The Extracellular Matrix and Pancreatic Cancer: A Complex Relationship

Weniger, Maximilian; Honselmann, Kim C.; Liss, Andrew S.

doi:10.3390/cancers10090316

Cited by 219 publications

(232 citation statements)

References 150 publications

(205 reference statements)

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“…In contrast, the most upregulated genes in late KIC cancer cells were associated with ribosome, glycolysis/gluconeogenesis, and amino acid biosynthesis, which is highly suggestive of increased translation and metabolically active cancer cells in established KIC tumors. Interestingly, pathways previously reported to be closely associated with the stroma and progression of PDA were also highlighted, such as ECM-receptor interaction [12], TGFß [13], and hippo signaling pathways [14]. We then compared early KIC cancer cells with the late KIC epithelial cancer cell population to understand the mechanisms that promoted the progression of PDA in the epithelial cancer cell compartment.…”

Section: Resultsmentioning

confidence: 99%

Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution

Hosein

Huang

Wang

et al. 2019

Preprint

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Background & AimsPancreatic ductal adenocarcinoma (PDA) is a major cause of cancer-related death with limited therapeutic options available. This highlights the need for improved understanding of the biology of PDA progression. The progression of PDA is a highly complex and dynamic process featuring changes in cancer cells and stromal cells; however, a comprehensive characterization of PDA cancer cell and stromal cell heterogeneity during disease progression is lacking. In this study, we aimed to profile cell populations and understand their phenotypic changes during PDA progression.MethodsWe employed single-cell RNA sequencing technology to agnostically profile cell heterogeneity during different stages of PDA progression in genetically engineered mouse models.ResultsOur data indicate that an epithelial-to-mesenchymal transition of cancer cells accompanies tumor progression. We also found distinct populations of macrophages with increasing inflammatory features during PDA progression. In addition, we noted the existence of three distinct molecular subtypes of fibroblasts in the normal mouse pancreas, which ultimately gave rise to two distinct populations of fibroblasts in advanced PDA, supporting recent reports on intratumoral fibroblast heterogeneity. Our data also suggest that cancer cells and fibroblasts are dynamically regulated by epigenetic mechanisms.ConclusionThis study systematically outlines the landscape of cellular heterogeneity during the progression of PDA. It strongly improves our understanding of the PDA biology and has the potential to aid in the development of therapeutic strategies against specific cell populations of the disease.

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Section: Resultsmentioning

confidence: 99%

Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution

Hosein

Huang

Wang

et al. 2019

Preprint

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“…The attribution of these two bands is not univocal, since they are associated to bending modes of aliphatic chains in proteins and lipids. Since PDAC has a dense fibrotic stroma, mainly composed of collagen, which impedes the tumor perfusion and the delivery of anticancer drugs , it seems reasonable to associate the detected spectral changes to collagen accumulation. The band at 1170 cm −1 , associated to non‐hydrogen bonds of CO stretching vibrations of glycosylated cellular molecules , is reported in literature as diagnostic of malignancy .…”

Section: Resultsmentioning

confidence: 92%

Investigation of human pancreatic cancer tissues by Fourier Transform Infrared Hyperspectral Imaging

Notarstefano

Conti

Pisani

et al. 2019

Journal of Biophotonics

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Fourier-transform infrared hyperspectral imaging (FTIR-HSI) provides hyperspectral images containing both morphological and chemical information. It is widely applied in the biomedical field to detect tumor lesions, even at the early stage, by identifying specific spectral biomarkers. Pancreatic neoplasms present different prognoses and are not always easily classified by conventional analyses. In this study, tissue samples with diagnosis of pancreatic ductal adenocarcinoma and pancreatic neuroendocrine tumor were analyzed by FTIR-HSI and the spectral data compared with those from healthy and dysplastic samples. Multivariate/univariate approaches were complemented to hyperspectral images, and definite spectral markers of the different lesions identified. The malignant lesions were recognizable both from healthy/dysplastic pancreatic tissues (high values of phospholipids and triglycerides with shorter, more branched and less unsaturated alkyl chains) and between each other (different amounts of total lipids, phosphates and carbohydrates). These findings highlight different metabolic pathways characterizing the different samples, well detectable by FTIR-HSI. K E Y W O R D SFourier transform infrared hyperspectral imaging, multivariate analysis, pancreatic ductal adenocarcinoma, pancreatic neuroendocrine tumors, spectral biomarkers

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“…Gas6 also stimulates the proliferation of cardiac fibroblasts [41]. Since fibrosis and collagen deposition have been suggested to re-strain the metastatic spreading of pancreatic cancer cells [42–45], we next investigated whether Gas6 blockade could affect collagen deposition in pancreatic tumors. Pancreatic tumor tissues from control and anti-Gas6 treated mice were stained with picrosirius red to assess collagen deposition.…”

Section: Resultsmentioning

confidence: 99%

Blockade of stromal Gas6 alters cancer cell plasticity, activates NK cells and inhibits pancreatic cancer metastasis

Mielgo

Ireland

Luckett

et al. 2019

Preprint

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Blockade of stromal Gas6 alters cancer cell plasticity, activates NK cells and inhibits 2 pancreatic cancer metastasis. 3 Running title 4Gas6 blockade prevents pancreatic cancer metastasis 5 6 Growth arrest-specific gene 6 (Gas6) is a multifunctional factor that regulates several 50 processes in normal physiology and pathophysiology [1].Gas6 binds to the Tyro3, 51 Axl and Mer (TAM) family of receptor tyrosine kinases (TAM receptors) with the 52 highest affinity for Axl [2]. Gas6 supports erythropoiesis, platelet aggregation, 53 angiogenesis, efferocytosis, and inhibits the immune response [3]. Gas6 is critical for 54 the maintenance of immune homeostasis and mice deficient in Gas6 or TAM 55 receptors experience severe autoimmune diseases [4]. Gas6 and its main receptor 56 Axl are overexpressed in several cancer types including, breast, ovarian, gastric, 57 glioblastoma, lung and pancreatic cancer and their expression correlates with a poor 58 prognosis [5]. Axl is ubiquitously expressed in all tissues [6] but is particularly notable 59 in cancer cells, macrophages, dendritic cells and natural killer cells for its role in 60 driving immunosuppression and tumor progression [7-9]. Several cancer studies 61 have focused on the role of Gas6-Axl signaling on the tumor cells and have 62 demonstrated that Axl activation supports tumor cells proliferation, epithelial-63 mesenchymal transition (EMT), drug resistance, migration and metastasis [5]. 64 Factors secreted within the tumor microenvironment are able to sustain Gas6/Axl 65 signaling. Hypoxia Inducible Factor (HIF) has been shown to bind to the Axl 66 promoter region and upregulate its expression on renal cell carcinoma cells [10]. 67 Secretion of IL-10 and M-CSF by tumor cells induces tumor associated 68 macrophages to secrete Gas6 [11].69However, only a few studies have investigated the role of Gas6-Axl signaling in the 70 immune response to breast cancer, ovarian cancer and melanoma [7, 9]. 71 4In solid tumors such as breast or pancreatic cancer, the tumor stroma can represent 72 up to 80% of the tumor mass and actively influences cancer progression, metastasis 73 [12][13][14] and resistance to therapies [15][16][17]. 74 Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal cancers 75 worldwide and better therapies are urgently needed [18]. Metastasis, therapy 76 resistance, and immunosuppression are key characteristics of pancreatic tumors [19, 77 20]. The Gas6-Axl pathway is activated in 70% of pancreatic cancer patients [21] 78 and is associated with a poor prognosis and increased frequency of distant 79 metastasis [22]. Blocking Gas6 or its receptor Axl inhibits cancer progression [23, 24] 80 and several Axl inhibitors are currently being tested in cancer patients, including 81 PDA patients. While the cancer cell autonomous functions of Gas6 are well 82 documented, the effect of Gas6 signaling in the stroma/immune compartment in 83 pancreatic cancer has not been fully explored. In these studies, we sought to 84 understand the effect of Gas6 bloc...

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The Extracellular Matrix and Pancreatic Cancer: A Complex Relationship

Cited by 219 publications

References 150 publications

Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution

Cellular heterogeneity during mouse pancreatic ductal adenocarcinoma progression at single-cell resolution

Investigation of human pancreatic cancer tissues by Fourier Transform Infrared Hyperspectral Imaging

Blockade of stromal Gas6 alters cancer cell plasticity, activates NK cells and inhibits pancreatic cancer metastasis

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