STIM1/SOX2 proteins are co-expressed in the tumor and microenvironmental stromal cells of pancreatic ductal adenocarcinoma and ampullary carcinoma
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ABSTRACT:
SUBMITTER: Sweed D
PROVIDER: S-EPMC10964627 | biostudies-literature | 2024 Jan
REPOSITORIES: biostudies-literature
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Project description:Desmoplasia describes the deposition of extensive extracellular matrix and defines primary pancreatic ductal adenocarcinoma (PDA). The acellular component of this stroma has been implicated in PDA pathogenesis and is being targeted therapeutically in clinical trials. By analyzing the stromal content of PDA samples from numerous annotated PDA data sets and correlating stromal content with both anatomic site and clinical outcome, we found PDA metastases in the liver, the primary cause of mortality to have less stroma, have higher tumor cellularity than primary tumors. Experimentally manipulating stromal matrix with an anti-lysyl oxidase like-2 (anti-LOXL2) antibody in syngeneic orthotopic PDA mouse models significantly decreased matrix content, led to lower tissue stiffness, lower contrast retention on computed tomography, and accelerated tumor growth, resulting in diminished overall survival. These studies suggest an important protective role of stroma in PDA and urge caution in clinically deploying stromal depletion strategies.
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Project description:Pancreatic ductal adenocarcinoma (PDA) is an extremely metastatic and lethal disease. Here, in both murine and human PDA, we demonstrate that extracellular matrix architecture regulates cell extrusion and subsequent invasion from intact ductal structures through tumor-associated collagen signatures (TACS). This results in early dissemination from histologically premalignant lesions and continual invasion from well-differentiated disease, and it suggests TACS as a biomarker to aid in the pathologic assessment of early disease. Furthermore, we show that pancreatitis results in invasion-conducive architectures, thus priming the stroma prior to malignant disease. Analysis in potentially novel microfluidic-derived microtissues and in vivo demonstrates decreased extrusion and invasion following focal adhesion kinase (FAK) inhibition, consistent with decreased metastasis. Thus, data suggest that targeting FAK or strategies to reengineer and normalize tumor microenvironments may have roles not only in very early disease, but also for limiting continued dissemination from unresectable disease. Likewise, it may be beneficial to employ stroma-targeting strategies to resolve precursor diseases such as pancreatitis in order to remove stromal architectures that increase risk for early dissemination.
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Project description:Background: Sensitive and specific non-invasive biomarkers are urgently needed in order to improve the survival of patients with pancreatic ductal adenocarcinoma (PDAC), which is the fourth leading cause of cancer-related death. We aim to identify serum hub miRNAs as potential diagnostic and prognostic biomarkers for PDAC. Methods: A total of 2578 serum miRNA expression data from 88 PDAC patients and 19 healthy subjects were downloaded from the Gene Expression Omnibus database. Weighted gene co-expression network analysis (WGCNA) was constructed and significant modules were extracted from the network by WGCNA R package. Network modules and hub miRNAs closely related to PDAC were identified. The prognostic value of hub miRNAs was assessed by Kaplan-Meier overall survival analysis. Results: Two modules strongly associated with PDAC were identified by WGCNA, which were labeled as turquoise and brown respectively. Within each module, twenty hub miRNAs were found. At the functional level, turquoise module was mainly associated with tumorigenesis pathways such as P53 and WNT signaling pathway, while the brown module was mostly related to the pathways of cancer such as RNA transport and MAPK signaling pathway. Utilizing overall survival analyses, five "real" miRNAs were able to stratify PDAC patients into low-risk and high-risk groups. Conclusions: The association of specific Hub miRNAs with the development of pancreatic cancer was established by WGCNA analysis. Five miRNAs (mir-16-2-3p, mir-890, mir-3201, mir-602, and mir-877) were identified as potential diagnostic and prognostic biomarkers for PDAC.
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Project description:Pancreatic ductal adenocarcinoma (PDAC) remains a lethal cancer. The poor prognosis calls for a more detailed understanding of disease biology in order to pave the way for the development of effective therapies. Typically, the pancreatic tumor is composed of a minority of malignant cells within an excessive tumor microenvironment (TME) consisting of extracellular matrix (ECM), fibroblasts, immune cells, and endothelial cells. Research conducted in recent years has particularly focused on cancer-associated fibroblasts (CAFs) which represent the most prominent cellular component of the desmoplastic stroma. Here, we review the complex crosstalk between CAFs, tumor cells, and other components of the TME, and illustrate how these interactions drive disease progression. We also discuss the emerging field of CAF heterogeneity, their tumor-supportive versus tumor-suppressive capacity, and the consequences for designing stroma-targeted therapies in the future.
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Project description:Pancreatic cancer is a highly lethal disease. Conventional therapeutics targeting pancreas cancer cell compartment using cytotoxics improved patient survival but at the expense of significant toxicity. Microscopically, the tumor is characterized by thick desmoplastic stroma that surrounds islands of pancreatic cancer cells. The tumor microenvironment has been found to play important roles in carcinogenesis, the development of drug resistance, and mediating immunosuppression. The understanding the tumor-stromal interaction has led to the development of novel therapeutic approaches. Here, we review the strategies that are currently in (or, near to) clinical evaluation and the underlying preclinical rationales.
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Project description:The incidence and death rate of pancreatic ductal adenocarcinoma (PDAC) have increased in recent years, therefore the identification of novel targets for treatment is extremely important. Interactions between cancer and stromal cells are critically involved in tumour formation and development of metastasis. Here we report that PDAC cells secrete BAG3, which binds and activates macrophages, inducing their activation and the secretion of PDAC supporting factors. We also identify IFITM-2 as a BAG3 receptor and show that it signals through PI3K and the p38 MAPK pathways. Finally, we show that the use of an anti-BAG3 antibody results in reduced tumour growth and prevents metastasis formation in three different mouse models. In conclusion, we identify a paracrine loop involved in PDAC growth and metastatic spreading, and show that an anti-BAG3 antibody has therapeutic potential.
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is characterized by a prominent stromal reaction that has been variably implicated in both tumor growth and tumor suppression. B-lymphocytes have been recently implicated in PDAC progression but their contribution to the characteristic stromal desmoplasia has never been assessed before. In the present work, we aimed to verify whether B-lymphocytes contribute to stromal cell activation in PDAC. CD19+ B-lymphocytes purified from peripheral blood of patients with PDAC were cultivated in the presence of human pancreatic fibroblasts and cancer-associated fibroblasts. Released pro-fibrotic soluble factors and collagen production were assessed by ELISA and Luminex assays. Quantitative RT-PCR was used to assess fibroblast activation in the presence of B cells. The expression of selected pro-fibrotic and inflammatory molecules was confirmed on PDAC tissue sections by multi-color immunofluorescence studies. We herein demonstrate that B-cells from PDAC patients (i) produce the pro-fibrotic molecule PDGF-B and stimulate collagen production by fibroblasts; (ii) express enzymes implicated in extracellular matrix remodeling including LOXL2; and (iii) produce the chemotactic factors CCL-4, CCL-5, and CCL-11. In addition we demonstrate that circulating plasmablasts are expanded in the peripheral blood of patients with PDAC, stimulate collagen production by fibroblasts, and infiltrate pancreatic lesions. Our results indicate that PDAC is characterized by perturbations of the B-cell compartment with expansion of B-lymphocyte subsets that directly contribute to the stromal reaction observed at disease site. These findings provide an additional rationale for modulating B-cell activity in patients with pancreatic cancer.
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Project description:New quantitative prognostic markers are needed for improved pancreatic ductal adenocarcinoma (PDAC) prognosis. Second harmonic generation microscopy has been used to show that collagen fiber alignment in PDAC is a negative prognostic factor. In this work, a series of PDAC and normal adjacent tissue (NAT) biopsies were imaged with spatial light interference microscopy (SLIM). Quantitative analysis performed on the biopsy SLIM images show that PDAC fiber structures have lower alignment per unit length, narrower width, and are longer than NAT controls. Importantly, fibrillar collagen in PDAC shows an inverse relationship between survival data and fiber width and length (p?<?0.05).
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Project description:Purpose: Pancreatic ductal adenocarcinoma (PDAC) is associated with an immunosuppressive milieu that supports immune system evasion and disease progression. Here, we interrogated genetic, stromal, and immunologic features of PDAC to delineate impact on prognosis and means to more effectively employ immunotherapy.Experimental Design: A cohort of 109 PDAC cases annotated for overall survival was utilized as a primary discovery cohort. Gene expression analysis defined immunologic subtypes of PDAC that were confirmed in the Cancer Genome Atlas dataset. Stromal and metabolic characteristics of PDAC cases were evaluated by histologic analysis and immunostaining. Enumeration of lymphocytes, as well as staining for CD8, FOXP3, CD68, CD163, PDL1, and CTLA4 characterized immune infiltrate. Neoantigens were determined by analysis of whole-exome sequencing data. Random-forest clustering was employed to define multimarker subtypes, with univariate and multivariate analyses interrogating prognostic significance.Results: PDAC cases exhibited distinct stromal phenotypes that were associated with prognosis, glycolytic and hypoxic biomarkers, and immune infiltrate composition. Immune infiltrate was diverse among PDAC cases and enrichment for M2 macrophages and select immune checkpoints regulators were specifically associated with survival. Composite analysis with neoantigen burden, immunologic, and stromal features defined novel subtypes of PDAC that could have bearing on sensitivity to immunologic therapy approaches. In addition, a subtype with low levels of neoantigens and minimal lymphocyte infiltrate was associated with improved overall survival.Conclusions: The mutational burden of PDAC is associated with distinct immunosuppressive mechanisms that are conditioned by the tumor stromal environment. The defined subtypes have significance for utilizing immunotherapy in the treatment of PDAC. Clin Cancer Res; 23(15); 4429-40. ©2017 AACR.
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Project description:Sonic hedgehog (Shh), a soluble ligand overexpressed by neoplastic cells in pancreatic ductal adenocarcinoma (PDAC), drives formation of a fibroblast-rich desmoplastic stroma. To better understand its role in malignant progression, we deleted Shh in a well-defined mouse model of PDAC. As predicted, Shh-deficient tumors had reduced stromal content. Surprisingly, such tumors were more aggressive and exhibited undifferentiated histology, increased vascularity, and heightened proliferation--features that were fully recapitulated in control mice treated with a Smoothened inhibitor. Furthermore, administration of VEGFR blocking antibody selectively improved survival of Shh-deficient tumors, indicating that Hedgehog-driven stroma suppresses tumor growth in part by restraining tumor angiogenesis. Together, these data demonstrate that some components of the tumor stroma can act to restrain tumor growth.
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