175 The Ets-Transcription Factor Etv1 Regulates Stromal Expansion and Metastasis in Pancreatic Cancer

Heeg, Steffen; Das, Koushik K.; Reichert, Maximilian; Takano, Shigetsugu; Bakir, Basil; Caspers, Julia; Hicks, Philip; Rustgi, Anil K.

doi:10.1016/s0016-5085(15)30164-5

Cited by 3 publications

(3 citation statements)

References 37 publications

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“…recombinase under the control of the pancreasspecific Pdx1 promoter. This model is well established and has been widely used in PDAC research [3][4][5][6][7].…”

Section: Ivyspring International Publishermentioning

confidence: 99%

Kindlin-2 enhances c-Myc translation through association with DDX3X to promote pancreatic ductal adenocarcinoma progression

Liu,

Jiang,

Ding

et al. 2023

Theranostics

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Rationale: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive solid tumor, with extremely low survival rates. Identifying key signaling pathways driving PDAC progression is crucial for the development of therapies to improve patient response rates. Kindlin-2, a multi-functional protein, is involved in numerous biological processes including cell proliferation, apoptosis and migration. However, little is known about the functions of Kindlin-2 in pancreatic cancer progression in vivo. Methods: In this study, we employ an in vivo PDAC mouse model to directly investigate the role of Kindlin-2 in PDAC progression. Then, we utilized RNA-sequencing, the molecular and cellular assays to determine the molecular mechanisms by which Kindlin-2 promotes PDAC progression. Results: We show that loss of Kindlin-2 markedly inhibits Kras G12D -driven pancreatic cancer progression in vivo as well as in vitro. Furthermore, we provide new mechanistic insight into how Kindlin-2 functions in this process, A fraction of Kindlin-2 was localized to the endoplasmic reticulum and associated with the RNA helicase DDX3X, a key regulator of mRNA translation. Loss of Kindlin-2 blocked DDX3X from binding to the 5'-untranslated region of c-Myc and inhibited DDX3X-mediated c-Myc translation, leading to reduced c-Myc-mediated glucose metabolism and tumor growth. Importantly, restoration of the expression of either the full-length Kindlin-2 or c-Myc, but not that of a DDX3X-binding-defective mutant of Kindlin-2, in Kindlin-2 deficient PDAC cells, reversed the inhibition of glycolysis and pancreatic cancer progression induced by the loss of Kindlin-2. Conclusion: Our studies reveal a novel Kindlin-2-DDX3X-c-Myc signaling axis in PDAC progression and suggest that inhibition of this signaling axis may provide a promising therapeutic approach to alleviate PDAC progression.

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“…recombinase under the control of the pancreasspecific Pdx1 promoter. This model is well established and has been widely used in PDAC research [3][4][5][6][7].…”

Section: Ivyspring International Publishermentioning

confidence: 99%

Kindlin-2 enhances c-Myc translation through association with DDX3X to promote pancreatic ductal adenocarcinoma progression

Liu,

Jiang,

Ding

et al. 2023

Theranostics

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“…The expression of ETV1 protein is upregulated in human and murine PDAC tissue, mainly localizes to nuclei where it acts to regulate transcription. 42 Animal studies suggest an Etv1-Sparc-Has2 pathway, which when disrupted leads to reduced number of tumor metastases and tumor volume, and stromal expansion. 42 Has2 was chosen through in silico screening for downstream targets of Etv1; however, the role of other murine HA synthases (ie, Has1 and Has3) was not evaluated in their study.…”

Section: Othermentioning

confidence: 99%

“…42 Animal studies suggest an Etv1-Sparc-Has2 pathway, which when disrupted leads to reduced number of tumor metastases and tumor volume, and stromal expansion. 42 Has2 was chosen through in silico screening for downstream targets of Etv1; however, the role of other murine HA synthases (ie, Has1 and Has3) was not evaluated in their study. In addition, the precise role of HA in this pathway was not determined.…”

Section: Othermentioning

confidence: 99%

Clinically Relevant Biology of Hyaluronic Acid in the Desmoplastic Stroma of Pancreatic Ductal Adenocarcinoma

Jahedi¹,

Ramachandran²,

Windsor³

et al. 2022

Pancreas

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Pancreatic ductal adenocarcinoma (PDAC) is notorious for its poor outcome. The presence of a dense desmoplastic stroma is a hallmark of this malignancy, and abundant hyaluronic acid (HA) within this stroma is a common feature of PDAC. At the end of 2019, an HA-targeting drug, after initial promise, failed phase 3 clinical trials in PDAC. This failure in the face of such strong evidence for biological importance forces us to turn back to the research and seek a better understanding of HA biology in PDAC. Therefore, in this review, we reexamine what is known about HA biology, the methods used to detect and quantify HA, and the ability of the biological models in which HA has been investigated to recapitulate an HA-rich desmoplastic tumor stroma. The role of HA in PDAC relies on its complex interplay with a range of HA-associated molecules, which have not been as extensively investigated as HA itself. Therefore, using large genomic data sets, we cataloged the abundance and activity in PDAC of molecules that modulate HA synthesis, degradation, protein interactions, and receptor binding. Based on their association with clinical characteristics and individual patient outcomes, we suggest a small number of HA-associated molecules that warrant further investigation as biomarkers and drug targets.

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Metastatic progression is associated with dynamic changes in the local microenvironment

et al. 2016

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Most cancer-associated deaths result from metastasis. However, it remains unknown whether the size, microenvironment or other features of a metastatic lesion dictate its behaviour or determine the efficacy of chemotherapy in the adjuvant (micrometastatic) setting. Here we delineate the natural history of metastasis in an autochthonous model of pancreatic ductal adenocarcinoma (PDAC), using lineage tracing to examine the evolution of disseminated cancer cells and their associated microenvironment. With increasing size, lesions shift from mesenchymal to epithelial histology, become hypovascular and accumulate a desmoplastic stroma, ultimately recapitulating the primary tumours from which they arose. Moreover, treatment with gemcitabine and nab-paclitaxel significantly reduces the overall number of metastases by inducing cell death in lesions of all sizes, challenging the paradigm that PDAC stroma imposes a critical barrier to drug delivery. These results illuminate the cellular dynamics of metastatic progression and suggest that adjuvant chemotherapy affords a survival benefit by directly targeting micrometastases.

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175 The Ets-Transcription Factor Etv1 Regulates Stromal Expansion and Metastasis in Pancreatic Cancer

Cited by 3 publications

References 37 publications

Kindlin-2 enhances c-Myc translation through association with DDX3X to promote pancreatic ductal adenocarcinoma progression

Kindlin-2 enhances c-Myc translation through association with DDX3X to promote pancreatic ductal adenocarcinoma progression

Clinically Relevant Biology of Hyaluronic Acid in the Desmoplastic Stroma of Pancreatic Ductal Adenocarcinoma

Metastatic progression is associated with dynamic changes in the local microenvironment

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