Microenvironmental control of breast cancer subtype elicited through paracrine platelet-derived growth factor-CC signaling

Roswall, Pernilla; Bocci, Matteo; Bartoschek, Michael; Li, Hong; Kristiansen, Glen; Jansson, Sara; Lehn, Sophie; Sjölund, Jonas; Reid, Steven; Larsson, Christer; Eriksson, Pontus; Anderberg, Charlotte; Cortez, Eliane; Saal, Lao H.; Orsmark-Pietras, Christina; Cordero, Eugenia; Hallermalm, Kristian; Häkkinen, Jari; Burvenich, Ingrid; Lim, Elgene; Orimo, Akira; Höglund, Mattias; Rydén, Lisa; Moch, Holger; Scott, Andrew M.; Eriksson, Ulf; Pietras, Kristian

doi:10.1038/nm.4494

Cited by 132 publications

(112 citation statements)

References 68 publications

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“…This result highlights the selective inhibition concept and the strategy of modifying rather than simply depleting the tumor stroma, which provides a novel direction for studies of pancreatic cancer. Another recent study on breast cancer indicated that the TME is capable of regulating breast cancer subtypes via a PDGF-CC-dependent pathway, which provides promising target ideas for PDAC to reexamine the role of the microenvironment 140 . Although there have been numerous studies on CAFs, the absence of large-scale randomized clinical trials to support these experimental data is apparent.…”

Section: Discussionmentioning

confidence: 99%

The impact of cancer-associated fibroblasts on major hallmarks of pancreatic cancer

Sun¹,

Zhang²,

Hu³

et al. 2018

Theranostics

148

123

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Pancreatic ductal adenocarcinoma (PDAC) constitutes one of the most challenging lethal tumors and has a very poor prognosis. In addition to cancer cells, the tumor microenvironment created by a repertoire of resident and recruited cells and the extracellular matrix also contribute to the acquisition of hallmarks of cancer. Among these factors, cancer-associated fibroblasts (CAFs) are critical components of the tumor microenvironment. CAFs originate from the activation of resident fibroblasts and pancreatic stellate cells, the differentiation of bone marrow-derived mesenchymal stem cells and epithelial-to-mesenchymal transition. CAFs acquire an activated phenotype via various cytokines and promote tumor proliferation and growth, accelerate invasion and metastasis, induce angiogenesis, promote inflammation and immune destruction, regulate tumor metabolism, and induce chemoresistance; these factors contribute to the acquisition of major hallmarks of PDAC. Therefore, an improved understanding of the impact of CAFs on the major hallmarks of PDAC will highlight the diagnostic and therapeutic values of these targeted cells.

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Section: Discussionmentioning

confidence: 99%

The impact of cancer-associated fibroblasts on major hallmarks of pancreatic cancer

Sun¹,

Zhang²,

Hu³

et al. 2018

Theranostics

148

123

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“…A recent study reporting immunohistochemical analyses of a cohort of 550 human breast cancer samples including 30 TNBCs reported expression of PDGFRβ in the stroma and not in tumor cells 56 , and suggested that the paracrine crosstalk existing between basal-like mammary cancer cells, expressing the PDGF-CC ligand, and cancer-associated fibroblasts, expressing both PDGFRβ and the cognate PDGFRα 57 , could be the most prominent route of PDGFR-dependent signal transduction in breast cancer. Herein, by extending the analysis on a TMA comprising 200 cases of human TNBC, we present novel data showing that PDGFRβ is also expressed in tumor cells belonging to a restricted subgroup of tumors of the mesenchymal subtype expressing either MMP-9 or ALDH proteins that appears as a highly invasive and stem-like phenotype.…”

Section: Discussionmentioning

confidence: 99%

Targeted imaging and inhibition of triple-negative breast cancer metastases by a PDGFRβ aptamer

Camorani¹,

Hill²,

Collina³

et al. 2018

Theranostics

102

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While the overall mortality for breast cancer has recently declined, management of triple-negative breast cancer (TNBC) is still challenging because of its aggressive clinical behavior and the lack of targeted therapies. Genomic profiling studies highlighted the high level of heterogeneity of this cancer, which comprises different subtypes with unique phenotypes and response to treatment. Platelet-derived growth factor receptor β (PDGFRβ) is an established mesenchymal/stem cell-specific marker in human glioblastoma and, as recently suggested, it may uniquely mark breast cancer cells with stem-like characteristics and/or that have undergone epithelial-mesenchymal transition.Methods: Immunohistochemical analysis for PDGFRβ expression was performed on a human TNBC tissue microarray. Functional assays were conducted on mesenchymal-like TNBC cells to investigate the effect of a previously validated PDGFRβ aptamer on invasive cell growth in three-dimensional culture conditions, migration, invasion and tube formation. The aptamer was labeled with a near-infrared (NIR) dye and its binding specificity to PDGFRβ was assessed both in vitro (confocal microscopy and flow cytometry analyses) and in vivo (fluorescence molecular tomography in mice bearing TNBC xenografts). A mouse model of TNBC lung metastases formation was established and NIR-labeled PDGFRβ aptamer was used to detect lung metastases in mice untreated or intravenously injected with unlabeled aptamer.Results: Here, we present novel data showing that tumor cell expression of PDGFRβ identifies a subgroup of mesenchymal tumors with invasive and stem-like phenotype, and propose a previously unappreciated role for PDGFRβ in driving TNBC cell invasiveness and metastases formation. We show that the PDGFRβ aptamer blocked invasive growth and migration/invasion of mesenchymal TNBC cell lines and prevented TNBC lung metastases formation. Further, upon NIR-labeling, the aptamer specifically bound to TNBC xenografts and detected lung metastases.Conclusions: We propose PDGFRβ as a reliable biomarker of a subgroup of mesenchymal TNBCs with invasive and stem-like phenotype as well as the use of the PDGFRβ aptamer as a high efficacious tool for imaging and suppression of TNBC lung metastases. This study will allow for the significant expansion of the current repertoire of strategies for managing patients with more aggressive TNBC.

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“…For those cases, stroma-targeted therapies could be of interest. In breast cancer, responsiveness to hormonal therapy seems to be regulated by signals in the cancer stroma as stroma interfering was able to convert basal, hormone treatment-resistant breast cancer into a luminal, treatment-responsive subtype (Brechbuhl et al, 2017;Roswall et al, 2018). For MetC, potential therapeutic targets in the tumor microenvironment may be available, such as immune or bone cells.…”

Section: And the Luminal A Luminalmentioning

confidence: 99%

Gene expression profiles define molecular subtypes of prostate cancer bone metastases with different outcomes and morphology traceable back to the primary tumor

et al. 2019

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Bone metastasis is the lethal end‐stage of prostate cancer (PC), but the biology of bone metastases is poorly understood. The overall aim of this study was therefore to explore molecular variability in PC bone metastases of potential importance for therapy. Specifically, genome‐wide expression profiles of bone metastases from untreated patients ( n = 12) and patients treated with androgen‐deprivation therapy (ADT, n = 60) were analyzed in relation to patient outcome and to morphological characteristics in metastases and paired primary tumors. Principal component analysis and unsupervised classification were used to identify sample clusters based on mRNA profiles. Clusters were characterized by gene set enrichment analysis and related to histological and clinical parameters using univariate and multivariate statistics. Selected proteins were analyzed by immunohistochemistry in metastases and matched primary tumors ( n = 52) and in transurethral resected prostate (TUR‐P) tissue of a separate cohort ( n = 59). Three molecular subtypes of bone metastases (MetA‐C) characterized by differences in gene expression pattern, morphology, and clinical behavior were identified. MetA (71% of the cases) showed increased expression of androgen receptor‐regulated genes, including prostate‐specific antigen (PSA), and glandular structures indicating a luminal cell phenotype. MetB (17%) showed expression profiles related to cell cycle activity and DNA damage, and a pronounced cellular atypia. MetC (12%) exhibited enriched stroma–epithelial cell interactions. MetB patients had the lowest serum PSA levels and the poorest prognosis after ADT. Combined analysis of PSA and Ki67 immunoreactivity (proliferation) in bone metastases, paired primary tumors, and TUR‐P samples was able to differentiate MetA‐like (high PSA, low Ki67) from MetB‐like (low PSA, high Ki67) tumors and demonstrate their different prognosis. In conclusion, bone metastases from PC patients are separated based on gene expression profiles into molecular subtypes with different morphology, biology, and clinical outcome. These findings deserve further exploration with the purpose of improving treatment of metastatic PC.

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Microenvironmental control of breast cancer subtype elicited through paracrine platelet-derived growth factor-CC signaling

Cited by 132 publications

References 68 publications

The impact of cancer-associated fibroblasts on major hallmarks of pancreatic cancer

The impact of cancer-associated fibroblasts on major hallmarks of pancreatic cancer

Targeted imaging and inhibition of triple-negative breast cancer metastases by a PDGFRβ aptamer

Gene expression profiles define molecular subtypes of prostate cancer bone metastases with different outcomes and morphology traceable back to the primary tumor

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