Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA347480 | ENA |
REPOSITORIES: ENA
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Project description:Cancer-associated fibroblasts (CAFs) are one of the most prominent and active components in the pancreatic tumor microenvironment. Our data show that CAFs are critical for PDAC survival upon glutamine deprivation. Specifically, we uncovered a role for nucleosides, which are secreted by CAFs through autophagy in an NUFIP1-depenent manner, increased glucose utilization and promoted growth of PDAC. Moreover, we demonstrate that CAF-derived nucleosides induced glucose consumption under glutamine-deprived conditions and displayed a dependence on MYC. Using an orthotopic mouse model of PDAC, we found that inhibiting nucleoside secretion by targeting NUFIP1 in the stroma reduced tumor weight. This finding highlights a previously unappreciated metabolic network within pancreatic tumors in which diverse nutrients are used to promote growth in an austere tumor microenvironment.
2021-10-19 | GSE185750 | GEO
Project description:There are two major subtype of cells in breast cancer. These cancer cells response differently to glutamine deprivation, here we use one luminal type of breast cancer cell (MCF7) and one basal type of breast cancer cell (MDAMB231) to compare the gene expression differences of these two types of cancer cells in glutamine deprivation. Many cancer cells depend on glutamine for survival and oncogenic transformation. Although targeting glutamine metabolism is proposed as novel therapies, their heterogeneity among different tumors is unknown. Here, we found only basal-type, but not luminal-type breast cancer cells, exhibited phenotypes of glutamine dependency and may benefit from glutamine-targeting therapeutics. The glutamine independence of luminal-type cells is caused by the specific expression of glutamine synthetase (GS), a pattern recapitulated in luminal breast cancers. The co-culture of luminal cells partially rescued the basal cells under glutamine deprivation, suggesting glutamine symbiosis. The luminal-specific expression of GS is directly induced GATA3 and down-regulates glutaminase expression to maintain subtype-specific glutamine metabolism. Collectively, these data indicate the distinct glutamine phenotypes among breast cells and enable the rational design of glutamine targeted therapies. Gene expression analysis in MCF7 and MDAMB231 cultured with or without glutamine for 24h
2012-01-01 | E-GEOD-26370 | biostudies-arrayexpress
Project description:There are two major subtype of cells in breast cancer. These cancer cells response differently to glutamine deprivation, here we use one luminal type of breast cancer cell (MCF7) and one basal type of breast cancer cell (MDAMB231) to compare the gene expression differences of these two types of cancer cells in glutamine deprivation. Many cancer cells depend on glutamine for survival and oncogenic transformation. Although targeting glutamine metabolism is proposed as novel therapies, their heterogeneity among different tumors is unknown. Here, we found only basal-type, but not luminal-type breast cancer cells, exhibited phenotypes of glutamine dependency and may benefit from glutamine-targeting therapeutics. The glutamine independence of luminal-type cells is caused by the specific expression of glutamine synthetase (GS), a pattern recapitulated in luminal breast cancers. The co-culture of luminal cells partially rescued the basal cells under glutamine deprivation, suggesting glutamine symbiosis. The luminal-specific expression of GS is directly induced GATA3 and down-regulates glutaminase expression to maintain subtype-specific glutamine metabolism. Collectively, these data indicate the distinct glutamine phenotypes among breast cells and enable the rational design of glutamine targeted therapies.
2012-01-01 | GSE26370 | GEO
Project description:Metabolic reprogramming is a hallmark of human cancer and cancer-specific metabolism provide opportunities for cancer diagnosis, prognosis, and treatment. However, how metabolic pathways affect the initiation and progression of colorectal cancer remain largely unknown. Here, we showed cysteine is highly enriched in colorectal tumors compared with adjacent non-tumor tissues to promote tumorigenesis of CRC. Both cystine and cysteine imports are essential to maintain intracellular cysteine level and promote tumor growth and survival. Transporter genes of cystine and cysteine are all upregulated in colorectal cancer by tumor microenvironment induced ROS through transcription factor ATF4. Glutathione synthetase GSS is upregulated and increases cysteine to reduced glutathione flux to support tumor growth and survival in colorectal cancer. Depletion of cystine and cysteine by a recombinant cyst(e)inase effectively reduced the growth of colorectal tumors. Moreover, scavenging cystine and cysteine induces autophagy of colorectal cancer cells through mTOR-ULK signaling axis. With this study, we demonstrate that cysteine metabolism is a key signature of CRC metabolic reprogramming and targeting cysteine metabolism might be an effective approach to treat colon cancer.
2023-01-21 | GSE223119 | GEO
Project description:Metabolic reprogramming is a hallmark of human cancer and cancer-specific metabolism provide opportunities for cancer diagnosis, prognosis, and treatment. However, how metabolic pathways affect the initiation and progression of colorectal cancer remain largely unknown. Here, we showed cysteine is highly enriched in colorectal tumors compared with adjacent non-tumor tissues to promote tumorigenesis of CRC. Both cystine and cysteine imports are essential to maintain intracellular cysteine level and promote tumor growth and survival. Transporter genes of cystine and cysteine are all upregulated in colorectal cancer by tumor microenvironment induced ROS through transcription factor ATF4. Glutathione synthetase GSS is upregulated and increases cysteine to reduced glutathione flux to support tumor growth and survival in colorectal cancer. Depletion of cystine and cysteine by a recombinant cyst(e)inase effectively reduced the growth of colorectal tumors. Moreover, scavenging cystine and cysteine induces autophagy of colorectal cancer cells through mTOR-ULK signaling axis. With this study, we demonstrate that cysteine metabolism is a key signature of CRC metabolic reprogramming and targeting cysteine metabolism might be an effective approach to treat colon cancer.
2023-01-21 | GSE223118 | GEO
Project description:Low grade serous ovarian cancer (LGSC) is a rare subtype of ovarian cancer, characterized by a slow growth rate, resistance to current treatment regimens, multiple recurrences and poor survival. LGSC arise from serous borderline tumor (SBT), however the mechanism of transformation is poorly understood. To better understand the biology of serous ovarian tumors, we performed whole proteome profiling of LGSC, SBT and the more common high grade serous (HGSC) ovarian tumors. Proteins associated with the tumor microenvironment were differentially expressed between LGSC and SBT or HGSC. In particular, fibroblast activation protein (FAP), a protein expressed in cancer associated fibroblasts, is abundantly expressed in LGSC. Furthermore, Tregs and M2 macrophages are more abundant in the stroma of LGSC compared to SBT. Together these data suggest that the tumor microenvironment provides a supportive environment for LGSC tumorigenesis and progression, and that targeting the tumor microenvironment of LGSC may be a viable therapeutic strategy.
2024-08-15 | PXD046360 | Pride
Project description:Highly malignant pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant immunosuppressive and fibrotic tumor microenvironment (TME). Future therapeutic attempts therefore demand targeting of both compartments in order to be effective. We show here that Dual Specificity and Tyrosine Phosphorylation-regulated Kinase 1B (DYRK1B) represents a compartment-agnostic anti-cancer target in PDAC. DYRK1B is mainly expressed by pancreatic epithelial cancer cells and modulates the influx and activity of TME-associated macrophages through effects on the cancer cells themselves as well as affecting the tumor secretome. Mechanistically, genetic ablation or pharmacological inhibition of DYRK1B strongly attracts tumoricidal macrophages and in addition downregulates the phagocytosis checkpoint and "don't eat me"-signal CD24 on cancer cells, resulting in enhanced tumor cell phagocytosis. Consequently, tumor cells lacking DYRK1B hardly expand in transplantation experiments despite doing so rapidly in culture. Furthermore, combining a small-molecule DYRK1B-directed therapy with mTOR inhibition and conventional chemotherapy stalls the growth of established tumors and results in significant extension of life span in a highly aggressive autochthonous model of PDAC. In light of DYRK inhibitors currently entering clinical phase testing, our data thus provide a novel and clinically translatable approach targeting the cancer cell compartment and its microenvironment, both.
2024-01-02 | MSV000093747 | MassIVE
Project description:In managing patients with rat sarcoma virus (RAS) wild-type (WT) metastatic colorectal cancer (mCRC), monoclonal antibodies against the epidermal growth factor receptor (EGFR) represent a key therapeutic strategy. However, their limited ongoing effectiveness in this setting underscores the importance of elucidating other factors that affect response, including underlying immunological and metabolic repertoires. An emerging therapeutic target, glutamine metabolism is crucial for cancer cell growth; symbiotically, tumor glutamine demand relative to the microenvironment disadvantages potential anti-tumor immunity. We conducted a phase I/II clinical trial in patients with RAS WT mCRC combining panitumumab, an EGFR inhibitor, and CB-839, a glutaminase inhibitor, hypothesizing that antagonizing glutamine-centric tri-carboxylic acid (TCA) cycle metabolism and mitogen-activated pathway kinase (MAPK)-mediated growth would favor response in well-selected patients. Here, we demonstrate that a novel B cell activation signature, ‘Bscore’ was associated with clinical benefit from combined therapy in patients who previously progressed on anti-EGFR therapy. Patient ‘Bscore’ was positively associated with treatment-induced change in lesion size. Furthermore, patients with lower ‘Bscore’ tended to exhibit greater tumor avidity of glutamine by non-invasive positron emission tomography (PET), suggesting the sensitivity of B cell activation to a glutamine-depleted microenvironment and highlighting future opportunities to enhance immune response in the treatment of mCRC and potentially other glutaminolysis-dependent solid tumors.
2025-01-13 | GSE274551 | GEO
Project description:Cultured cancer cells frequently rely on the consumption of glutamine and its subsequent hydrolysis to glutamate by the mitochondrial enzyme glutaminase (GLS). However, this metabolic addiction can be lost in the tumor microenvironment (TME), rendering GLS inhibitors ineffective in the clinic. Here, we show that seemingly glutamine-addicted breast cancer cells ultimately adapt to chronic glutamine starvation, or targeted GLS inhibition, via the AMPK-mediated upregulation of the serine synthesis pathway (SSP). In this context, the key product of the SSP is not serine itself, but a-ketoglutarate (a-KG). Mechanistically, we find that the phylogenetically distinct transaminase phosphoserine aminotransferase 1 (PSAT1) has a unique capacity for sustained a-KG production when glutamate is severely depleted. Breast cancer cells with intrinsic or acquired resistance to glutamine starvation or GLS inhibition are highly dependent on SSP-supplied a-KG. Accordingly, pharmacological disruption of the SSP prevents adaptation to glutamine blockade, yielding a potent drug synergism that abolishes breast tumor growth in vivo. These findings highlight how metabolic redundancy can be context dependent, with the catalytic properties of different metabolic enzymes that act on the same substrate determining which pathways can support tumor growth in a particular nutrient environment. This in turn has practical consequences for therapies targeting cancer metabolism.
2024-07-05 | GSE263696 | GEO