The Experts below are selected from a list of 1248 Experts worldwide ranked by ideXlab platform
Cosimo Commisso - One of the best experts on this subject based on the ideXlab platform.
-
human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein
Cancer Research, 2015Co-Authors: Jurre J Kamphorst, Michel Nofal, Cosimo Commisso, Elda Grabocka, Sean R Hackett, Wenyun Lu, Matthew Vander G Heiden, George Miller, Jeffrey A DrebinAbstract:Glucose and amino acids are key nutrients supporting cell growth. Amino acids are imported as monomers, but an alternative route induced by oncogenic KRAS involves uptake of extracellular proteins via macropinocytosis and subsequent lysosomal degradation of these proteins as a source of amino acids. In this study, we examined the metabolism of pancreatic ductal adenocarcinoma (PDAC), a poorly vascularized lethal KRAS-driven malignancy. Metabolomic comparisons of human PDAC and benign adjacent tissue revealed that tumor tissue was low in glucose, upper glycolytic intermediates, creatine phosphate, and the amino acids glutamine and serine, two major metabolic substrates. Surprisingly, PDAC accumulated essential amino acids. Such accumulation could arise from extracellular proteins being degraded through macropinocytosis in quantities necessary to meet glutamine requirements, which in turn produces excess of most other amino acids. Consistent with this hypothesis, active macropinocytosis is observed in primary human PDAC specimens. Moreover, in the presence of physiologic albumin, we found that cultured murine PDAC cells grow indefinitely in media lacking single essential amino acids and replicate once in the absence of free amino acids. Growth under these conditions was characterized by simultaneous glutamine depletion and essential amino acid accumulation. Overall, our findings argue that the scavenging of extracellular proteins is an important mode of nutrient uptake in PDAC. Cancer Res; 75(3); 544–53. ©2014 AACR.
-
macropinocytosis of protein is an amino acid supply route in ras transformed cells
Nature, 2013Co-Authors: Cosimo Commisso, Michel Nofal, Shaw M Davidso, Rengi G Soydanerazeloglu, Seth J Parke, Jurre J Kamphors, Sea R Hacke, Elda Grabocka, Jeffrey A Drebi, Craig ThompsoAbstract:Macropinocytosis is a highly conserved endocytic process by which extracellular fluid and its contents are internalized into cells through large, heterogeneous vesicles known as macropinosomes. Oncogenic Ras proteins have been shown to stimulate macropinocytosis but the functional contribution of this uptake mechanism to the transformed phenotype remains unknown. Here we show that Ras-transformed cells use macropinocytosis to transport extracellular protein into the cell. The internalized protein undergoes proteolytic degradation, yielding amino acids including glutamine that can enter central carbon metabolism. Accordingly, the dependence of Ras-transformed cells on free extracellular glutamine for growth can be suppressed by the macropinocytic uptake of protein. Consistent with macropinocytosis representing an important route of nutrient uptake in tumours, its pharmacological inhibition compromises the growth of Ras-transformed pancreatic tumour xenografts. These results identify macropinocytosis as a mechanism by which cancer cells support their unique metabolic needs and point to the possible exploitation of this process in the design of anticancer therapies.
-
macropinocytosis of protein is an amino acid supply route in ras transformed cells
Nature, 2013Co-Authors: Cosimo Commisso, Michel Nofal, Rengi G Soydanerazeloglu, Elda Grabocka, Shawn M Davidson, Seth J Parker, Jurre J Kamphorst, Sean R Hackett, Jeffrey A Drebin, Craig B ThompsonAbstract:Oncogenic Ras has previously been shown to promote macropinocytosis; here it is demonstrated that this process allows tumour cells to use extracellular proteins to generate amino acids necessary to support tumour growth. This paper describes a previously unrecognized pathway of nutrient supply to cancer cells. Oncogenic Ras proteins are known to promote macropinocytosis, an endocytic process by which extracellular fluid and its contents are internalized into cells through vesicles known as macropinosomes. Dafna Bar-Sagi and colleagues now demonstrate that Ras-transformed cells can use this process to 'feed' on extracellular protein. The macropinocytosed protein undergoes degradation, giving rise to free amino acids necessary to support tumour growth. This finding suggests that inhibition of macropinocytosis may be effective against a subset of cancers. Macropinocytosis is a highly conserved endocytic process by which extracellular fluid and its contents are internalized into cells through large, heterogeneous vesicles known as macropinosomes. Oncogenic Ras proteins have been shown to stimulate macropinocytosis but the functional contribution of this uptake mechanism to the transformed phenotype remains unknown1,2,3. Here we show that Ras-transformed cells use macropinocytosis to transport extracellular protein into the cell. The internalized protein undergoes proteolytic degradation, yielding amino acids including glutamine that can enter central carbon metabolism. Accordingly, the dependence of Ras-transformed cells on free extracellular glutamine for growth can be suppressed by the macropinocytic uptake of protein. Consistent with macropinocytosis representing an important route of nutrient uptake in tumours, its pharmacological inhibition compromises the growth of Ras-transformed pancreatic tumour xenografts. These results identify macropinocytosis as a mechanism by which cancer cells support their unique metabolic needs and point to the possible exploitation of this process in the design of anticancer therapies.
Michel Nofal - One of the best experts on this subject based on the ideXlab platform.
-
mtor inhibition restores amino acid balance in cells dependent on catabolism of extracellular protein
Molecular Cell, 2017Co-Authors: Michel Nofal, Kevin Zhang, Joshua D RabinowitzAbstract:Summary Scavenging of extracellular protein via macropinocytosis is an alternative to monomeric amino acid uptake. In pancreatic cancer, macropinocytosis is driven by oncogenic Ras signaling and contributes substantially to amino acid supply. While Ras signaling promotes scavenging, mTOR signaling suppresses it. Here, we present an integrated experimental-computational method that enables quantitative comparison of protein scavenging rates across cell lines and conditions. Using it, we find that, independently of mTORC1, amino acid scarcity induces protein scavenging and that under such conditions the impact of mTOR signaling on protein scavenging rate is minimal. Nevertheless, mTOR inhibition promotes growth of cells reliant on eating extracellular protein. This growth enhancement depends on mTORC1's canonical function in controlling translation rate: mTOR inhibition slows translation, thereby matching protein synthesis to the limited amino acid supply. Thus, paradoxically, in amino acid-poor conditions the pro-anabolic effects of mTORC1 are functionally opposed to growth.
-
human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein
Cancer Research, 2015Co-Authors: Jurre J Kamphorst, Michel Nofal, Cosimo Commisso, Elda Grabocka, Sean R Hackett, Wenyun Lu, Matthew Vander G Heiden, George Miller, Jeffrey A DrebinAbstract:Glucose and amino acids are key nutrients supporting cell growth. Amino acids are imported as monomers, but an alternative route induced by oncogenic KRAS involves uptake of extracellular proteins via macropinocytosis and subsequent lysosomal degradation of these proteins as a source of amino acids. In this study, we examined the metabolism of pancreatic ductal adenocarcinoma (PDAC), a poorly vascularized lethal KRAS-driven malignancy. Metabolomic comparisons of human PDAC and benign adjacent tissue revealed that tumor tissue was low in glucose, upper glycolytic intermediates, creatine phosphate, and the amino acids glutamine and serine, two major metabolic substrates. Surprisingly, PDAC accumulated essential amino acids. Such accumulation could arise from extracellular proteins being degraded through macropinocytosis in quantities necessary to meet glutamine requirements, which in turn produces excess of most other amino acids. Consistent with this hypothesis, active macropinocytosis is observed in primary human PDAC specimens. Moreover, in the presence of physiologic albumin, we found that cultured murine PDAC cells grow indefinitely in media lacking single essential amino acids and replicate once in the absence of free amino acids. Growth under these conditions was characterized by simultaneous glutamine depletion and essential amino acid accumulation. Overall, our findings argue that the scavenging of extracellular proteins is an important mode of nutrient uptake in PDAC. Cancer Res; 75(3); 544–53. ©2014 AACR.
-
macropinocytosis of protein is an amino acid supply route in ras transformed cells
Nature, 2013Co-Authors: Cosimo Commisso, Michel Nofal, Shaw M Davidso, Rengi G Soydanerazeloglu, Seth J Parke, Jurre J Kamphors, Sea R Hacke, Elda Grabocka, Jeffrey A Drebi, Craig ThompsoAbstract:Macropinocytosis is a highly conserved endocytic process by which extracellular fluid and its contents are internalized into cells through large, heterogeneous vesicles known as macropinosomes. Oncogenic Ras proteins have been shown to stimulate macropinocytosis but the functional contribution of this uptake mechanism to the transformed phenotype remains unknown. Here we show that Ras-transformed cells use macropinocytosis to transport extracellular protein into the cell. The internalized protein undergoes proteolytic degradation, yielding amino acids including glutamine that can enter central carbon metabolism. Accordingly, the dependence of Ras-transformed cells on free extracellular glutamine for growth can be suppressed by the macropinocytic uptake of protein. Consistent with macropinocytosis representing an important route of nutrient uptake in tumours, its pharmacological inhibition compromises the growth of Ras-transformed pancreatic tumour xenografts. These results identify macropinocytosis as a mechanism by which cancer cells support their unique metabolic needs and point to the possible exploitation of this process in the design of anticancer therapies.
-
macropinocytosis of protein is an amino acid supply route in ras transformed cells
Nature, 2013Co-Authors: Cosimo Commisso, Michel Nofal, Rengi G Soydanerazeloglu, Elda Grabocka, Shawn M Davidson, Seth J Parker, Jurre J Kamphorst, Sean R Hackett, Jeffrey A Drebin, Craig B ThompsonAbstract:Oncogenic Ras has previously been shown to promote macropinocytosis; here it is demonstrated that this process allows tumour cells to use extracellular proteins to generate amino acids necessary to support tumour growth. This paper describes a previously unrecognized pathway of nutrient supply to cancer cells. Oncogenic Ras proteins are known to promote macropinocytosis, an endocytic process by which extracellular fluid and its contents are internalized into cells through vesicles known as macropinosomes. Dafna Bar-Sagi and colleagues now demonstrate that Ras-transformed cells can use this process to 'feed' on extracellular protein. The macropinocytosed protein undergoes degradation, giving rise to free amino acids necessary to support tumour growth. This finding suggests that inhibition of macropinocytosis may be effective against a subset of cancers. Macropinocytosis is a highly conserved endocytic process by which extracellular fluid and its contents are internalized into cells through large, heterogeneous vesicles known as macropinosomes. Oncogenic Ras proteins have been shown to stimulate macropinocytosis but the functional contribution of this uptake mechanism to the transformed phenotype remains unknown1,2,3. Here we show that Ras-transformed cells use macropinocytosis to transport extracellular protein into the cell. The internalized protein undergoes proteolytic degradation, yielding amino acids including glutamine that can enter central carbon metabolism. Accordingly, the dependence of Ras-transformed cells on free extracellular glutamine for growth can be suppressed by the macropinocytic uptake of protein. Consistent with macropinocytosis representing an important route of nutrient uptake in tumours, its pharmacological inhibition compromises the growth of Ras-transformed pancreatic tumour xenografts. These results identify macropinocytosis as a mechanism by which cancer cells support their unique metabolic needs and point to the possible exploitation of this process in the design of anticancer therapies.
U Sahin - One of the best experts on this subject based on the ideXlab platform.
-
Uptake of synthetic naked RNA by skin-resident dendritic cells via macropinocytosis allows antigen expression and induction of T-cell responses in mice
Cancer Immunology Immunotherapy, 2016Co-Authors: A Selmi, M Diken, Ö Türeci, U Sahin, Fulvia Vascotto, Kordula Kautz-neu, Esther Stebut, S KreiterAbstract:Intradermal administration of antigen-encoding RNA has entered clinical testing for cancer vaccination. However, insight into the underlying mechanism of RNA uptake, translation and antigen presentation is still limited. Utilizing pharmacologically optimized naked RNA, the dose–response kinetics revealed a rise in reporter signal with increasing RNA amounts and a prolonged RNA translation of reporter protein up to 30 days after intradermal injection. Dendritic cells (DCs) in the dermis were shown to engulf RNA, and the signal arising from the reporter RNA was significantly diminished after DC depletion. Macropinocytosis was relevant for intradermal RNA uptake and translation in vitro and in vivo. By combining intradermal RNA vaccination and inhibition of macropinocytosis, we show that effective priming of antigen-specific CD8^+ T-cells also relies on this uptake mechanism. This report demonstrates that direct antigen translation by dermal DCs after intradermal naked RNA vaccination is relevant for efficient priming of antigen-specific T-cells.
-
Selective uptake of naked vaccine RNA by dendritic cells is driven by macropinocytosis and abrogated upon DC maturation
Gene Therapy, 2011Co-Authors: M Diken, S Kreiter, A Selmi, C M Britten, C Huber, Ö Türeci, U SahinAbstract:Even though it is known for more than one decade that antigen-encoding RNA can deliver antigenic information to induce antigen-specific immunity against cancer, the nature and mechanism of RNA uptake have remained enigmatic. In this study, we investigated the pharmacokinetics of naked RNA administered into the lymph node. We observed that RNA is rapidly and selectively uptaken by lymph node dendritic cells (DCs). Furthermore, in vitro and in vivo studies revealed that the efficient internalization of RNA by human and murine DCs is primarily driven by macropinocytosis. Selective inhibition of macropinocytosis by compounds or as a consequence of DC maturation abrogated RNA internalization and delivery of encoded antigens. Our findings imply that bioavailability of recombinant RNA vaccines in vivo highly depends on the density and the maturation stage of DCs at the administration site and are of importance for the design of RNA-based clinical immunotherapy protocols.
Elda Grabocka - One of the best experts on this subject based on the ideXlab platform.
-
human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein
Cancer Research, 2015Co-Authors: Jurre J Kamphorst, Michel Nofal, Cosimo Commisso, Elda Grabocka, Sean R Hackett, Wenyun Lu, Matthew Vander G Heiden, George Miller, Jeffrey A DrebinAbstract:Glucose and amino acids are key nutrients supporting cell growth. Amino acids are imported as monomers, but an alternative route induced by oncogenic KRAS involves uptake of extracellular proteins via macropinocytosis and subsequent lysosomal degradation of these proteins as a source of amino acids. In this study, we examined the metabolism of pancreatic ductal adenocarcinoma (PDAC), a poorly vascularized lethal KRAS-driven malignancy. Metabolomic comparisons of human PDAC and benign adjacent tissue revealed that tumor tissue was low in glucose, upper glycolytic intermediates, creatine phosphate, and the amino acids glutamine and serine, two major metabolic substrates. Surprisingly, PDAC accumulated essential amino acids. Such accumulation could arise from extracellular proteins being degraded through macropinocytosis in quantities necessary to meet glutamine requirements, which in turn produces excess of most other amino acids. Consistent with this hypothesis, active macropinocytosis is observed in primary human PDAC specimens. Moreover, in the presence of physiologic albumin, we found that cultured murine PDAC cells grow indefinitely in media lacking single essential amino acids and replicate once in the absence of free amino acids. Growth under these conditions was characterized by simultaneous glutamine depletion and essential amino acid accumulation. Overall, our findings argue that the scavenging of extracellular proteins is an important mode of nutrient uptake in PDAC. Cancer Res; 75(3); 544–53. ©2014 AACR.
-
macropinocytosis of protein is an amino acid supply route in ras transformed cells
Nature, 2013Co-Authors: Cosimo Commisso, Michel Nofal, Shaw M Davidso, Rengi G Soydanerazeloglu, Seth J Parke, Jurre J Kamphors, Sea R Hacke, Elda Grabocka, Jeffrey A Drebi, Craig ThompsoAbstract:Macropinocytosis is a highly conserved endocytic process by which extracellular fluid and its contents are internalized into cells through large, heterogeneous vesicles known as macropinosomes. Oncogenic Ras proteins have been shown to stimulate macropinocytosis but the functional contribution of this uptake mechanism to the transformed phenotype remains unknown. Here we show that Ras-transformed cells use macropinocytosis to transport extracellular protein into the cell. The internalized protein undergoes proteolytic degradation, yielding amino acids including glutamine that can enter central carbon metabolism. Accordingly, the dependence of Ras-transformed cells on free extracellular glutamine for growth can be suppressed by the macropinocytic uptake of protein. Consistent with macropinocytosis representing an important route of nutrient uptake in tumours, its pharmacological inhibition compromises the growth of Ras-transformed pancreatic tumour xenografts. These results identify macropinocytosis as a mechanism by which cancer cells support their unique metabolic needs and point to the possible exploitation of this process in the design of anticancer therapies.
-
macropinocytosis of protein is an amino acid supply route in ras transformed cells
Nature, 2013Co-Authors: Cosimo Commisso, Michel Nofal, Rengi G Soydanerazeloglu, Elda Grabocka, Shawn M Davidson, Seth J Parker, Jurre J Kamphorst, Sean R Hackett, Jeffrey A Drebin, Craig B ThompsonAbstract:Oncogenic Ras has previously been shown to promote macropinocytosis; here it is demonstrated that this process allows tumour cells to use extracellular proteins to generate amino acids necessary to support tumour growth. This paper describes a previously unrecognized pathway of nutrient supply to cancer cells. Oncogenic Ras proteins are known to promote macropinocytosis, an endocytic process by which extracellular fluid and its contents are internalized into cells through vesicles known as macropinosomes. Dafna Bar-Sagi and colleagues now demonstrate that Ras-transformed cells can use this process to 'feed' on extracellular protein. The macropinocytosed protein undergoes degradation, giving rise to free amino acids necessary to support tumour growth. This finding suggests that inhibition of macropinocytosis may be effective against a subset of cancers. Macropinocytosis is a highly conserved endocytic process by which extracellular fluid and its contents are internalized into cells through large, heterogeneous vesicles known as macropinosomes. Oncogenic Ras proteins have been shown to stimulate macropinocytosis but the functional contribution of this uptake mechanism to the transformed phenotype remains unknown1,2,3. Here we show that Ras-transformed cells use macropinocytosis to transport extracellular protein into the cell. The internalized protein undergoes proteolytic degradation, yielding amino acids including glutamine that can enter central carbon metabolism. Accordingly, the dependence of Ras-transformed cells on free extracellular glutamine for growth can be suppressed by the macropinocytic uptake of protein. Consistent with macropinocytosis representing an important route of nutrient uptake in tumours, its pharmacological inhibition compromises the growth of Ras-transformed pancreatic tumour xenografts. These results identify macropinocytosis as a mechanism by which cancer cells support their unique metabolic needs and point to the possible exploitation of this process in the design of anticancer therapies.
S Kreiter - One of the best experts on this subject based on the ideXlab platform.
-
Uptake of synthetic naked RNA by skin-resident dendritic cells via macropinocytosis allows antigen expression and induction of T-cell responses in mice
Cancer Immunology Immunotherapy, 2016Co-Authors: A Selmi, M Diken, Ö Türeci, U Sahin, Fulvia Vascotto, Kordula Kautz-neu, Esther Stebut, S KreiterAbstract:Intradermal administration of antigen-encoding RNA has entered clinical testing for cancer vaccination. However, insight into the underlying mechanism of RNA uptake, translation and antigen presentation is still limited. Utilizing pharmacologically optimized naked RNA, the dose–response kinetics revealed a rise in reporter signal with increasing RNA amounts and a prolonged RNA translation of reporter protein up to 30 days after intradermal injection. Dendritic cells (DCs) in the dermis were shown to engulf RNA, and the signal arising from the reporter RNA was significantly diminished after DC depletion. Macropinocytosis was relevant for intradermal RNA uptake and translation in vitro and in vivo. By combining intradermal RNA vaccination and inhibition of macropinocytosis, we show that effective priming of antigen-specific CD8^+ T-cells also relies on this uptake mechanism. This report demonstrates that direct antigen translation by dermal DCs after intradermal naked RNA vaccination is relevant for efficient priming of antigen-specific T-cells.
-
Selective uptake of naked vaccine RNA by dendritic cells is driven by macropinocytosis and abrogated upon DC maturation
Gene Therapy, 2011Co-Authors: M Diken, S Kreiter, A Selmi, C M Britten, C Huber, Ö Türeci, U SahinAbstract:Even though it is known for more than one decade that antigen-encoding RNA can deliver antigenic information to induce antigen-specific immunity against cancer, the nature and mechanism of RNA uptake have remained enigmatic. In this study, we investigated the pharmacokinetics of naked RNA administered into the lymph node. We observed that RNA is rapidly and selectively uptaken by lymph node dendritic cells (DCs). Furthermore, in vitro and in vivo studies revealed that the efficient internalization of RNA by human and murine DCs is primarily driven by macropinocytosis. Selective inhibition of macropinocytosis by compounds or as a consequence of DC maturation abrogated RNA internalization and delivery of encoded antigens. Our findings imply that bioavailability of recombinant RNA vaccines in vivo highly depends on the density and the maturation stage of DCs at the administration site and are of importance for the design of RNA-based clinical immunotherapy protocols.