Pancreatic cancer stroma: an update on therapeutic targeting strategies

Hosein, Abdel; Brekken, Rolf A.; Maitra, Anirban

doi:10.1038/s41575-020-0300-1

Cited by 595 publications

(522 citation statements)

References 177 publications

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“…It is widely accepted that PDAC stroma contributes to the poor outcome of PDAC ranging from EMT, metastasis, chemoresistance and immune evasion and is covered by a very nice review by Hosein et al 2 The major causes that underlie the poor prognosis of PDAC is extreme resistance to chemotherapy and early dissemination. In addition, PDAC has a much higher propensity to disseminate, compared to other cancer types such as lung and colon cancers that share similar oncogenic mutations.…”

Section: Therapeutic Targeting Of Pdac Stroma: Recent Lessonsmentioning

confidence: 99%

“…The ensuing hypoxic and nutrient-poor tumor microenvironment (TME) also serves as a cradle for highly resilient PDAC cells that are metabolically adapted to this inhospitable environment. 2 , 3 In addition, CAFs secrete various chemokines and cytokines that enhance tumor progression and therapeutic resistance. A critical pathophysiological process that associates PDAC cells with these feats is epithelial-mesenchymal transition (EMT).…”

Section: Introductionmentioning

confidence: 99%

“…Several excellent reviews were published in recent years on the underlying signaling mechanisms and role of EMT in cancer, 5 – 7 , 9 – 12 as well as the pathogenic role of stroma in PDAC. 2 , 3 , 13 However, a dedicated review on how stroma promotes EMT in PDAC is lacking. In this study we critically reviewed seminal and recent literature and provided a focused review on signaling mechanisms by which distinct elements of stroma, namely CAFs, ECM and hypoxia, promote EMT of PDAC cells.…”

Section: Introductionmentioning

confidence: 99%

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Beyond just a tight fortress: contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer

Bulle

Lim

2020

Sig Transduct Target Ther

122

123

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Novel effective treatment is direly needed for patients with pancreatic ductal adenocarcinoma (PDAC). Therapeutics that target the driver mutations, especially the KRAS oncoprotein and its effector cascades, have been ineffective. It is increasing clear that the extensive fibro-inflammatory stroma (or desmoplasia) of PDAC plays an active role in the progression and therapeutic resistance of PDAC. The desmoplastic stroma is composed of dense extracellular matrix (ECM) deposited mainly by the cancer-associated-fibroblasts (CAFs) and infiltrated with various types of immune cells. The dense ECM functions as a physical barrier that limits tumor vasculatures and distribution of therapeutics to PDAC cells. In addition, mounting evidence have demonstrated that both CAFs and ECM promote PDAC cells aggressiveness through multiple mechanisms, particularly engagement of the epithelial-mesenchymal transition (EMT) program. Acquisition of a mesenchymal-like phenotype renders PDAC cells more invasive and resistant to therapy-induced apoptosis. Here, we critically review seminal and recent articles on the signaling mechanisms by which each stromal element promotes EMT in PDAC. We discussed the experimental models that are currently employed and best suited to study EMT in PDAC, which are instrumental in increasing the chance of successful clinical translation.

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Section: Therapeutic Targeting Of Pdac Stroma: Recent Lessonsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Beyond just a tight fortress: contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer

Bulle

Lim

2020

Sig Transduct Target Ther

122

123

View full text Add to dashboard Cite

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“…Previous studies suggested that the tumor progression of PDAC as well as its deadly malignancy are highly associated with the tumor microenvironment. Thus, targeting the stromal compartment in PDAC may have anticancer effects and enhance chemo-/radio-sensitivity [50][51][52]. Our results imply that inhibition of PDAC gene signature (genes related to cell-cell and cell-ECM interactions) may be beneficial for treating PDAC via a remodeling of the tumor microenvironment.…”

Section: Discussionmentioning

confidence: 73%

Bioinformatics Data Mining Repurposes the JAK2 (Janus Kinase 2) Inhibitor Fedratinib for Treating Pancreatic Ductal Adenocarcinoma by Reversing the KRAS (Kirsten Rat Sarcoma 2 Viral Oncogene Homolog)-Driven Gene Signature

Liu

Hsieh

Yang

2020

JPM

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Pancreatic ductal adenocarcinoma (PDAC) is still one of the most aggressive and lethal cancer types due to the late diagnosis, high metastatic potential, and drug resistance. The development of novel therapeutic strategies is urgently needed. KRAS (Kirsten rat sarcoma 2 viral oncogene homolog) is the major driver mutation gene for PDAC tumorigenesis. In this study, we mined cancer genomics data and identified a common KRAS-driven gene signature in PDAC, which is related to cell–cell and cell–extracellular matrix (ECM) interactions. Higher expression of this gene signature was associated with poorer overall survival of PDAC patients. Connectivity Map (CMap) analysis and drug sensitivity profiling predicted that a clinically approved JAK2 (Janus kinase 2)-selective inhibitor, fedratinib (also known as TG-101348), could reverse the KRAS-driven gene signature and exhibit KRAS-dependent anticancer activity in PDAC cells. As an approved treatment for myelofibrosis, the pharmacological and toxicological profiles of fedratinib have been well characterized. It may be repurposed for treating KRAS-driven PDAC in the future.

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“…Inadequate angiogenesis causes ischemia in myocardial infarction, stroke, and neurodegenerative or obesity-associated disorders, whereas excessive angiogenesis promotes many ailments including cancer, inflammatory disorders such as atherosclerosis, and eye diseases. Anti-angiogenic therapies (AATs) have been developed to combat tumor metastasis (Hosein et al, 2020). Nowadays, AATs strategies include blood vessel pruning, disruption or normalization of the tumor vasculature, and tumor immunosensitization but did not yield satisfactory efficacy (Cully, 2017;Cloughesy et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

MiR-9 Promotes Angiogenesis via Targeting on Sphingosine-1- Phosphate Receptor 1

Yao

Xie

Zeng

2020

Front. Cell Dev. Biol.

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We previously demonstrated that vascular endothelial cells released VEGF-enriched exosomes to promote the tumor vasculogenesis and progression after anti-angiogenic therapies (AATs). To clarify how microRNA (miR)-9 promoted the angiogenesis of tumorassociated endothelial cells, in the present study, we investigated the association between miR-9 and sphingosine-1-phosphate (S1P) receptors in angiogenesis. The levels of miR-9 and S1P receptors in normal and tumor endothelial cells were compared with EndoDB database and their correlations were analyzed. The levels of S1P 1 , S1P 2 , and S1P 3 were detected in miR-9 overexpressing endothelial cells by qRT-PCR and western blot. The binding sites of miR-9 on S1P 1 and S1P 3 were predicted and tested by dual-luciferase reporter assays. Then, angiogenesis in endothelial cells overexpressing both S1P 1 and miR-9 was detected. The results showed that miR-9 is overexpressed in ECs from medulloblastoma and glioblastoma xenograft, which is negatively associated with S1P 1 and S1P 3. Overexpression of miR-9 significantly inhibited S1P 1 and S1P 3 in both mRNA and protein levels. We predicted that binding sites exist between miR-9 and S1P 1 , S1P 3 , but only S1P 1 was directly targeted by miR-9. Overexpression of S1P 1 significantly suppressed the miR-9-induced angiogenesis. Therefore, miR-9 induces angiogenesis via targeting on S1P 1 .

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Pancreatic cancer stroma: an update on therapeutic targeting strategies

Cited by 595 publications

References 177 publications

Beyond just a tight fortress: contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer

Beyond just a tight fortress: contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer

Bioinformatics Data Mining Repurposes the JAK2 (Janus Kinase 2) Inhibitor Fedratinib for Treating Pancreatic Ductal Adenocarcinoma by Reversing the KRAS (Kirsten Rat Sarcoma 2 Viral Oncogene Homolog)-Driven Gene Signature

MiR-9 Promotes Angiogenesis via Targeting on Sphingosine-1- Phosphate Receptor 1

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