The androgen receptor/filamin A complex as a target in prostate cancer microenvironment

Donato, Marzia Di; Zamagni, Alice; Galasso, Giovanni; Zazzo, Erika Di; Giovannelli, Pia; Barone, Maria Vittoria; Zanoni, Michele; Gunelli, Roberta; Costantini, Matteo; Auricchio, Ferdinando; Migliaccio, Antimo; Tesei, Anna; Castoria, Gabriella

doi:10.1038/s41419-021-03402-7

Cited by 53 publications

(68 citation statements)

References 72 publications

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“…CM was collected and centrifuged, while the cells were detached by trypsin and counted. CM was normalized to 1 × 10 6 MDA-MB-231 cells and MMP-9 proteolytic activity was assayed in CM as reported ( Di Donato et al, 2021 ). It appeared as a clear band migrating at ≈92 kDa on a blue background.…”

Section: Methodsmentioning

confidence: 99%

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Targeting the Nerve Growth Factor Signaling Impairs the Proliferative and Migratory Phenotype of Triple-Negative Breast Cancer Cells

Donato

Galasso

Giovannelli

et al. 2021

Front. Cell Dev. Biol.

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Triple-negative breast cancer is a heterogeneous disease that still lacks specific therapeutic approaches. The identification of new biomarkers, predictive of the disease’s aggressiveness and pharmacological response, is a challenge for a more tailored approach in the clinical management of patients. Nerve growth factor, initially identified as a key factor for neuronal survival and differentiation, turned out to be a multifaceted molecule with pleiotropic effects in quite divergent cell types, including cancer cells. Many solid tumors exhibit derangements of the nerve growth factor and its receptors, including the tropomyosin receptor kinase A. This receptor is expressed in triple-negative breast cancer, although its role in the pathogenesis and aggressiveness of this disease is still under investigation. We now report that triple-negative breast cancer-derived MDA-MB-231 and MDA-MB-453 cells express appreciable levels of tropomyosin receptor kinase A and release a biologically active nerve growth factor. Activation of tropomyosin receptor kinase by nerve growth factor treatment positively affects the migration, invasion, and proliferation of triple-negative breast cancer cells. An increase in the size of triple-negative breast cancer cell spheroids is also detected. This latter effect might occur through the nerve growth factor-induced release of matrix metalloproteinase 9, which contributes to the reorganization of the extracellular matrix and cell invasiveness. The tropomyosin receptor kinase A inhibitor GW441756 reverses all these responses. Co-immunoprecipitation experiments in both cell lines show that nerve growth factor triggers the assembly of the TrkA/β1-integrin/FAK/Src complex, thereby activating several downstream effectors. GW441756 prevents the complex assembly induced by nerve growth factor as well as the activation of its dependent signaling. Pharmacological inhibition of the tyrosine kinases Src and FAK (focal adhesion kinase), together with the silencing of β1-integrin, shows that the tyrosine kinases impinge on both proliferation and motility, while β1-integrin is needed for motility induced by nerve growth factor in triple-negative breast cancer cells. The present data support the key role of the nerve growth factor/tropomyosin receptor kinase A pathway in triple-negative breast cancer and offer new hints in the diagnostic and therapeutic management of patients.

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Section: Methodsmentioning

confidence: 99%

“…Spheroids were generated as reported ( Di Donato et al, 2021 ). MDA-MB-231 and MDA-MB-453 cells (3 × 10 4 ) were mixed in each well with 250 μl of phenol red-free growth factor-reduced Matrigel (10 mg/ml; BD Biosciences) and 50 μl of spheroid plating medium.…”

Section: Methodsmentioning

confidence: 99%

Targeting the Nerve Growth Factor Signaling Impairs the Proliferative and Migratory Phenotype of Triple-Negative Breast Cancer Cells

Donato

Galasso

Giovannelli

et al. 2021

Front. Cell Dev. Biol.

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“…The phosphorylated p27 at Ser 10 was stabilized and attributable to cell cycle arrest at G0/G1 of fibroblasts (Castoria et al, 2014). Meanwhile, the AR/FlnA complex also triggered the activation of focal adhesion kinase FAK, Rac1, and paxillin via recruiting integrin beta 1, promoting cell migration of NIH3T3, HT1080 cells, and PCa-derived fibroblasts (Castoria et al, 2011;Di Donato et al, 2021). These findings suggest the therapeutic value of targeting the AR/FlnA complex to suppress the malignant activity of CAFs.…”

Section: Interaction Between Androgen Receptor Signaling In Cancer-associated Fibroblasts and Prostate Cancermentioning

confidence: 86%

The Role of Androgen Receptor in Cross Talk Between Stromal Cells and Prostate Cancer Epithelial Cells

Tang

Cheng

Dai

et al. 2021

Front. Cell Dev. Biol.

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Prostate cancer (PCa) lists as the second most lethal cancer for men in western countries, and androgen receptor (AR) plays a central role in its initiation and progression, which prompts the development of androgen deprivation therapy (ADT) as the standard treatment. Prostate tumor microenvironment, consisting of stromal cells and extracellular matrix (ECM), has dynamic interactions with PCa epithelial cells and affects their growth and invasiveness. Studies have shown that both genomic and non-genomic AR signaling pathways are involved in the biological regulation of PCa epithelial cells. In addition, AR signaling in prostate stroma is also involved in PCa carcinogenesis and progression. Loss of AR in PCa stroma is clinically observed as PCa progresses to advanced stage. Especially, downregulation of AR in stromal fibroblasts dysregulates the expression levels of ECM proteins, thus creating a suitable environment for PCa cells to metastasize. Importantly, ADT treatment enhances this reciprocal interaction and predisposes stromal cells to promote cell invasion of PCa cells. During this process, AR in PCa epithelium actively responds to various stimuli derived from the surrounding stromal cells and undergoes enhanced degradation while elevating the expression of certain genes such as MMP9 responsible for cell invasion. AR reduction in epithelial cells also accelerates these cells to differentiate into cancer stem-like cells and neuroendocrine cells, which are AR-negative PCa cells and inherently resistant to ADT treatments. Overall, understanding of the cross talk between tumor microenvironment and PCa at the molecular level may assist the development of novel therapeutic strategies against this disease. This review will provide a snapshot of AR’s action when the interaction of stromal cells and PCa cells occurs.

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“…These CAFs are components of the tumor microenvironment playing crucial roles in tumor progression and treatment response [60,61]. Interesting approaches were developed by Di Donato et al [23]., where the prostate tumor growth was stimulated by androgen in co-cultures using CAFs derived from patients with positive AR (androgen receptor) and cell lines that were either AR positive or negative [23]. Bladder cancer progression, migration, and invasion were also shown to be triggered by factors secreted by CAFs [22].…”

Section: Discussionmentioning

confidence: 99%

“…Bladder cancer progression, migration, and invasion were also shown to be triggered by factors secreted by CAFs [22]. In both cases, inhibiting CAF signaling sufficed to decrease tumor aggressiveness [22,23]. Although several studies indicated the influence of the microenvironment in response to chemotherapy, we selected only cells showing epithelial features (cells 2 and 3) to evaluate the treatment response since the selected drugs target the tumor cells and not the microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Penile Cancer-Derived Cells Molecularly Characterized as Models to Guide Targeted Therapies

Kuasne

Canto

Aagaard

et al. 2021

Cells

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Penile cancer (PeCa) is a common disease in poor and developing countries, showing high morbidity rates. Despite the recent progress in understanding the molecular events involved in PeCa, the lack of well-characterized in vitro models precludes new advances in anticancer drug development. Here we describe the establishment of five human primary penile cancer-derived cell cultures, including two epithelial and three cancer-associated fibroblast (CAF) cells. Using high-throughput genomic approaches, we found that the epithelial PeCa derived- cells recapitulate the molecular alterations of their primary tumors and present the same deregulated signaling pathways. The differentially expressed genes and proteins identified are components of key oncogenic pathways, including EGFR and PI3K/AKT/mTOR. We showed that epithelial PeCa derived cells presented a good response to cisplatin, a common therapeutic approach used in PeCa patients. The growth of a PeCa-derived cell overexpressing EGFR was inhibited by EGFR inhibitors (cetuximab, gefitinib, and erlotinib). We also identified CAF signature markers in three PeCa-derived cells with fibroblast-like morphology, indicating that those cells are suitable models for PeCa microenvironment studies. We thus demonstrate the utility of PeCa cell models to dissect mechanisms that promote penile carcinogenesis, which are useful models to evaluate therapeutic approaches for the disease.

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The androgen receptor/filamin A complex as a target in prostate cancer microenvironment

Cited by 53 publications

References 72 publications

Targeting the Nerve Growth Factor Signaling Impairs the Proliferative and Migratory Phenotype of Triple-Negative Breast Cancer Cells

Targeting the Nerve Growth Factor Signaling Impairs the Proliferative and Migratory Phenotype of Triple-Negative Breast Cancer Cells

The Role of Androgen Receptor in Cross Talk Between Stromal Cells and Prostate Cancer Epithelial Cells

Penile Cancer-Derived Cells Molecularly Characterized as Models to Guide Targeted Therapies

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