The role of lineage specifiers in pancreatic ductal adenocarcinoma

Camolotto, Soledad A.; Belova, Veronika K; Snyder, Eric L.

doi:10.21037/jgo.2018.05.04

Cited by 11 publications

(11 citation statements)

References 61 publications

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“…Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, with the lowest 5-years survival rate of all cancers ( Siegel et al, 2021 ). Cell type infidelity seems to play an important role in PDAC initiation and progression and might even drive therapy resistance ( Collisson et al, 2011 ; Moffitt et al, 2015 ; Bailey P. et al, 2016 ; Camolotto et al, 2018 ). Here, we briefly discuss the mechanisms leading to cell fate commitment within the normal exocrine pancreas (where PDAC arises from), the role of cell infidelity in cancer progression and therapy resistance and how these concepts fit within the challenging clinical context of PDAC.…”

Section: Introductionmentioning

confidence: 99%

Cell Lineage Infidelity in PDAC Progression and Therapy Resistance

Malinova

Veghini

Real

et al. 2021

Front. Cell Dev. Biol.

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Infidelity to cell fate occurs when differentiated cells lose their original identity and either revert to a more multipotent state or transdifferentiate into a different cell type, either within the same embryonic lineage or in an entirely different one. Whilst in certain circumstances, such as in wound repair, this process is beneficial, it can be hijacked by cancer cells to drive disease initiation and progression. Cell phenotype switching has been shown to also serve as a mechanism of drug resistance in some epithelial cancers. In pancreatic ductal adenocarcinoma (PDAC), the role of lineage infidelity and phenotype switching is still unclear. Two consensus molecular subtypes of PDAC have been proposed that mainly reflect the existence of cell lineages with different degrees of fidelity to pancreatic endodermal precursors. Indeed, the classical subtype of PDAC is characterised by the expression of endodermal lineage specifying transcription factors, while the more aggressive basal-like/squamous subtype is defined by epigenetic downregulation of endodermal genes and alterations in chromatin modifiers. Here, we summarise the current knowledge of mechanisms (genetic and epigenetic) of cell fate switching in PDAC and discuss how pancreatic organoids might help increase our understanding of both cell-intrinsic and cell-extrinsic factors governing lineage infidelity during the distinct phases of PDAC evolution.

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Section: Introductionmentioning

confidence: 99%

Cell Lineage Infidelity in PDAC Progression and Therapy Resistance

Malinova

Veghini

Real

et al. 2021

Front. Cell Dev. Biol.

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“…The major difference between squamous and progenitor carcinoma would be the transcription factors in endodermal development and differentiation. TGF-β and MYC were usually overexpressed among the squamous carcinoma, but not progenitor carcinoma [44]. In view of the upregulation of TGF-β among squamous carcinoma, gemcitabine treatment may down-regulate TGF-β in pancreatic tumor and resulting a better treatment outcomes achieved among the squamous carcinoma.…”

Section: Discussionmentioning

confidence: 97%

“…A healthy individual will have no squamous cells in the pancreas. As compared to progenitor cells carcinoma, squamous cell carcinoma of the pancreas is associated with poor prognosis, more aggressive with higher metastasis rate and no targeted therapy [43,44]. The major difference between squamous and progenitor carcinoma would be the transcription factors in endodermal development and differentiation.…”

Section: Discussionmentioning

confidence: 99%

The synergism of Clinacanthus nutans Lindau extracts with gemcitabine: downregulation of anti-apoptotic markers in squamous pancreatic ductal adenocarcinoma

Hii

Lim

Leong

et al. 2019

BMC Complement Altern Med

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Background Clinacanthus nutans extracts have been consumed by the cancer patients with the hope that the extracts can kill cancers more effectively than conventional chemotherapies. Our previous study reported its anti-inflammatory effects were caused by inhibiting Toll-like Receptor-4 (TLR-4) activation. However, we are unsure of its anticancer effect, and its interaction with existing chemotherapy. Methods We investigated the anti-proliferative efficacy of polar leaf extracts (LP), non-polar leaf extracts (LN), polar stem extract (SP) and non-polar stem extracts (SN) in human breast, colorectal, lung, endometrial, nasopharyngeal, and pancreatic cancer cells using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, MTT assay. The most potent extracts was tested along with gemcitabine using our established drug combination analysis. The effect of the combinatory treatment in apoptosis were quantified using enzyme-linked immunosorbent assay (ELISA), Annexin V assay, antibody array and immunoblotting. Statistical significance was analysed using one-way analysis of variance (ANOVA) and post hoc Dunnett’s test. A p-value of less than 0.05 (p < 0.05) was considered statistical significance. Results All extracts tested were not able to induce potent anti-proliferative effects. However, it was found that pancreatic ductal adenocarcinoma, PDAC (AsPC1, BxPC3 and SW1990) were the cell lines most sensitive cell lines to SN extracts. This is the first report of C. nutans SN extracts acting in synergy with gemcitabine, the first line chemotherapy for pancreatic cancer, as compared to conventional monotherapy. In the presence of SN extracts, we can reduce the dose of gemcitabine 2.38–5.28 folds but still maintain the effects of gemcitabine in PDAC. SN extracts potentiated the killing of gemcitabine in PDAC by apoptosis. Bax was upregulated while bcl-2, cIAP-2, and XIAP levels were downregulated in SW1990 and BxPC3 cells treated with gemcitabine and SN extracts. The synergism was independent of TLR-4 expression in pancreatic cancer cells. Conclusion These results provide strong evidence of C. nutans extracts being inefficacious as monotherapy for cancer. Hence, it should not be used as a total substitution for any chemotherapy agents. However, SN extracts may synergise with gemcitabine in the anti-tumor mechanism.

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“…Our study showed that primary and metastatic PDACs had significantly lower expression of KMT2D and loss of KMT2D promoted PDAC invasion and migration, which supports a tumor-suppressive role of KMT2D in PDAC. Loss of KMT2D also induced a gene signature closely resembling the Moffitt basal-like subtype, which confers a significantly worse prognosis compared to the classical subtype 21,45,46 . These PDAC subtypes have distinct epigenetic landscapes that drive transcriptional alterations.…”

Section: Discussionmentioning

confidence: 98%

KMT2D links TGF-β Signalling to Non-Canonical Activin Pathway and Regulates Pancreatic Cancer Cell Plasticity

Kim

Cao

et al. 2020

Preprint

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Although KMT2D, also known as MLL2, is known to play an essential role in development, differentiation, and tumor suppression, its role in pancreatic cancer development is not well understood. Here, we discovered a novel signaling axis mediated by KMT2D, which links TGF-β to the activin A pathway. We found that TGF-β upregulates a microRNA, miR-147b, which in turn leads to posttranscriptional silencing of KMT2D. Loss of KMT2D induces the expression and secretion of activin A, which activates a non-canonical p38 MAPK-mediated pathway to modulate cancer cell plasticity, promote a mesenchymal phenotype, and enhance tumor invasion and metastasis in mice. We observed a decreased KMT2D expression in human primary and metastatic pancreatic cancer. Furthermore, inhibition or knockdown of activin A reversed the pro-tumoral role of KMT2D. These findings reveal a tumor-suppressive role of KMT2D and identify miR-147b and activin A as novel therapeutic targets in pancreatic cancer.

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The role of lineage specifiers in pancreatic ductal adenocarcinoma

Cited by 11 publications

References 61 publications

Cell Lineage Infidelity in PDAC Progression and Therapy Resistance

Cell Lineage Infidelity in PDAC Progression and Therapy Resistance

The synergism of Clinacanthus nutans Lindau extracts with gemcitabine: downregulation of anti-apoptotic markers in squamous pancreatic ductal adenocarcinoma

KMT2D links TGF-β Signalling to Non-Canonical Activin Pathway and Regulates Pancreatic Cancer Cell Plasticity

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