CD9 identifies pancreatic cancer stem cells and modulates glutamine metabolism to fuel tumour growth

Wang, Victoria M.-Y.; Ferreira, Rute M. M.; Almagro, Jorge; Evan, Theodore; Legrave, Nathalie; Thin, May Zaw; Frith, David; Carvalho, Joana; Barry, David J.; Snijders, Ambrosius P.; Herbert, Eleanor; Nye, Emma; MacRae, James I.; Behrens, Axel

doi:10.1038/s41556-019-0407-1

Cited by 107 publications

(104 citation statements)

References 71 publications

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“…To nd a more speci c marker of AML LSCs, we analyzed three RNA-sequencing data of LSCs and an AML MRD microarray data. From which we chose CD9, the most intensively upregulated membrane molecule, as a candidate marker for AML LSCs, which has been reported to be involved in several types of CSCs, including pancreatic cancer stem cells, breast cancer stem cells, ovarian cancer stem cells, glioblastoma stem cells, LSCs in B-acute lymphoblastic leukemia [15,20,22,[45][46].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, it was reported that CD9 plays an important role in cell adhesion, movement, differentiation, proliferation, apoptosis and resistance [15][16][17][18][19]. Although CD9 has been reported to identify cancer stem cells in several types of cancers including pancreatic cancer, glioblastoma and B-acute lymphoblastic leukemia, and is related to the prognosis of AML, biological characteristic and regulatory mechanism of CD9 + AML LSCs remain elucidated [15,[20][21][22].…”

Section: Introductionmentioning

confidence: 99%

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CD9 Defines Acute Myeloid Leukemia Stem Cells and is Regulated by Alpha-2-Macroglobulin

Liu¹,

Wang²,

Zhang³

et al. 2020

Preprint

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Background: Leukemia stem cells (LSCs) are responsible for the initiation, progress and relapse of acute myeloid leukemia (AML). Therefore, the therapy strategy of targeting LSCs is hopeful to eradicate AML. In this study, we aim to identify LSC-specific surface markers and uncover the underlying mechanism of AML LSCs.Methods: Microarray gene expression data were used to investigate the candidate AML-LSC specific markers. CD9 expression was evaluated by flow cytometry in AML cell lines, patients with AML and normal donors. The biological characteristics of CD9-positive (CD9+) cells were analyzed by in vitro proliferation, chemotherapeutic drug resistance, migration and in vivo xenotransplantation assays. The molecular mechanism involved in CD9+ cell function was investigated by gene expression profiling. Effect of alpha-2-macroglobulin (A2M) on CD9+ cells was analyzed by proliferation, drug resistance and migration assays.Results: CD9 as a cell surface protein was specifically expressed on AML LSCs, but almost not expressed on normal hematopoietic stem cells (HSCs). CD9+ cells exhibited more resistance to chemotherapy drugs and higher migration potential than CD9-negative (CD9-) cells. More importantly, CD9+ cells possess the ability to reconstitute human AML in immunocompromised mice and promote tumor growth, suggesting CD9+ cells define the LSC population. Furthermore, we identified A2M plays a crucial role in CD9+ LSCs stemness maintenance. Down-regulation of A2M impairs drug-resistance and migration of CD9+ cells.Conclusion: Our findings suggest that CD9 is a new biomarker of AML LSCs and may serve as a promising therapeutic target.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CD9 Defines Acute Myeloid Leukemia Stem Cells and is Regulated by Alpha-2-Macroglobulin

Liu¹,

Wang²,

Zhang³

et al. 2020

Preprint

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“…In a mouse model targeting the CK19 ductal population to induce PDAC, a population of cells highly expressive of the tetraspanin CD9 were found in the early stages of tumorigenesis. 147 The level of CD9 expression affected the ability of these cells to form organoids and initiate new tumours, and functionally CD9 interacted with the glutamine transporter ASCT2 to enhance glutamine uptake. Tuft cells, identified by the expression of Dclk1, are another cell type to emerge early in the tumorigenic process in GEMMs, and, like gastrointestinal tuft cells, possessed numerous bundles of microtubules and abundant apical cilia.…”

Section: Alisonmentioning

confidence: 99%

The cellular origins of cancer with particular reference to the gastrointestinal tract

Alison

2020

Int J Experimental Path

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Summary Stem cells or their closely related committed progenitor cells are the likely founder cells of most neoplasms. In the continually renewing and hierarchically organized epithelia of the oesophagus, stomach and intestine, homeostatic stem cells are located at the beginning of the cell flux, in the basal layer of the oesophagus, the isthmic region of gastric oxyntic glands and at the bottom of gastric pyloric‐antral glands and colonic crypts. The introduction of mutant oncogenes such as KrasG12D or loss of Tp53 or Apc to specific cell types expressing the likes of Lgr5 and Mist1 can be readily accomplished in genetically engineered mouse models to initiate tumorigenesis. Other origins of cancer are discussed including ‘reserve’ stem cells that may be activated by damage or through disruption of morphogen gradients along the crypt axis. In the liver and pancreas, with little cell turnover and no obvious stem cell markers, the importance of regenerative hyperplasia associated with chronic inflammation to tumour initiation is vividly apparent, though inflammatory conditions in the renewing populations are also permissive for tumour induction. In the liver, hepatocytes, biliary epithelial cells and hepatic progenitor cells are embryologically related, and all can give rise to hepatocellular carcinoma and cholangiocarcinoma. In the exocrine pancreas, both acinar and ductal cells can give rise to pancreatic ductal adenocarcinoma (PDAC), although the preceding preneoplastic states are quite different: acinar‐ductal metaplasia gives rise to pancreatic intraepithelial neoplasia culminating in PDAC, while ducts give rise to PDAC via. mucinous cell metaplasia that may have a polyclonal origin.

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“…Nonetheless, so far their identification and targeting has been difficult due to the lack of specific markers. The recent publication by Wang et al [45] identified the tetraspanin CD9 as a CSC marker for PDAC. Interestingly, CD9 had previously been identified as a CSC marker in glioblastoma [46] and B-cell acute lymphoblastic leukemia [47].…”

Section: Highlighed By M Helena Vasconcelosmentioning

confidence: 99%

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–6

et al. 2019

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CD9 identifies pancreatic cancer stem cells and modulates glutamine metabolism to fuel tumour growth

Cited by 107 publications

References 71 publications

CD9 Defines Acute Myeloid Leukemia Stem Cells and is Regulated by Alpha-2-Macroglobulin

CD9 Defines Acute Myeloid Leukemia Stem Cells and is Regulated by Alpha-2-Macroglobulin

The cellular origins of cancer with particular reference to the gastrointestinal tract

Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes–6

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