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TGF? signaling limits lineage plasticity in prostate cancer.

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 cells. However, de-differentiated cells account for the majority of cells in micro-metastases consistent with a preferential contribution to metastasis. We suggest that active TGFß signaling limits lineage plasticity in prostate luminal cells, and that de-differentiation of luminal tumor cells can drive progression to metastatic disease.

SUBMITTER: Hao Y

PROVIDER: S-EPMC5983872 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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TGFβ signaling limits lineage plasticity in prostate cancer.

Hao Yi Y Bjerke Glen A GA Pietrzak Karolina K Melhuish Tiffany A TA Han Yu Y Turner Stephen D SD Frierson Henry F HF Wotton David D

PLoS genetics 20180521 5

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 ...[more]

PMID: 29782499

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Project description:BackgroundThe family of TGF-? ligands is large and its members are involved in many different signaling processes. These signaling processes strongly differ in type with TGF-? ligands eliciting both sustained or transient responses. Members of the TGF-? family can also act as morphogen and cellular responses would then be expected to provide a direct read-out of the extracellular ligand concentration. A number of different models have been proposed to reconcile these different behaviours. We were interested to define the set of minimal modifications that are required to change the type of signal processing in the TGF-? signaling network.ResultsTo define the key aspects for signaling plasticity we focused on the core of the TGF-? signaling network. With the help of a parameter screen we identified ranges of kinetic parameters and protein concentrations that give rise to transient, sustained, or oscillatory responses to constant stimuli, as well as those parameter ranges that enable a proportional response to time-varying ligand concentrations (as expected in the read-out of morphogens). A combination of a strong negative feedback and fast shuttling to the nucleus biases signaling to a transient rather than a sustained response, while oscillations were obtained if ligand binding to the receptor is weak and the turn-over of the I-Smad is fast. A proportional read-out required inefficient receptor activation in addition to a low affinity of receptor-ligand binding. We find that targeted modification of single parameters suffices to alter the response type. The intensity of a constant signal (i.e. the ligand concentration), on the other hand, affected only the strength but not the type of the response.ConclusionsThe architecture of the TGF-? pathway enables the observed signaling plasticity. The observed range of signaling outputs to TGF-? ligand in different cell types and under different conditions can be explained with differences in cellular protein concentrations and with changes in effective rate constants due to cross-talk with other signaling pathways. It will be interesting to uncover the exact cellular differences as well as the details of the cross-talks in future work.

Project description:The androgen receptor (AR) signaling pathway is critical for growth and differentiation of prostate cancer cells. For that reason, androgen deprivation therapy with medical or surgical castration is the principal treatment for metastatic prostate cancer. More recently, new potent AR signaling inhibitors (ARSIs) have been developed. These drugs improve survival for men with metastatic castration-resistant prostate cancer (CRPC), the lethal form of the disease. However, ARSI resistance is nearly universal. One recently appreciated resistance mechanism is lineage plasticity or switch from an AR-driven, luminal differentiation program to an alternate differentiation program. Importantly, lineage plasticity appears to be increasing in incidence in the era of new ARSIs, strongly implicating AR suppression in this process. Lineage plasticity and shift from AR-driven tumors occur on a continuum, ranging from AR-expressing tumors with low AR activity to AR-null tumors that have activation of alternate differentiation programs versus the canonical luminal program found in AR-driven tumors. In many cases, AR loss coincides with the activation of a neuronal program, most commonly exemplified as therapy-induced neuroendocrine prostate cancer (t-NEPC). While genetic events clearly contribute to prostate cancer lineage plasticity, it is also clear that epigenetic events-including chromatin modifications and DNA methylation-play a major role. Many epigenetic factors are now targetable with drugs, establishing the importance of clarifying critical epigenetic factors that promote lineage plasticity. Furthermore, epigenetic marks are readily measurable, demonstrating the importance of clarifying which measurements will help to identify tumors that have undergone or are at risk of undergoing lineage plasticity. In this review, we discuss the role of AR pathway loss and activation of a neuronal differentiation program as key contributors to t-NEPC lineage plasticity. We also discuss new epigenetic therapeutic strategies to reverse lineage plasticity, including those that have recently entered clinical trials.

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TGF? signaling limits lineage plasticity in prostate cancer.

Publications

TGFβ signaling limits lineage plasticity in prostate cancer.

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