Abstract
Targeting tumour-initiating cells (TICs) would lead to new therapies to cure cancer. We previously demonstrated that TICs have the capacity to survive under suspension conditions, while other cells undergo anoikis. Here we show that TICs exhibit increased phosphorylation levels of S727STAT3 because of PP2A inactivation. Collagen 17 gene expression is upregulated in a STAT3-dependent manner, which also stabilizes laminin 5 and engages cells to form hemidesmosome-like junctions in response. Blocking the PP2A-S727STAT3-collagen 17 pathway inhibits the suspension survival of TICs and their ability to form tumours in mice, while activation of the same pathway increases the suspension survival and tumour-initiation capacities of bulk cancer cells. The S727STAT3 phosphorylation levels correlate with collagen 17 expression in colon tumour samples, and correlate inversely with survival. Finally, this signalling axis enhances the ability of TIC to form tumours in mouse models of malignant lung cancer pleural effusion and spontaneous colon cancer metastasis.
Highlights
Targeting tumour-initiating cells (TICs) would lead to new therapies to cure cancer
Our data show that collagen XVII-laminin5 upregulated by PP2A-S727STAT3 mediates anoikis resistance, which plays an important role in the determination of tumour initiation and metastasis in cancer stem cells
To exclude the possibility that suspension survival by TICs in spheres was mediated by merely cell aggregation, we demonstrated the expression of Col XVII and laminin 5 (Supplementary Fig. 4a) and the existence of hemidesmosomelike plaques (Supplementary Fig. 4b), an organized extracellular matrices (ECM) ultrastructure in the basal lamina of the skin epidermis and normal mucosa, in spheres but not in the aggregates of bulk cancer cells formed by hanging drop culture or spheres formed by cancer cells with Col XVII and laminin 5 knockdown (Supplementary Fig. 4b)
Summary
Targeting tumour-initiating cells (TICs) would lead to new therapies to cure cancer. We previously demonstrated that TICs have the capacity to survive under suspension conditions, while other cells undergo anoikis. The S727STAT3 phosphorylation levels correlate with collagen 17 expression in colon tumour samples, and correlate inversely with survival This signalling axis enhances the ability of TIC to form tumours in mouse models of malignant lung cancer pleural effusion and spontaneous colon cancer metastasis. Cancer cells when delivered in matrigel, a mixture of ECM, increase the ability to initiate tumour formation4 These data highly suggest that the original ECM around cancer cells are important for their survival and growth at the metastasis and tumour-initiation microenvironments, which at most are characterized as suspension conditions. Our data show that collagen XVII-laminin upregulated by PP2A-S727STAT3 mediates anoikis resistance, which plays an important role in the determination of tumour initiation and metastasis in cancer stem cells
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