Targeting FOXA1-mediated repression of TGF-β signaling suppresses castration-resistant prostate cancer progression

Song, Bing; Su-Hong, Park，; Zhao, Jonathan C.; Fong, Ka Wing; Li, Shangze; Lee, Yongik; Yang, Yeqing; Sridhar, Subhasree; Lü, Xiaodong; Abdulkadir, Sarki A.; Vessella, Robert L.; Morrissey, Colm; Kuzel, Timothy M.; Catàlona, William J.; Yang, Ximing J.; Yu, Jindan

doi:10.1172/jci122367

Cited by 116 publications

(103 citation statements)

References 46 publications

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“…More broadly, we identify upregulation of expression programs associated with TGF-β signalling and EMT following exposure to enzalutamide. This is consistent with evidence from pre-clinical models that inhibition of TGF-β signalling promotes reversion of EMT and may sensitize cancer cells to enzalutamide 45,46 . Recent work focused on human mCRPC bone metastases identify tumour associated macrophages as a source of TGFB1 expression, providing a target cell population for further study and possible therapeutic targeting (Baryawno, N. et al .…”

Section: Discussionsupporting

confidence: 89%

Transcriptional mediators of treatment resistance in lethal prostate cancer

Cuoco

Crowdis

et al. 2020

Preprint

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Metastatic castration resistant prostate cancer (mCRPC) is primarily treated with therapies that prevent transcriptional activity of the androgen receptor (AR), cause DNA damage, or prevent cell division. Clinical resistance to these therapies, including second-generation androgen-targeting compounds such as enzalutamide and abiraterone, is nearly universal. Other treatment modalities, including immune checkpoint inhibitors, have provided minimal benefit except in rare subsets of patients1,2. Both tumour intrinsic and extrinsic cellular programs contributing to therapeutic resistance remain areas of active investigation. Here we use full-length single-cell RNA-sequencing (scRNA-seq) to identify the transcriptional states of cancer and immune cells in the mCRPC microenvironment. Within cancer cells, we identified transcriptional patterns that mediate a significant proportion of inherited risk for prostate cancer, extensive heterogeneity in AR splicing within and between tumours, and vastly divergent regulatory programs between adenocarcinoma and small cell carcinoma. Moreover, upregulation of TGF-β signalling and epithelial-mesenchymal transition (EMT) were both associated with resistance to enzalutamide. We found that some lymph node metastases, but no bone metastases, were heavily infiltrated by dysfunctional CD8+ T cells, including cells undergoing dramatic clonal expansion during enzalutamide treatment. Our findings suggest avenues for rational therapeutic approaches targeting both tumour-intrinsic and immunological pathways to combat resistance to current treatment options.

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Section: Discussionsupporting

confidence: 89%

Transcriptional mediators of treatment resistance in lethal prostate cancer

Cuoco

Crowdis

et al. 2020

Preprint

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“…TGF-b is widely reported to play a significant role in blocking immune responses, including the function of neutrophils [46][47][48], which significantly decreased in the early lung squamous carcinomas [49] and distinctly inhibited the expression of ORM1 in leukocytes in our study. Fridlender et al [41] also found that the blockade of TGF-b could induce the N1 phenotype in neutrophils, which express immunoactivating cytokines and low levels of arginase and are able to kill cancer cells.…”

Section: Discussionsupporting

confidence: 61%

Dramatically changed immune‐related molecules as early diagnostic biomarkers of non‐small cell lung cancer

Jin

et al. 2019

The FEBS Journal

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Non‐small cell lung cancer (NSCLC) is the main type of lung cancer, with a low 5‐year survival rate because of the absence of effective clinical biomarkers for early diagnosis. Based on the immunosurveillance theory, we proposed that changes in the immune system are more pronounced than tumour‐associated antigens during the early stage of cancer. Therefore, a new strategy was designed to screen early diagnostic biomarkers from peripheral leukocytes in early‐stage NSCLCs with transcriptome sequencing. A total of 358 immune‐related differentially expressed genes were identified between early‐NSCLC patients and healthy individuals. Orosomucoid‐1 (ORM1, a acute phase protein), the total ORM and chitotriosidase‐1 (involved in degradation of chitobiose) were selected for further verification in 210 serum samples by western blotting, ELISA and nephelometry immunoassay (based on immuno‐scatter turbidmetry). Receiver operating characteristic curve analysis show that ORM1 and total ORM have excellent diagnostic efficacies, with area under the curve of 0.862 and 0.920, respectively, which significantly distinguished very early‐NSCLC (IA) from healthy samples. Flow cytometry results showed that CD15+ neutrophils made up 73% of ORM1+ peripheral leukocytes. In mouse lung cancer model, serum ORM1, but not liver ORM1, changed significantly in the early stage of NSCLC. ORM1 expression in peripheral leukocytes was regulated by TGF‐β and mediated by the TGF‐β/Smad signalling pathway. Our results indicated that combined ORM and TGF‐β could be a promising clinical biomarker in the diagnosis of early NSCLC.

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“…These inhibitory NF-κβ effects could not be reversed by the incubation of cells with TGF-β, suggesting that these factors may synergistically induce invasion and EMT in prostate cancer cells [253]. TGF-β-mediated EMT can also be inhibited by Elf5 (through suppression of SMAD3 phosphorylation [254] or FoxA1 [255], and induced by SOX5 [105], CML, CRM1 [256], TRPM7 [257], or SENP1. Interestingly, the latter effect involves SENP1-induced deSUMOylation of SMAD4, leading to its inhibition and induction of EMT [258].…”

Section: Prostate Cancermentioning

confidence: 99%

TGF-β and microRNA Interplay in Genitourinary Cancers

Bogusławska¹,

Kryst

Poletajew

et al. 2019

Cells

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Genitourinary cancers (GCs) include a large group of different types of tumors localizing to the kidney, bladder, prostate, testis, and penis. Despite highly divergent molecular patterns, most GCs share commonly disturbed signaling pathways that involve the activity of TGF-β (transforming growth factor beta). TGF-β is a pleiotropic cytokine that regulates key cancer-related molecular and cellular processes, including proliferation, migration, invasion, apoptosis, and chemoresistance. The understanding of the mechanisms of TGF-β actions in cancer is hindered by the “TGF-β paradox” in which early stages of cancerogenic process are suppressed by TGF-β while advanced stages are stimulated by its activity. A growing body of evidence suggests that these paradoxical TGF-β actions could result from the interplay with microRNAs: Short, non-coding RNAs that regulate gene expression by binding to target transcripts and inducing mRNA degradation or inhibition of translation. Here, we discuss the current knowledge of TGF-β signaling in GCs. Importantly, TGF-β signaling and microRNA-mediated regulation of gene expression often act in complicated feedback circuits that involve other crucial regulators of cancer progression (e.g., androgen receptor). Furthermore, recently published in vitro and in vivo studies clearly indicate that the interplay between microRNAs and the TGF-β signaling pathway offers new potential treatment options for GC patients.

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Targeting FOXA1-mediated repression of TGF-β signaling suppresses castration-resistant prostate cancer progression

Cited by 116 publications

References 46 publications

Transcriptional mediators of treatment resistance in lethal prostate cancer

Transcriptional mediators of treatment resistance in lethal prostate cancer

Dramatically changed immune‐related molecules as early diagnostic biomarkers of non‐small cell lung cancer

TGF-β and microRNA Interplay in Genitourinary Cancers

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