Paracrine and Autocrine Signals Induce and Maintain Mesenchymal and Stem Cell States in the Breast

Scheel, Christina; Eaton, Elinor Ng; Li, Sophia Hsin-Jung; Chaffer, Christine L.; Reinhardt, Ferenc; Kah, Kong Jie; Bell, George W.; Guo, Wenjun; Rubin, Jeffrey S.; Richardson, Andrea L.; Weinberg, Robert A.

doi:10.1016/j.cell.2011.04.029

Cited by 788 publications

(761 citation statements)

References 38 publications

Supporting

Mentioning

689

Contrasting

Unclassified

Order By: Relevance

“…Considering the association of the paracrine compartment with EMT induction and maintenance, 34 we investigated its involvement in the enhanced EMT observed in the absence of TAp73. W1 media in contrast to decreased abilities shown by W1 cells upon incubation with 4A media; this would suggest that secretome composition impacts EMT-associated abilities.…”

Section: Resultsmentioning

confidence: 99%

TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

et al. 2016

View full text Add to dashboard Cite

Advances made in pancreatic cancer therapy have been far from sufficient and have allowed only a slight improvement in global survival of patients with pancreatic ductal adenocarcinoma (PDA). Recent progresses in chemotherapy have offered some hope for an otherwise gloomy outlook, however, only a limited number of patients are eligible because of important cytotoxicity. In this context, enhancing our knowledge on PDA initiation and evolution is crucial to highlight certain weaknesses on which to specifically target therapy. We found that loss of transcriptionally active p73 (TAp73), a p53 family member, impacted PDA development. In two relevant and specific engineered pancreatic cancer mouse models, we observed that TAp73 deficiency reduced survival and enhanced epithelial-to-mesenchymal transition (EMT). Through proteomic analysis of conditioned media from TAp73 wild-type (WT) and deficient pancreatic tumor cells, we identified a secreted protein, biglycan (BGN), which is necessary and sufficient to mediate this pro-EMT effect. Interestingly, BGN is modulated by and modulates the transforming growth factor-β (TGF-β) pathway, a key regulator of the EMT process. We further examined this link and revealed that TAp73 impacts the TGF-β pathway by direct regulation of BGN expression and Sma and Mad-related proteins (SMADs) expression/ activity. Absence of TAp73 leads to activation of TGF-β signaling through a SMAD-independent pathway, favoring oncogenic TGF-β effects and EMT. Altogether, our data highlight the implication of TAp73 in the aggressiveness of pancreatic carcinogenesis through modulation of the TGF-β signaling. By suggesting TAp73 as a predictive marker for response to TGF-β inhibitors, our study could improve the classification of PDA patients with a view to offering combined therapy involving TGF-β inhibitors.

show abstract

Section: Resultsmentioning

confidence: 99%

TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

et al. 2016

View full text Add to dashboard Cite

show abstract

“…The radiationinduced phenotypic heterogeneity, we report, might reflect transient cellular plasticity as well as stress-evoked responses of preexistent subsets cells seen in the parental DU145 and PC-3 cell populations. [40][41][42][43][44][45][46][47][48][49][50][51][52] Ionizing radiation can promote traits of EMT in normal human mammary epithelium, 41 lung carcinoma 42,43 and colorectal cancer cells. 44 Furthermore, besides their role in E-cadherin repression, 45,46 Slug and Snail have been implicated in radioresistance-associated EMT.…”

Section: Discussionmentioning

confidence: 99%

“…49 Another intriguing aspect of our results is the link between EMT and stem-like cell traits. Epithelial cancer cells undergoing EMT exhibit also features of stemness, 50,51 and Snail induces both EMT and stem cell-like features in squamous cell carcinoma. 52 We show that besides elevated Snail, radiation-surviving non-adherent CaP cells featured enhanced expression of stem cell-associated genes CD133, 53 Oct-4, Sox2 and Nanog, the latter three capable of reprogramming various differentiated cells toward stemness.…”

Section: Discussionmentioning

confidence: 99%

Radiotherapy-induced plasticity of prostate cancer mobilizes stem-like non-adherent, Erk signaling-dependent cells

et al. 2014

View full text Add to dashboard Cite

Fractionated ionizing radiation combined with surgery or hormone therapy represents the first-choice treatment for medium to high-risk localized prostate carcinoma. One of the main reasons for the failure of radiotherapy in prostate cancer is radioresistance and further dissemination of surviving cells. In this study, exposure of four metastasis-derived human prostate cancer cell lines (DU145, PC-3, LNCaP and 22RV1) to clinically relevant daily fractions of ionizing radiation (35 doses of 2 Gy) resulted in generation of two radiation-surviving populations: adherent senescent-like cells expressing common senescenceassociated markers and non-adherent anoikis-resistant stem cell-like cells with active Notch signaling and expression of stem cell markers CD133, Oct-4, Sox2 and Nanog. While a subset of the radiation-surviving adherent cells resumed proliferation shortly after completion of the irradiation regimen, the non-adherent cells started to proliferate only on their reattachment several weeks after the radiation-induced loss of adhesion. Like the parental non-irradiated cells, radiation-surviving re-adherent DU145 cells were tumorigenic in immunocompromised mice. The radiation-induced loss of adhesion was dependent on expression of Snail, as siRNA/shRNA-mediated knockdown of Snail prevented cell detachment. On the other hand, survival of the non-adherent cells required active Erk signaling, as chemical inhibition of Erk1/2 by a MEK-selective inhibitor or Erk1/2 knockdown resulted in anoikis-mediated death in the non-adherent cell fraction. Notably, whereas combined inhibition of Erk and PI3K-Akt signaling triggered cell death in the non-adherent cell fraction and blocked proliferation of the adherent population of the prostate cancer cells, such combined treatment had only marginal if any impact on growth of control normal human diploid cells. These results contribute to better understanding of radiation-induced stress response and heterogeneity of human metastatic prostate cancer cells, document treatment-induced plasticity and phenotypically distinct cell subsets, and suggest the way to exploit their differential sensitivity to radiosensitizing drugs in overcoming radioresistance. Cell Death and Differentiation (2015) 22, 898-911; doi:10.1038/cdd.2014.97; published online 11 July 2014Prostate carcinoma (CaP) is the most frequent type of cancer in men, and the sixth cause of cancer-associated death in men worldwide. 1 Despite the advances in diagnosis and therapy of CaP, the mortality has remained almost unchanged for the last decades. Currently, the most successful treatment for localized CaP is prostatectomy with postoperative fractionated radiotherapy, significantly improving metastasis-free and overall survival, where the median of a 15-year survival is around 47% of patients. 2,3 The rest of the patients develop a metastatic disease that is incurable due to the resistance of CaP to androgen ablation, radiotherapy and chemotherapy. Therefore, understanding the mechanisms of radioresistance and chemoresista...

show abstract

“…Implementation of the process is dependent on the activity of several signaling pathways, which have to collaborate to efficiently induce the EMT program [50]. These include the MAPK, PI3K, Wnt/β-catenin, NFκB, Notchand Hippo/Warts pathways [51].…”

Section: Genesis Of Cancer Stem Cells and Reactivated Signaling Pathwaysmentioning

confidence: 99%

“…These include the MAPK, PI3K, Wnt/β-catenin, NFκB, Notchand Hippo/Warts pathways [51]. During EMT, specific transcription factors are activated, such as SNAIL and TWIST, which subsequently initiate a stem cell transcriptional program [50]. Expression of epithelial genes like E-cadherin is reduced, in contrast to characteristic mesenchymal ''stemness'' genes including Oct-4 and Nanog [49].…”

Section: Genesis Of Cancer Stem Cells and Reactivated Signaling Pathwaysmentioning

confidence: 99%

Cancer stem cells and addicted cancer cells

Logtenberg¹,

Boonstra²

2013

Oncol Discov

View full text Add to dashboard Cite

Advanced tumors represent a genetically heterogeneous population of cells, which compromise subpopulations with distinct properties. Research indicates that a specific population of cells within the heterogeneous population contain stem cell-like properties. These 'cancer stem cells' are much like normal stem cells and have the capacity to self-renew, sustain the entire cancerous tissues and provide a reservoir of cells for recurrence after therapy and drug resistance. Cancer stem cells can arise from normal, adult stem cells, from progenitor cells or from fully matured cell types. They are likely generated by the process of epithelial-mesenchymal transition, through which differentiated cells acquire stem-cell like properties. This process potentially underlies the mechanism by which metastases evolve. Furthermore, mutations may render cancer cells dependent on the activity of one or more specific signaling pathways in the cell. This phenomenon is termed 'oncogene addiction' and represents the Achilles' heel of the cancer cell. As the concept of oncogene addiction in tumor cells proves to be very complex, additional models have been proposed to account for the variations in pathway dependencies and their intricate interactions. The combined knowledge concerning cancer stem cells, oncogene addiction and drug therapy resistance may lead to the identification of new avenues to improved drug strategies that address tumor heterogeneity and mechanisms of escape.

show abstract

Paracrine and Autocrine Signals Induce and Maintain Mesenchymal and Stem Cell States in the Breast

Cited by 788 publications

References 38 publications

TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

TAp73 loss favors Smad-independent TGF-β signaling that drives EMT in pancreatic ductal adenocarcinoma

Radiotherapy-induced plasticity of prostate cancer mobilizes stem-like non-adherent, Erk signaling-dependent cells

Cancer stem cells and addicted cancer cells

Contact Info

Product

Resources

About