiliary malignant neoplasms with only 10%of 5-year survival rate.Promising immunotherapy with the blockade of immune checkpoints has no clear benefit in CC...Background:Cholangiocarcinoma(CCA)is one of the primary hepatobiliary malignant neoplasms with only 10%of 5-year survival rate.Promising immunotherapy with the blockade of immune checkpoints has no clear benefit in CCA.The inhibition of YAP1 signaling by verteporfin has shown encouraging results by inhibiting cell proliferation and inducing apoptosis.This study aimed to evaluate the potential benefit of the combination of verteporfin and anti-programmed cell death 1(PD-1)in CCA mouse model.Methods:We assessed the cytotoxicity of verteporfin in human CCA cell lines in vitro,including both intrahepatic CCA and extrahepatic CCA cells.We examined the in vitro effect of verteporfin on cell proliferation,apoptosis,and stemness.We evaluated the in vivo efflcacy of verteporfin,anti-PD-1,and a combination of both in subcutaneous CCA mouse model.Results:Our study showed that verteporfin reduced tumor cell growth and enhanced apoptosis of human CCA tumor cells in vitro in a dose-dependent fashion.Nevertheless,verteporfin impaired stemness evidenced by reduced spheroid formation and colony formation,decreased numbers of cells with aldehyde dehydrogenase activity and positive cancer stem cell markers(all P<0.05).The combination of verteporfin and anti-PD-1 reduced tumor burden in CCA subcutaneous SB1 tumor model compared to either agent alone.Conclusions:Verteporfin exhibits antitumor effects in both intrahepatic and extrahepatic CCA cell lines and the combination with anti-PD-1 inhibited tumor growth.展开更多
Pre-Metastatic Niches(PMNs)result from communications between primary tumors and the microenvironment of future distant metastasis via tumor-derived factors.In this issue of Cancer Cell,Liu et al.show that TLR3 activa...Pre-Metastatic Niches(PMNs)result from communications between primary tumors and the microenvironment of future distant metastasis via tumor-derived factors.In this issue of Cancer Cell,Liu et al.show that TLR3 activation in lung epithelial cells by tumor exosomal RNAs triggers neutrophil recruitment,which contributes to PMN formation and metastasis.展开更多
The field of circulating tumor cell(CTC)enrichment has seen many emerging technologies in recent years,which have resulted in the identification and monitoring of clinically relevant,CTC-based biomarkers that can be a...The field of circulating tumor cell(CTC)enrichment has seen many emerging technologies in recent years,which have resulted in the identification and monitoring of clinically relevant,CTC-based biomarkers that can be analyzed routinely without invasive procedures.Several molecular platforms have been used to investigate the molecular profile of the disease,from high throughput gene expression analyses down to single cell biological dissection.The established presence of CTC heterogeneity nevertheless constitutes a challenge for cell isolation as the several subpopulations can potentially display different molecular characteristics;in this scenario,careful consideration must be given to the isolation approach,whereas methods that discriminate against certain subpopulations may result in the exclusion of CTCs that carry biological relevance.In the context of prostate cancer,CTC molecular interrogation can enable longitudinal monitoring of key biological features during treatment with substantial clinical impact,as several biomarkers could predict tumor response to AR signaling inhibitors(abiraterone,enzalutamide)or standard chemotherapy(taxanes).Thus,CTCs represent a valuable opportunity to personalize medicine in current clinical practice.展开更多
Aim:We reviewed the radiographic response of three patients with metastatic castration-resistant prostate cancer treated with CRXL301,a docetaxel nanoparticle.For these three patients,we isolated and analyzed circulat...Aim:We reviewed the radiographic response of three patients with metastatic castration-resistant prostate cancer treated with CRXL301,a docetaxel nanoparticle.For these three patients,we isolated and analyzed circulating tumor cells(CTCs)to explore microtubule(MT)drug-target engagement(MT-DTE)as a biomarker of response to treatment.MT-DTE was based on a quantitative assessment of the MT cytoskeleton in CTCs from pre-and posttreatment patient samples as a potential read-out of CRXL301 activity.Methods:We isolated CTCs using negative CD45+depletion and subjected them to multiplex confocal microscopy using our established protocol.CTCs were identified as CD45-/CK+/DAPI+cells and MT-DTE was determined using our developed imaging algorithm.We quantified MT bundling in CTCs across multiple time points,from baseline to on-treatment to disease progression.Here,we describe the longitudinal analysis of MT-DTE in CTCs from patients treated with CRXL301 and its correlation with response to treatment.Results:We collected CTCs at seven time points from three metastatic castration-resistant prostate cancer patients.Clinical response was evaluated by Response Evaluation Criteria in Solid Tumors(RECIST)v.1.1 criteria in those patients with measurable disease.Of the three patients enrolled,one experienced partial response(-50%)to CRXL301 and two patients were unevaluable given bone only disease.Notably,however,these two patients showed stable disease clinically based on bone scans.MT-DTE across all time points revealed that,early time points within four and 24 h of drug administration exhibited the highest levels of drug engagement(MT-DTE)as compared to baseline.However,these early time points did not correlate with clinical response.We observed that the CTCs collected one week after the first or second dose of CRXL301 treatment in the responding patient had numerically higher levels of MT-DTE as compared to the other two patients.Conclusion:Taxane on-target activity can be detected and analyzed quantitatively in CTCs by tubulin immunofluorescence.Early time points,within 24 h of drug administration,showed high levels of DTE but did not correlate with clinical response.MT-DTE in CTCs collected after one week on treatment correlated best with treatment response.The clinical utility of the 1-week CTC DTE should be tested and validated in future clinical trials involving taxanes.展开更多
The treatment of metastatic cancers remains a challenge in the clinic,with recurrences persisting at high rates even after surgical resection of primary tumors.Beyond the perseverance of circulating tumor cells after ...The treatment of metastatic cancers remains a challenge in the clinic,with recurrences persisting at high rates even after surgical resection of primary tumors.Beyond the perseverance of circulating tumor cells after resection,this phenomenon is abetted by the formation of the premetastatic niche(PMN),a distant environment ripe for the colonization of new metastases,which is conditioned by factors and extracellular vesicles secreted by the primary tumor.In their recent paper,Lu et al.demonstrate how such PMNs in the lung can be disrupted by low-dose adjuvant epigenetic therapy,and propose a novel therapeutic avenue to supplement tumor resection.展开更多
TCDD-inducible poly(ADP-ribose)polymerase(TIPARP,best known as PARP7)has previously been shown to promote oncogenesis by limiting the cytosolic accumulation of potentially interferogenic nucleic acids in malignant cel...TCDD-inducible poly(ADP-ribose)polymerase(TIPARP,best known as PARP7)has previously been shown to promote oncogenesis by limiting the cytosolic accumulation of potentially interferogenic nucleic acids in malignant cells or the precursors thereof.Recent data indicate that the oncogenic activity of PARP7 is derived at least partially from its ability to suppress apoptotic cell death upon mono-ADP-ribosylation of FOS-like 1,AP-1 transcription factor subunit(FOSL1,best known as FRA1)[1].展开更多
Background The Inspiration4(I4)mission,the first all-civilian orbital flight mission,investigated the physiological effects of short-duration spaceflight through a multi-omic approach.Despite advances,there remains mu...Background The Inspiration4(I4)mission,the first all-civilian orbital flight mission,investigated the physiological effects of short-duration spaceflight through a multi-omic approach.Despite advances,there remains much to learn about human adaptation to spaceflight's unique challenges,including microgravity,immune system perturbations,and radiation exposure.Methods To provide a detailed genetics analysis of the mission,we collected dried blood spots pre-,during,and post-flight for DNA extraction.Telomere length was measured by quantitative PCR,while whole genome and cfDNA sequencing provided insight into genomic stability and immune adaptations.A robust bioinformatic pipeline was used for data analysis,including variant calling to assess mutational burden.Result Telomere elongation occurred during spaceflight and shortened after return to Earth.Cell-free DNA analysis revealed increased immune cell signatures post-flight.No significant clonal hematopoiesis of indeterminate potential(CHIP)or whole-genome instability was observed.The long-term gene expression changes across immune cells suggested cellular adaptations to the space environment persisting months post-flight.Conclusion Our findings provide valuable insights into the physiological consequences of short-duration spaceflight,with telomere dynamics and immune cell gene expression adapting to spaceflight and persisting after return to Earth.CHIP sequencing data will serve as a reference point for studying the early development of CHIP in astronauts,an understudied phenomenon as previous studies have focused on career astronauts.This study will serve as a reference point for future commercial and non-commercial spaceflight,low Earth orbit(LEO)missions,and deep-space exploration.展开更多
文摘Prostate cancer is a clinically heterogeneous disease, with some men having indolent disease that can safely be observed, while others have aggressive, lethal disease. Over the past decade, researchers have begun to unravel some of the genomic heterogeneity that contributes to these varying clinical phenotypes. Distinct molecular sub-classes of prostate cancer have been identified, and the uniqueness of these sub-classes has been leveraged to predict clinical outcomes, design novel biomarkers for prostate cancer diagnosis, and develop novel therapeutics. Recent work has also elucidated the temporal and spatial heterogeneity of prostate cancer, helping us understand disease pathogenesis, response to therapy, and progression. New genomic techniques have provided us with a window into the remarkable clinical and genomic heterogeneity of prostate cancer, and this new perspective will increasingly impact patient care.
文摘Integrin β4 (ITGB4) is emerging as a pivotal player in breast cancer progression, particularly in aggressive and invasive subtypes such as triple-negative breast cancer (TNBC). This review broadly summarizes current research on ITGB4’s involvement in breast cancer, focusing on its role in metastasis, metabolic reprogramming, drug resistance, and immunoregulation that collectively influence tumor behavior with implications for the development of innovative and more efficacious therapeutic modalities.
基金supported by the Physician-Scientist Early Investigator Program at National Cancer Institute,National Institute of Health(ZIA BC 011888)。
文摘Background:Cholangiocarcinoma(CCA)is one of the primary hepatobiliary malignant neoplasms with only 10%of 5-year survival rate.Promising immunotherapy with the blockade of immune checkpoints has no clear benefit in CCA.The inhibition of YAP1 signaling by verteporfin has shown encouraging results by inhibiting cell proliferation and inducing apoptosis.This study aimed to evaluate the potential benefit of the combination of verteporfin and anti-programmed cell death 1(PD-1)in CCA mouse model.Methods:We assessed the cytotoxicity of verteporfin in human CCA cell lines in vitro,including both intrahepatic CCA and extrahepatic CCA cells.We examined the in vitro effect of verteporfin on cell proliferation,apoptosis,and stemness.We evaluated the in vivo efflcacy of verteporfin,anti-PD-1,and a combination of both in subcutaneous CCA mouse model.Results:Our study showed that verteporfin reduced tumor cell growth and enhanced apoptosis of human CCA tumor cells in vitro in a dose-dependent fashion.Nevertheless,verteporfin impaired stemness evidenced by reduced spheroid formation and colony formation,decreased numbers of cells with aldehyde dehydrogenase activity and positive cancer stem cell markers(all P<0.05).The combination of verteporfin and anti-PD-1 reduced tumor burden in CCA subcutaneous SB1 tumor model compared to either agent alone.Conclusions:Verteporfin exhibits antitumor effects in both intrahepatic and extrahepatic CCA cell lines and the combination with anti-PD-1 inhibited tumor growth.
文摘Pre-Metastatic Niches(PMNs)result from communications between primary tumors and the microenvironment of future distant metastasis via tumor-derived factors.In this issue of Cancer Cell,Liu et al.show that TLR3 activation in lung epithelial cells by tumor exosomal RNAs triggers neutrophil recruitment,which contributes to PMN formation and metastasis.
基金supported by the Clinical and Translational Science Center at Weill Cornell NIH/NCATS grant ULTR00457(to GG)the NIH T32 Training grant 5T32CA062948-22(to GG)by the National Institutes of Health(NIH)Grants R01 CA137020(to PG)and R01 CA179100(to PG).
文摘The field of circulating tumor cell(CTC)enrichment has seen many emerging technologies in recent years,which have resulted in the identification and monitoring of clinically relevant,CTC-based biomarkers that can be analyzed routinely without invasive procedures.Several molecular platforms have been used to investigate the molecular profile of the disease,from high throughput gene expression analyses down to single cell biological dissection.The established presence of CTC heterogeneity nevertheless constitutes a challenge for cell isolation as the several subpopulations can potentially display different molecular characteristics;in this scenario,careful consideration must be given to the isolation approach,whereas methods that discriminate against certain subpopulations may result in the exclusion of CTCs that carry biological relevance.In the context of prostate cancer,CTC molecular interrogation can enable longitudinal monitoring of key biological features during treatment with substantial clinical impact,as several biomarkers could predict tumor response to AR signaling inhibitors(abiraterone,enzalutamide)or standard chemotherapy(taxanes).Thus,CTCs represent a valuable opportunity to personalize medicine in current clinical practice.
文摘Aim:We reviewed the radiographic response of three patients with metastatic castration-resistant prostate cancer treated with CRXL301,a docetaxel nanoparticle.For these three patients,we isolated and analyzed circulating tumor cells(CTCs)to explore microtubule(MT)drug-target engagement(MT-DTE)as a biomarker of response to treatment.MT-DTE was based on a quantitative assessment of the MT cytoskeleton in CTCs from pre-and posttreatment patient samples as a potential read-out of CRXL301 activity.Methods:We isolated CTCs using negative CD45+depletion and subjected them to multiplex confocal microscopy using our established protocol.CTCs were identified as CD45-/CK+/DAPI+cells and MT-DTE was determined using our developed imaging algorithm.We quantified MT bundling in CTCs across multiple time points,from baseline to on-treatment to disease progression.Here,we describe the longitudinal analysis of MT-DTE in CTCs from patients treated with CRXL301 and its correlation with response to treatment.Results:We collected CTCs at seven time points from three metastatic castration-resistant prostate cancer patients.Clinical response was evaluated by Response Evaluation Criteria in Solid Tumors(RECIST)v.1.1 criteria in those patients with measurable disease.Of the three patients enrolled,one experienced partial response(-50%)to CRXL301 and two patients were unevaluable given bone only disease.Notably,however,these two patients showed stable disease clinically based on bone scans.MT-DTE across all time points revealed that,early time points within four and 24 h of drug administration exhibited the highest levels of drug engagement(MT-DTE)as compared to baseline.However,these early time points did not correlate with clinical response.We observed that the CTCs collected one week after the first or second dose of CRXL301 treatment in the responding patient had numerically higher levels of MT-DTE as compared to the other two patients.Conclusion:Taxane on-target activity can be detected and analyzed quantitatively in CTCs by tubulin immunofluorescence.Early time points,within 24 h of drug administration,showed high levels of DTE but did not correlate with clinical response.MT-DTE in CTCs collected after one week on treatment correlated best with treatment response.The clinical utility of the 1-week CTC DTE should be tested and validated in future clinical trials involving taxanes.
基金A.P.G.is supported by a Susan G.Komen Postdoctoral Fellowship and a Pathway to Independence Award from NCI(K99CA218686)NIH Grants RO1GM51405,RO1CA46595 and RO3CA212562 provide research support for the Blenis laboratory.
文摘The treatment of metastatic cancers remains a challenge in the clinic,with recurrences persisting at high rates even after surgical resection of primary tumors.Beyond the perseverance of circulating tumor cells after resection,this phenomenon is abetted by the formation of the premetastatic niche(PMN),a distant environment ripe for the colonization of new metastases,which is conditioned by factors and extracellular vesicles secreted by the primary tumor.In their recent paper,Lu et al.demonstrate how such PMNs in the lung can be disrupted by low-dose adjuvant epigenetic therapy,and propose a novel therapeutic avenue to supplement tumor resection.
基金supported(as a PI,unless otherwise indicated)by one NIH R01 grant(#CA271915)by two Breakthrough Level 2 grants from the US DoD BCRP(#BC180476P1,#BC210945)+15 种基金by a grant from the STARR Cancer Consortium(#I16-0064)by a Transformative Breast Cancer Consortium Grant from the US DoD BCRP(#W81XWH2120034,PI:Formenti)by a U54 grant from NIH/NCI(#CA274291,PIs:Deasy,Formenti,Weichselbaum)by the 2019 Laura Ziskin Prize in Translational Research(#ZP-6177,PI:Formenti)from the Stand Up to Cancer(SU2C)Foundationby a Mantle Cell Lymphoma Research Initiative(MCL-RI,PI:Chen-Kiang)grant from the Leukemia and Lymphoma Society(LLS)by a Rapid Response Grant from the Functional Genomics Initiative(New York,US)by a pre-SPORE grant(PIs:Demaria,Formenti)a Collaborative Research Initiative Grant and a Clinical Trials Innovation Grant from the Sandra and Edward Meyer Cancer Center(New York,US)by startup funds from the Dept.of Radiation Oncology at Weill Cornell Medicine(New York,US)by industrial collaborations with Lytix Biopharma(Oslo,Norway),Promontory(New York,US)and Onxeo(Paris,France)by donations from Promontory(New York,US)the Luke Heller TECPR2 Foundation(Boston,US),Sotio a.s.(Prague,Czech Republic)Lytix Biopharma(Oslo,Norway)Onxeo(Paris,France)Ricerchiamo(Brescia,Italy)Noxopharm(Chatswood,Australia).
文摘TCDD-inducible poly(ADP-ribose)polymerase(TIPARP,best known as PARP7)has previously been shown to promote oncogenesis by limiting the cytosolic accumulation of potentially interferogenic nucleic acids in malignant cells or the precursors thereof.Recent data indicate that the oncogenic activity of PARP7 is derived at least partially from its ability to suppress apoptotic cell death upon mono-ADP-ribosylation of FOS-like 1,AP-1 transcription factor subunit(FOSL1,best known as FRA1)[1].
基金supported by the Leukemia and Lymphoma Society (Grants No.LLS 9238-16 and MCL7001-18)the National Institutes of Health (Grants No.P01CA214274,R01CA249054 and R01MH117406)the WorldQuant Foundation,NASA (Grants No.80NSSC19K0432,80NSSC22K0254,NNH18ZTT001N-FG2,NNX13AE45G,NNX14AH50G,NNX17AB26G).
文摘Background The Inspiration4(I4)mission,the first all-civilian orbital flight mission,investigated the physiological effects of short-duration spaceflight through a multi-omic approach.Despite advances,there remains much to learn about human adaptation to spaceflight's unique challenges,including microgravity,immune system perturbations,and radiation exposure.Methods To provide a detailed genetics analysis of the mission,we collected dried blood spots pre-,during,and post-flight for DNA extraction.Telomere length was measured by quantitative PCR,while whole genome and cfDNA sequencing provided insight into genomic stability and immune adaptations.A robust bioinformatic pipeline was used for data analysis,including variant calling to assess mutational burden.Result Telomere elongation occurred during spaceflight and shortened after return to Earth.Cell-free DNA analysis revealed increased immune cell signatures post-flight.No significant clonal hematopoiesis of indeterminate potential(CHIP)or whole-genome instability was observed.The long-term gene expression changes across immune cells suggested cellular adaptations to the space environment persisting months post-flight.Conclusion Our findings provide valuable insights into the physiological consequences of short-duration spaceflight,with telomere dynamics and immune cell gene expression adapting to spaceflight and persisting after return to Earth.CHIP sequencing data will serve as a reference point for studying the early development of CHIP in astronauts,an understudied phenomenon as previous studies have focused on career astronauts.This study will serve as a reference point for future commercial and non-commercial spaceflight,low Earth orbit(LEO)missions,and deep-space exploration.
