TGFβ signaling limits lineage plasticity in prostate cancer

PLoS Genetics
Yi HaoD Wotton

Abstract

Although treatment options for localized prostate cancer (CaP) are initially effective, the five-year survival for metastatic CaP is below 30%. Mutation or deletion of the PTEN tumor suppressor is a frequent event in metastatic CaP, and inactivation of the transforming growth factor (TGF) ß signaling pathway is associated with more advanced disease. We previously demonstrated that mouse models of CaP based on inactivation of Pten and the TGFß type II receptor (Tgfbr2) rapidly become invasive and metastatic. Here we show that mouse prostate tumors lacking Pten and Tgfbr2 have higher expression of stem cell markers and genes indicative of basal epithelial cells, and that basal cell proliferation is increased compared to Pten mutants. To better model the primarily luminal phenotype of human CaP we mutated Pten and Tgfbr2 specifically in luminal cells, and found that these tumors also progress to invasive and metastatic cancer. Accompanying the transition to invasive cancer we observed de-differentiation of luminal tumor cells to an intermediate cell type with both basal and luminal markers, as well as differentiation to basal cells. Proliferation rates in these de-differentiated cells were lower than in either basal or luminal cel...Continue Reading

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Citations

Mar 11, 2020·Nature Reviews. Clinical Oncology·Álvaro Quintanal-VillalongaCharles M Rudin
Jun 10, 2021·Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc·Eunhyang ParkNam Hoon Cho

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Datasets Mentioned

BETA
GSE108017

Methods Mentioned

BETA
RNA-seq
xenografts
transgenics
PCR

Software Mentioned

DAVID
Adobe Photoshop
FastQC
ENRICHR
Primer3
STAR
R
HotShot
NIS Elements
GSEA

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