Cadherin 11 Promotes Immunosuppression and Extracellular Matrix Deposition to Support Growth of Pancreatic Tumors and Resistance to Gemcitabine in Mice

Peran, Ivana; Dakshanamurthy, Sivanesan; McCoy, Matthew; Mavropoulos, Anastasia; Allo, Bedilu; Sebastian, Aimy; Hum, Nicholas R.; Sprague, Sara C.; Martin, Kelly A.; Pishvaian, Michael J.; Vietsch, Eveline E.; Wellstein, Anton; Atkins, Michael B.; Weiner, Louis M.; Quong, Andrew A.; Loots, Gabriela G.; Yoo, Stephen; Assefnia, Shahin; Byers, Stephen W.

doi:10.1053/j.gastro.2020.11.044

Cited by 55 publications

(59 citation statements)

References 70 publications

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“…These findings were validated using IHC analysis of 102 HCC samples. CAFs in the cancer microenvironment are derived from the activation of fibroblasts (Fukino et al, 2004), EMT of epithelial cells (William Petersen et al, 2001;Peran et al, 2020), EMT of endothelial cells (Zeisberg et al, 2007;Xu et al, 2021), and differentiation of bone marrow mesenchymal cells (Quante et al, 2011;Raz et al, 2018). LX2 cells used in this research are spontaneously immortalized stellate cells, while CAFs represent a very heterogeneous cell population with different origins, so we verified the feature of stellate cells of LX2 cells compared with primary HSCs (Supplementary Figure 8A).…”

Section: Discussionsupporting

confidence: 63%

Sulfatase 2-Induced Cancer-Associated Fibroblasts Promote Hepatocellular Carcinoma Progression via Inhibition of Apoptosis and Induction of Epithelial-to-Mesenchymal Transition

Shang

Gai

Song

et al. 2021

Front. Cell Dev. Biol.

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BackgroundSulfatase 2 (SULF2) removes the 6-O-sulfate groups from heparan sulfate proteoglycans (HSPG) and consequently alters the binding sites for various signaling molecules. Here, we elucidated the role of SULF2 in the differentiation of hepatic stellate cells (HSCs) into carcinoma-associated fibroblasts (CAFs) in the hepatocellular carcinoma (HCC) microenvironment and the mechanism underlying CAF-mediated HCC growth.MethodsThe clinical relevance of SULF2 and CAFs was examined using in silico and immunohistochemical (IHC) analyses. Functional studies were performed to evaluate the role of SULF2 in the differentiation of HSCs into CAFs and elucidate the mechanism underlying CAF-mediated HCC growth. Mechanistic studies were performed using the chromatin immunoprecipitation, luciferase reporter, and RNA immunoprecipitation assays. The in vitro findings were verified using the nude HCC xenograft mouse model.ResultsThe Cancer Genome Atlas (TCGA) database and IHC analyses revealed that the expression of CAF markers, which was positively correlated with that of SULF2 in the HCC tissues, predicted unfavorable postsurgical outcomes. Co-culturing HSCs with HCC cells expressing SULF2 promoted CAF differentiation. Additionally, CAFs repressed HCC cell apoptosis by activating the SDF-1/CXCR4/PI3K/AKT signaling pathway. Meanwhile, SULF2-induced CAFs promoted epithelial-to-mesenchymal transition (EMT) of HCC cells by modulating the SDF-1/CXCR4/OIP5-AS1/miR-153-3p/SNAI1 axis. Studies using HCC xenograft mouse models demonstrated that OIP5-AS1 induced EMT by upregulating SNAI1 and promoted HCC growth in vivo.ConclusionThese data indicated that SULF2 secreted by the HCC cells induced the differentiation of HSCs into CAFs through the TGFβ1/SMAD3 signaling pathway. SULF2-induced CAFs attenuated HCC apoptosis by activating the SDF-1/CXCR4/PI3K/AKT signaling pathway and induced EMT through the SDF-1/CXCR4/OIP5-AS1/miR-153-3p/SNAI1 axis. This study revealed a novel mechanism involved in the crosstalk between HCC cells and CAFs in the tumor microenvironment, which can aid in the development of novel and efficient therapeutic strategies for primary liver cancer.

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Section: Discussionsupporting

confidence: 63%

Sulfatase 2-Induced Cancer-Associated Fibroblasts Promote Hepatocellular Carcinoma Progression via Inhibition of Apoptosis and Induction of Epithelial-to-Mesenchymal Transition

Shang

Gai

Song

et al. 2021

Front. Cell Dev. Biol.

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“…CAFs are major components of stromal cells in several tumors and influence the stroma by secreting excess extracellular matrix and interfering with collagen crosslinking, thus modulating tumor stiffness and facilitating cancer progression [ 116 – 121 ]. For example, cadherin 11 promotes extracellular matrix deposition to support the growth of pancreatic carcinoma and resistance to gemcitabine [ 122 ]. Moreover, CAF-derived factors may alter the immune microenvironment by inhibiting immune effector cell activity and recruiting immune-suppressive cells, allowing cancer cells to evade immune surveillance [ 123 – 128 ].…”

Section: Applications Of Single-cell Sequencing In Cancer Biologymentioning

confidence: 99%

Applications of single-cell sequencing in cancer research: progress and perspectives

et al. 2021

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Single-cell sequencing, including genomics, transcriptomics, epigenomics, proteomics and metabolomics sequencing, is a powerful tool to decipher the cellular and molecular landscape at a single-cell resolution, unlike bulk sequencing, which provides averaged data. The use of single-cell sequencing in cancer research has revolutionized our understanding of the biological characteristics and dynamics within cancer lesions. In this review, we summarize emerging single-cell sequencing technologies and recent cancer research progress obtained by single-cell sequencing, including information related to the landscapes of malignant cells and immune cells, tumor heterogeneity, circulating tumor cells and the underlying mechanisms of tumor biological behaviors. Overall, the prospects of single-cell sequencing in facilitating diagnosis, targeted therapy and prognostic prediction among a spectrum of tumors are bright. In the near future, advances in single-cell sequencing will undoubtedly improve our understanding of the biological characteristics of tumors and highlight potential precise therapeutic targets for patients.

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“…It is well known that there is a close relationship between pancreatic fibrosis and PC [ 62 ]. Many pro-fibrotic cells and cancer-associated fibroblasts (CAFs) are abundantly present in PDAC [ 63 ]. Most studies have shown that pancreatic fibrosis level is closely related to the survival rate of the patients after chemotherapy [ 64 , 65 ].…”

Section: The Role Of Fibrosis In Pcmentioning

confidence: 99%

“…The strategy of targeting the interaction between CAFs, the immune system, and cancer cells can enhance the anti-tumor activity. Recently, it has been reported that knockout of the adhesion molecule, cadherin 11 ( CDH11 ), which is mainly produced by CAFs, inhibits the growth of the pancreatic tumor, increases the response to GEM, reverses the immunosuppression of CAFs, and ultimately significantly prolongs the survival of mice [ 63 ].…”

Section: The Role Of Fibrosis In Pcmentioning

confidence: 99%

Targeting Fibrosis: The Bridge That Connects Pancreatitis and Pancreatic Cancer

Huang

Iovanna

Santofimia‐Castaño

2021

IJMS

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Pancreatic fibrosis is caused by the excessive deposits of extracellular matrix (ECM) and collagen fibers during repeated necrosis to repair damaged pancreatic tissue. Pancreatic fibrosis is frequently present in chronic pancreatitis (CP) and pancreatic cancer (PC). Clinically, pancreatic fibrosis is a pathological feature of pancreatitis and pancreatic cancer. However, many new studies have found that pancreatic fibrosis is involved in the transformation from pancreatitis to pancreatic cancer. Thus, the role of fibrosis in the crosstalk between pancreatitis and pancreatic cancer is critical and still elusive; therefore, it deserves more attention. Here, we review the development of pancreatic fibrosis in inflammation and cancer, and we discuss the therapeutic strategies for alleviating pancreatic fibrosis. We further propose that cellular stress response might be a key driver that links fibrosis to cancer initiation and progression. Therefore, targeting stress proteins, such as nuclear protein 1 (NUPR1), could be an interesting strategy for pancreatic fibrosis and PC treatment.

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Cadherin 11 Promotes Immunosuppression and Extracellular Matrix Deposition to Support Growth of Pancreatic Tumors and Resistance to Gemcitabine in Mice

Cited by 55 publications

References 70 publications

Sulfatase 2-Induced Cancer-Associated Fibroblasts Promote Hepatocellular Carcinoma Progression via Inhibition of Apoptosis and Induction of Epithelial-to-Mesenchymal Transition

Sulfatase 2-Induced Cancer-Associated Fibroblasts Promote Hepatocellular Carcinoma Progression via Inhibition of Apoptosis and Induction of Epithelial-to-Mesenchymal Transition

Applications of single-cell sequencing in cancer research: progress and perspectives

Targeting Fibrosis: The Bridge That Connects Pancreatitis and Pancreatic Cancer

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