CD74 promotes perineural invasion of cancer cells and mediates neuroplasticity via the AKT/EGR-1/GDNF axis in pancreatic ductal adenocarcinoma

Zhang, Junfeng; Tao, Ling‐Ye; Yang, Minwei; Xu, Dapeng; Jiang, Shu-Heng; Fu, Xueliang; Liu, Dejun; Huo, Yan‐Miao; Liu, Wei; Yang, Jianyu; Hua, Rong; Lü, Ping; Sun, Yongwei

doi:10.1016/j.canlet.2021.03.016

Cited by 35 publications

(20 citation statements)

References 46 publications

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“…The assessment of differentially expressed genes and transcriptional regulatory networks between NKX6-2 positive and negative spots within LG IPMNs were quite revealing in this regard. For example, epilesional spots with minimal NKX6-2 expression in LG IPMNs showed higher levels of PDAC-associated markers, such as CD74, CXCL2, LY6E , and CLDN4 , as well as KRT17 , a marker of the aggressive basal subtype of PDAC, pointing to a transcriptional reprogramming away from the indolent NKX6-2-expressing epithelium (18,27,28,31). On the other hand, enrichment of the classical-like signature was observed in spots with high NKX6-2 expression, with higher levels of GATA6 staining quantified in NKX6-2-expressing nuclei by cyclic IF (15,30).…”

Section: Discussionmentioning

confidence: 99%

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Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of The Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential

Sans

Makino

Min

et al. 2022

Preprint

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Intraductal Papillary Mucinous Neoplasms (IPMNs) of the pancreas are bona fide precursor lesions of pancreatic ductal adenocarcinoma (PDAC). The most common subtype of IPMNs harbor a gastric foveolar type lining epithelium, and these low-grade mucinous neoplasms are harbingers of IPMNs with high-grade dysplasia and cancer. The molecular underpinning of gastric differentiation in IPMNs is unknown, although identifying drivers of this indolent phenotype might enable opportunities for intercepting progression to high-grade IPMN and cancer. We conducted spatial transcriptomics on a cohort of patient IPMNs, followed by orthogonal and cross species validation studies, which established the transcription factor NKX6-2 as a key determinant of gastric cell identity in low-grade IPMNs. Loss of NKX6-2 expression is a consistent feature of IPMN progression, while restitution of NKX6-2 in murine IPMN lines recapitulates the aforementioned gastric transcriptional program. Our study identifies NKX6-2 as a previously unknown transcription factor driving indolent gastric differentiation in IPMN pathogenesis.

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Section: Discussionmentioning

confidence: 99%

“…4F, S7C). On the other hand, higher expression of CXCL2, CD74, CLDN4, LY6E, and SPP1, many of which have been associated with PDAC progression and neoplastic progression of IPMN (18,(27)(28)(29), was observed in epilesional spots with minimal NKX6-2 expression (Fig. 4F, S7D).…”

Section: Elevated Epithelial Nkx6-2 Expression Is Associated With Gas...mentioning

confidence: 99%

Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of The Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential

Sans

Makino

Min

et al. 2022

Preprint

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“…Importantly, CD74 protein overexpression was detected in some malignant tumors, including cervical squamous cell carcinoma, urothelial bladder carcinoma, and in inflammatory bowel disease [49][50][51]. Zhang et al, 2021 reported that CD74 upregulation promotes the invasive ability of pancreatic ductal adenocarcinoma cells and modulates the expression of GDNF (glial cell-derived neurotrophic factor) via the AKT/EGR-1 pathway, enhancing perineural invasion [52].…”

Section: Discussionmentioning

confidence: 99%

Master Regulators of Epithelial-Mesenchymal Transition and WNT Signaling Pathways in Juvenile Nasopharyngeal Angiofibromas

et al. 2021

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Juvenile nasopharyngeal angiofibroma (JNA) is a rare fibrovascular benign tumor showing an invasive growth pattern and affecting mainly male adolescents. We investigated the role of epithelial–mesenchymal transition (EMT) and WNT signaling pathways in JNA. Gene expression profiles using nine JNA paired with four inferior nasal turbinate samples were interrogated using a customized 2.3K microarray platform containing genes mainly involved in EMT and WNT/PI3K pathways. The expression of selected genes (BCL2, CAV1, CD74, COL4A2, FZD7, ING1, LAMB1, and RAC2) and proteins (BCL2, CAV1, CD74, FZD7, RAF1, WNT5A, and WNT5B) was investigated by RT-qPCR (28 cases) and immunohistochemistry (40 cases), respectively. Among 104 differentially expressed genes, we found a significantly increased expression of COL4A2 and LAMB1 and a decreased expression of BCL2 and RAC2 by RT-qPCR. The immunohistochemistry analysis revealed a low expression of BCL2 and a negative to moderate expression of FZD7 in most samples, while increased CAV1 and RAF1 expression were detected. Moderate to strong CD74 protein expression was observed in endothelial and inflammatory cells. A significant number of JNAs (78%) presented reduced WNT5A and increased WNT5B expression. Overall, the transcript and protein profile indicated the involvement of EMT and WNT pathways in JNA. These candidates are promising druggable targets for treating JNA.

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“…Until now, 3D imaging of PanIN lesions allowed visualisation of glial activation in an early stage of tumorigenesis and demonstrated a 5-fold increase in GFAP+ fibers [ 159 ]. Furthermore, many soluble factors of neurotrophic or axon-guiding nature such as NGF [ 147 , 160 ], brain-derived neurotrophic factor (BDNF) [ 147 , 161 ], neurotrophin 3 (NT-3) [ 147 , 162 ], glial-cell-derived neurotrophic factor (GDNF) [ 163 ], neurturin [ 164 ], artemin [ 165 , 166 ], sonic hedgehog [ 167 , 168 ], SEMA3D [ 169 ], and others are overexpressed by pancreatic tumour cells. SCs are well known to express the same factors in injury settings [ 43 ].…”

Section: Schwann Cell Involvement In Physiology and Disorders Of The ...mentioning

confidence: 99%

Schwann Cells in Digestive System Disorders

Goluba

Kunrade

Riekstiņa

et al. 2022

Cells

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Proper functioning of the digestive system is ensured by coordinated action of the central and peripheral nervous systems (PNS). Peripheral innervation of the digestive system can be viewed as intrinsic and extrinsic. The intrinsic portion is mainly composed of the neurons and glia of the enteric nervous system (ENS), while the extrinsic part is formed by sympathetic, parasympathetic, and sensory branches of the PNS. Glial cells are a crucial component of digestive tract innervation, and a great deal of research evidence highlights the important status of ENS glia in health and disease. In this review, we shift the focus a bit and discuss the functions of Schwann cells (SCs), the glial cells of the extrinsic innervation of the digestive system. For more context, we also provide information on the basic findings regarding the function of innervation in disorders of the digestive organs. We find diverse SC roles described particularly in the mouth, the pancreas, and the intestine. We note that most of the scientific evidence concerns the involvement of SCs in cancer progression and pain, but some research identifies stem cell functions and potential for regenerative medicine.

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CD74 promotes perineural invasion of cancer cells and mediates neuroplasticity via the AKT/EGR-1/GDNF axis in pancreatic ductal adenocarcinoma

Cited by 35 publications

References 46 publications

Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of The Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential

Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms of The Pancreas Identifies NKX6-2 as a Driver of Gastric Differentiation and Indolent Biological Potential

Master Regulators of Epithelial-Mesenchymal Transition and WNT Signaling Pathways in Juvenile Nasopharyngeal Angiofibromas

Schwann Cells in Digestive System Disorders

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