Wnt‐3a‐activated human fibroblasts promote human keratinocyte proliferation and matrix destruction

Sobel, Katrin; Tham, Marius; Stark, Hans Jürgen; Stammer, Hermann; Prätzel-Wunder, Silke; Bickenbach, Jackie R.; Boukamp, Petra

doi:10.1002/ijc.29336

Cited by 28 publications

(19 citation statements)

References 49 publications

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“…In breast cancer cells, WBP2 cooperates with β-catenin and YAP/TAZ to drive TCF-mediated gene transcription downstream of WNT signalling62. Consistent with findings from other groups demonstrating that NHKs are only weakly responsive to WNT signals63, our NHK screen did not reveal any involvement of WNT signalling in controlling YAP activity in human epidermal SCs and in driving their clonal expansion. Thus, different cell types appear to engage YAP/WBP2 via distinct signalling mechanisms for different transcriptional outputs.…”

Section: Discussionsupporting

confidence: 89%

A genome-wide screen identifies YAP/WBP2 interplay conferring growth advantage on human epidermal stem cells

et al. 2017

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Individual human epidermal cells differ in their self-renewal ability. To uncover the molecular basis for this heterogeneity, we performed genome-wide pooled RNA interference screens and identified genes conferring a clonal growth advantage on normal and neoplastic (cutaneous squamous cell carcinoma, cSCC) human epidermal cells. The Hippo effector YAP was amongst the top positive growth regulators in both screens. By integrating the Hippo network interactome with our data sets, we identify WW-binding protein 2 (WBP2) as an important co-factor of YAP that enhances YAP/TEAD-mediated gene transcription. YAP and WPB2 are upregulated in actively proliferating cells of mouse and human epidermis and cSCC, and downregulated during terminal differentiation. WBP2 deletion in mouse skin results in reduced proliferation in neonatal and wounded adult epidermis. In reconstituted epidermis YAP/WBP2 activity is controlled by intercellular adhesion rather than canonical Hippo signalling. We propose that defective intercellular adhesion contributes to uncontrolled cSCC growth by preventing inhibition of YAP/WBP2.

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Section: Discussionsupporting

confidence: 89%

A genome-wide screen identifies YAP/WBP2 interplay conferring growth advantage on human epidermal stem cells

et al. 2017

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“…GSEA analysis also showed an enrichment (almost significant) of genes upregulated by Wnt3A in NIH3T3 (FDR q ‐val = 0.08; FWER p ‐val = 0.10; Supporting Information Fig. S7C) and dermal fibroblasts (FDR q ‐val = 0.08; FWER p ‐val = 0.18; Supporting Information Fig. S7D) among genes induced by Wnt3A in CCD‐18Co cells.…”

Section: Discussionmentioning

confidence: 86%

The human PKP2/plakophilin‐2 gene is induced by Wnt/β‐catenin in normal and colon cancer‐associated fibroblasts

Niell

Larriba

Ferrer-Mayorga

et al. 2017

Intl Journal of Cancer

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Colorectal cancer results from the malignant transformation of colonic epithelial cells. Stromal fibroblasts are the main component of the tumour microenvironment, and play an important role in the progression of this and other neoplasias. Wnt/β‐catenin signalling is essential for colon homeostasis, but aberrant, constitutive activation of this pathway is a hallmark of colorectal cancer. Here we present the first transcriptomic study on the effect of a Wnt factor on human colonic myofibroblasts. Wnt3A regulates the expression of 1,136 genes, of which 662 are upregulated and 474 are downregulated in CCD‐18Co cells. A set of genes encoding inhibitors of the Wnt/β‐catenin pathway stand out among those induced by Wnt3A, which suggests that there is a feedback inhibitory mechanism. We also show that the PKP2 gene encoding the desmosomal protein Plakophilin‐2 is a novel direct transcriptional target of Wnt/β‐catenin in normal and colon cancer‐associated fibroblasts. PKP2 is induced by β‐catenin/TCF through three binding sites in the gene promoter and one additional binding site located in an enhancer 20 kb upstream from the transcription start site. Moreover, Plakophilin‐2 antagonizes Wnt/β‐catenin transcriptional activity in HEK‐293T cells, which suggests that it may act as an intracellular inhibitor of the Wnt/β‐catenin pathway. Our results demonstrate that stromal fibroblasts respond to canonical Wnt signalling and that Plakophilin‐2 plays a role in the feedback control of this effect suggesting that the response to Wnt factors in the stroma may modulate Wnt activity in the tumour cells.

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“…This idea is supported by a very recent study reporting fewer stromal CAFs in pancreatic cancer patients after treatment with nanoparticles containing paclitaxel [95]. Wnt signaling deregulation in human SCCs has been evidenced not only in cancer cells but also in stromal broblasts [96], suggesting that Wnt pathway might act in a paracrine fashion to promote skin carcinogenesis. Fibroblasts treated with Onco-P20 reduced the level of b-catenin expression and increased the production of soluble factors capable to diffuse similar Wnt pathway modulation to neighboring cells.…”

Section: Discussionmentioning

confidence: 72%

Simultaneous Targeting Tumor Cells and Cancer-Associated Fibroblasts with a Paclitaxel-Hyaluronan Bioconjugate: in vitro Evaluation in Non-Melanoma Skin Cancer

Bellei

Caputo

Migliano

et al. 2020

Preprint

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Abstract Background: Cancers are complex organs which encompass not only the tumor cells but also cells within the surrounding stroma. Such cells, mainly cancer associated fibroblasts (CAFs) and immune infiltrating cells, facilitate many aspects of cancer development providing a structural and supportive framework rich of bioactive compounds. So far, there are emerging studies proposing the combination of conventional anti-cancer therapy, directed against neoplastic cells, to molecules targeting tumor microenviroment. Methods: The study was designed to evaluated the pharmacological properties of the anti-tumor agent paclitaxel conjugated to hyaluronic acid (HA) on non-melanoma skin cancer (NMSC) and on the surronding dermal fibroblasts. This molecule, named Oncofid-P20 (Onco-P20), targets preferentially cells expressing high level of CD44, the natural ligand of HA.Results: Consistent with paclitaxel’s mechanism of action involving interferences with the normal breackdown of microtubules during cell division, highly sensible carcinoma cells underwent rapidly to apoptotic cell death. Interestingly, less sensible cells such as dermal fibroblasts resisted to the Onco-P20 treatment and experirenced a senescent-like status characterized by morphological change, decreaded proliferation, and significant modification of the gene espression profile. Onco-P20-treated fibroblasts lowered growth factors production, down-modulate Wnt signal pathway and acquired a pro-inflammatory profile. Independently to the direct exposure to taxol, in presence of Onco-P20-treated fibroblasts or their conditioned medium, carcinoma cells reduced the proliferation rate. Similar to NHF, fibroblasts isolated from skin cancer tumor lesion or from tissue adjacent to the tumor acquired an anti-neoplastic activity under Oncofid-P20 treatment.Conclusion: Collectively, our data demonstrated that Onco-P20, exerting both a direct and a NHF-mediated indirect paracrine effect on carcinoma cells, is a good candidate for an innovative therapy alternative to surgery for treatment of NMSC.

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Wnt‐3a‐activated human fibroblasts promote human keratinocyte proliferation and matrix destruction

Cited by 28 publications

References 49 publications

A genome-wide screen identifies YAP/WBP2 interplay conferring growth advantage on human epidermal stem cells

A genome-wide screen identifies YAP/WBP2 interplay conferring growth advantage on human epidermal stem cells

The human PKP2/plakophilin‐2 gene is induced by Wnt/β‐catenin in normal and colon cancer‐associated fibroblasts

Simultaneous Targeting Tumor Cells and Cancer-Associated Fibroblasts with a Paclitaxel-Hyaluronan Bioconjugate: in vitro Evaluation in Non-Melanoma Skin Cancer

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