Role of the PP2A Pathway in Cholangiocarcinoma: State of the Art and Future Perspectives

Cristóbal, Ion; Lamarca, Ángela

doi:10.3390/cancers14215422

Cited by 2 publications

(3 citation statements)

References 33 publications

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“…Interestingly, we documented the selective modulation of only twenty proteins, ten upregulated and ten downregulated. We observed the upregulation of key oncogenes described in other tumoral models, such as PN1 [ 28 ] and NDUFC1 [ 30 ], while, on the other hand, we found downregulation of the crucial tumor suppressors PP2A [ 29 , 31 , 35 ], ENO3 [ 32 ] and NOTCH3 [ 33 ]. Among the modulated proteins, collagen VII was detected only in HuCC-T1 lysates from cocultures, suggesting the modulation of TGFβ signaling.…”

Section: Discussionmentioning

confidence: 76%

“…It also inhibits EMT by dephosphorylating β-catenin and allowing its degradation to occur [ 29 ]. In CCA, and more specifically HuCC-T1 cells, the role of PP2A as an inhibitor of EMT, invasiveness and proliferation has been clarified [ 31 , 35 ]. Notably, PP2A inhibits TGFβ signaling by TGFBR1 dephosphorylation, and downregulation of PP2A in prostate cancer leads to enhanced TGFβ signaling [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

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Cholangiocarcinoma Malignant Traits Are Promoted by Schwann Cells through TGFβ Signaling in a Model of Perineural Invasion

de Franchis,

Petrungaro,

Pizzichini

et al. 2024

Cells

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The term cholangiocarcinoma (CCA) defines a class of epithelial malignancies originating from bile ducts. Although it has been demonstrated that CCA patients with perineural invasion (PNI) have a worse prognosis, the biological features of this phenomenon are yet unclear. Our data show that in human intrahepatic CCA specimens with documented PNI, nerve-infiltrating CCA cells display positivity of the epithelial marker cytokeratin 7, lower with respect to the rest of the tumor mass. In an in vitro 3D model, CCA cells move towards a peripheral nerve explant allowing contact with Schwann cells (SCs) emerging from the nerve. Here, we show that SCs produce soluble factors that favor the migration, invasion, survival and proliferation of CCA cells in vitro. This effect is accompanied by a cadherin switch, suggestive of an epithelial–mesenchymal transition. The influence of SCs in promoting the ability of CCA cells to migrate and invade the extracellular matrix is hampered by a specific TGFβ receptor 1 (TGFBR1) antagonist. Differential proteomic data indicate that the exposure of CCA cells to SC secreted factors induces the upregulation of key oncogenes and the concomitant downregulation of some tumor suppressors. Taken together, these data concur in identifying SCs as possible promoters of a more aggressive CCA phenotype, ascribing a central role to TGFβ signaling in regulating this process.

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Section: Discussionmentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Cholangiocarcinoma Malignant Traits Are Promoted by Schwann Cells through TGFβ Signaling in a Model of Perineural Invasion

de Franchis,

Petrungaro,

Pizzichini

et al. 2024

Cells

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“…In the liver, PP2A inactivation has been predominantly associated with HCC [ 31 , 32 , 33 ] and less frequently, with CCA [ 34 ]. However, the clinical picture remains largely incomplete and the impact of PP2A inhibition on the efficiency of (targeted) PLC therapies remains unresolved.…”

Section: Introductionmentioning

confidence: 99%

A Novel Mouse Model of Combined Hepatocellular-Cholangiocarcinoma Induced by Diethylnitrosamine and Loss of Ppp2r5d

Domènech Omella,

Cortesi,

Verbinnen

et al. 2023

Cancers

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Primary liver cancer (PLC) can be classified in hepatocellular (HCC), cholangiocarcinoma (CCA), and combined hepatocellular-cholangiocarcinoma (cHCC-CCA). The molecular mechanisms involved in PLC development and phenotype decision are still not well understood. Complete deletion of Ppp2r5d, encoding the B56δ subunit of Protein Phosphatase 2A (PP2A), results in spontaneous HCC development in mice via a c-MYC-dependent mechanism. In the present study, we aimed to examine the role of Ppp2r5d in an independent mouse model of diethylnitrosamine (DEN)-induced hepatocarcinogenesis. Ppp2r5d deletion (heterozygous and homozygous) accelerated HCC development, corroborating its tumor-suppressive function in liver and suggesting Ppp2r5d may be haploinsufficient. Ppp2r5d-deficient HCCs stained positively for c-MYC, consistent with increased AKT activation in pre-malignant and tumor tissues of Ppp2r5d-deficient mice. We also found increased YAP activation in Ppp2r5d-deficient tumors. Remarkably, in older mice, Ppp2r5d deletion resulted in cHCC-CCA development in this model, with the CCA component showing increased expression of progenitor markers (SOX9 and EpCAM). Finally, we observed an upregulation of Ppp2r5d in tumors from wildtype and heterozygous mice, revealing a tumor-specific control mechanism of Ppp2r5d expression, and suggestive of the involvement of Ppp2r5d in a negative feedback regulation restricting tumor growth. Our study highlights the tumor-suppressive role of mouse PP2A-B56δ in both HCC and cHCC-CCA, which may have important implications for human PLC development and targeted treatment.

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Role of the PP2A Pathway in Cholangiocarcinoma: State of the Art and Future Perspectives

Abstract: Cholangiocarcinoma represents a heterogeneous disease at both a clinical and molecular level [...]

Cited by 2 publications

References 33 publications

Cholangiocarcinoma Malignant Traits Are Promoted by Schwann Cells through TGFβ Signaling in a Model of Perineural Invasion

Cholangiocarcinoma Malignant Traits Are Promoted by Schwann Cells through TGFβ Signaling in a Model of Perineural Invasion

A Novel Mouse Model of Combined Hepatocellular-Cholangiocarcinoma Induced by Diethylnitrosamine and Loss of Ppp2r5d

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