ORCID Profile
0000-0001-6207-6690
Current Organisation
Peter MacCallum Cancer Centre
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Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424149
Abstract: PCR primers
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424167.V1
Abstract: Figure S1 shows the association of BMP4 expression with tumour aggressiveness and with metastasis-free survival
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424167
Abstract: Figure S1 shows the association of BMP4 expression with tumour aggressiveness and with metastasis-free survival
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424146
Abstract: BMP4 expression in human breast cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424140.V1
Abstract: BMP4 and SMAD7 in clinical s les
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424146.V1
Abstract: BMP4 expression in human breast cancer
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6511693
Abstract: Abstract Metastasis is the major cause of death in patients with cancer with no therapeutic cure, treatments remain largely palliative. As such, new targets and therapeutic strategies are urgently required. Here, we show that bone morphogenetic protein-4 (BMP4) blocks metastasis in animal models of breast cancer and predicts improved survival in patients. In preclinical models of spontaneous metastasis, BMP4 acted as an autocrine mediator to modulate a range of known metastasis-regulating genes, including i Smad7 /i , via activation of canonical BMP-SMAD signaling. Restored BMP4 expression or therapeutically administered BMP4 protein, blocked metastasis and increased survival by sensitizing cancer cells to anoikis, thereby reducing the number of circulating tumor cells. Gene silencing of i Bmp4 /i or its downstream mediator i Smad7 /i , reversed this phenotype. Administration of recombinant BMP4 markedly reduced spontaneous metastasis to lung and bone. Elevated levels of BMP4 and SMAD7 were prognostic for improved recurrence-free survival and overall survival in patients with breast cancer, indicating the importance of canonical BMP4 signaling in the suppression of metastasis and highlighting new avenues for therapy against metastatic disease. Significance: Targeting the BMP4–SMAD7 signaling axis presents a novel therapeutic strategy to combat metastatic breast cancer, a disease that has had no reduction in patient mortality over 20 years. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424164
Abstract: Figure S2 shows the effect of BMP4 on the in vitro properties of tumour cells and response of tumours in vivo.
Publisher: Elsevier BV
Date: 2021
DOI: 10.1016/J.DRUDIS.2021.08.010
Abstract: The development of novel therapeutics is associated with high rates of attrition, with unexpected adverse events being a major cause of failure. Serious adverse events have led to organ failure, cancer development and deaths that were not expected outcomes in clinical trials. These life-threatening events were not identified during therapeutic development due to the lack of preclinical safety tests that faithfully represented human physiology. We highlight the successful application of several novel technologies, including high-throughput screening, organs-on-chips, microbiome-containing drug-testing platforms and humanised mouse models, for mechanistic studies and prediction of toxicity. We propose the incorporation of similar preclinical tests into future drug development to reduce the likelihood of hazardous therapeutics entering later-stage clinical trials.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424143
Abstract: Anoikis genes regulated by BMP4
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.C.6511693.V1
Abstract: Abstract Metastasis is the major cause of death in patients with cancer with no therapeutic cure, treatments remain largely palliative. As such, new targets and therapeutic strategies are urgently required. Here, we show that bone morphogenetic protein-4 (BMP4) blocks metastasis in animal models of breast cancer and predicts improved survival in patients. In preclinical models of spontaneous metastasis, BMP4 acted as an autocrine mediator to modulate a range of known metastasis-regulating genes, including i Smad7 /i , via activation of canonical BMP-SMAD signaling. Restored BMP4 expression or therapeutically administered BMP4 protein, blocked metastasis and increased survival by sensitizing cancer cells to anoikis, thereby reducing the number of circulating tumor cells. Gene silencing of i Bmp4 /i or its downstream mediator i Smad7 /i , reversed this phenotype. Administration of recombinant BMP4 markedly reduced spontaneous metastasis to lung and bone. Elevated levels of BMP4 and SMAD7 were prognostic for improved recurrence-free survival and overall survival in patients with breast cancer, indicating the importance of canonical BMP4 signaling in the suppression of metastasis and highlighting new avenues for therapy against metastatic disease. Significance: Targeting the BMP4–SMAD7 signaling axis presents a novel therapeutic strategy to combat metastatic breast cancer, a disease that has had no reduction in patient mortality over 20 years. /
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424161
Abstract: Figure S3 shows that BMP4 does not alter migration or invasion in vitro and that BMP7 can also inhibit metastasis.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424140
Abstract: BMP4 and SMAD7 in clinical s les
Publisher: The Company of Biologists
Date: 2018
DOI: 10.1242/DMM.034850
Abstract: Breast cancer brain metastasis remains largely incurable. While several mouse models have been developed to investigate the genes and mechanisms regulating breast cancer brain metastasis, these models often lack clinical relevance since they require the use of immune-compromised mice and/or are poorly metastatic to brain from the mammary gland. We describe the development and characterisation of an aggressive brain metastatic variant of the 4T1 syngeneic model (4T1Br4) that spontaneously metastasises to multiple organs, but is selectively more metastatic to the brain from the mammary gland than parental 4T1 tumours. By immunohistochemistry, 4T1Br4 tumours and brain metastases display a triple negative phenotype, consistent with the high propensity of this breast cancer subtype to spread to brain. In vitro assays indicate that 4T1Br4 cells have an enhanced ability to adhere to or migrate across a brain-derived endothelial monolayer and greater invasive response to brain-derived soluble factors compared to 4T1 cells. These properties are likely to contribute to the brain-selectivity of 4T1Br4 tumours. Expression profiling and gene set enrichment analyses demonstrate the clinical relevance of the 4T1Br4 model at the transcriptomic level. Pathway analyses implicate tumour-intrinsic immune regulation and vascular interactions in successful brain colonisation, revealing potential therapeutic targets. Evaluation of two histone deacetylase inhibitors, SB939 and 1179.4b, shows partial efficacy against 4T1Br4 metastasis to brain and other sites in vivo and potent radio-sensitising properties in vitro. The 4T1Br4 model provides a clinically relevant tool for mechanistic studies and to evaluate novel therapies against brain metastasis.
Publisher: Springer Science and Business Media LLC
Date: 11-02-2014
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424152.V1
Abstract: Supplementary methods
Publisher: Cold Spring Harbor Laboratory
Date: 06-04-2018
DOI: 10.1101/296384
Abstract: Breast cancer brain metastasis remains largely incurable. While several mouse models have been developed to investigate the genes and mechanisms regulating breast cancer brain metastasis, these models often lack clinical relevance since they require the use of immune-compromised mice and/or are poorly metastatic to brain from the mammary gland. We describe the development and characterisation of an aggressive brain metastatic variant of the 4T1 syngeneic model (4T1Br4) that spontaneously metastasises to multiple organs, but is selectively more metastatic to the brain from the mammary gland than parental 4T1 tumours. By immunohistochemistry, 4T1Br4 tumours and brain metastases display a triple negative phenotype, consistent with the high propensity of this breast cancer subtype to spread to brain. In vitro assays indicate that 4T1Br4 cells have an enhanced ability to adhere to or migrate across a brain-derived endothelial monolayer and greater invasive response to brain-derived soluble factors compared to 4T1 cells. These properties are likely to contribute to the brain-selectivity of 4T1Br4 tumours. Expression profiling and gene set enrichment analyses demonstrate the clinical relevance of the 4T1Br4 model at the transcriptomic level. Pathway analyses implicate tumour-intrinsic immune regulation and vascular interactions in successful brain colonisation, revealing potential therapeutic targets. Evaluation of two histone deacetylase inhibitors, SB939 and 1179.4b, shows partial efficacy against 4T1Br4 metastasis to brain and other sites in vivo and potent radio-sensitising properties in vitro . The 4T1Br4 model provides a clinically relevant tool for mechanistic studies and to evaluate novel therapies against brain metastasis. We introduce a new syngeneic mouse model of spontaneous breast cancer brain metastasis, demonstrate its phenotypic, functional and transcriptomic relevance to human TNBC brain metastasis and test novel therapies.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424149.V1
Abstract: PCR primers
Publisher: American Association for Cancer Research (AACR)
Date: 13-03-2020
DOI: 10.1158/0008-5472.CAN-19-0743
Abstract: Targeting the BMP4–SMAD7 signaling axis presents a novel therapeutic strategy to combat metastatic breast cancer, a disease that has had no reduction in patient mortality over 20 years.
Publisher: Springer Science and Business Media LLC
Date: 11-07-2022
DOI: 10.1038/S41389-022-00413-7
Abstract: MiR-21 was identified as a gene whose expression correlated with the extent of metastasis of murine mammary tumours. Since miR-21 is recognised as being associated with poor prognosis in cancer, we investigated its contribution to mammary tumour growth and metastasis in tumours with capacity for spontaneous metastasis. Unexpectedly, we found that suppression of miR-21 activity in highly metastatic tumours resulted in regression of primary tumour growth in immunocompetent mice but did not impede growth in immunocompromised mice. Analysis of the immune infiltrate of the primary tumours at the time when the tumours started to regress revealed an influx of both CD4 + and CD8 + activated T cells and a reduction in PD-L1 + infiltrating monocytes, providing an explanation for the observed tumour regression. Loss of anti-tumour immune suppression caused by decreased miR-21 activity was confirmed by transcriptomic analysis of primary tumours. This analysis also revealed reduced expression of genes associated with cell cycle progression upon loss of miR-21 activity. A second activity of miR-21 was the promotion of metastasis as shown by the loss of metastatic capacity of miR-21 knockdown tumours established in immunocompromised mice, despite no impact on primary tumour growth. A proteomic analysis of tumour cells with altered miR-21 activity revealed deregulation of proteins known to be associated with tumour progression. The development of therapies targeting miR-21, possibly via targeted delivery to tumour cells, could be an effective therapy to combat primary tumour growth and suppress the development of metastatic disease.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424164.V1
Abstract: Figure S2 shows the effect of BMP4 on the in vitro properties of tumour cells and response of tumours in vivo.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424158
Abstract: Figure S4 demonstrates a role for SMAD7 in mediating the inhibition of metastasis by BMP4.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424143.V1
Abstract: Anoikis genes regulated by BMP4
Publisher: Informa UK Limited
Date: 04-03-2019
DOI: 10.1080/08977194.2019.1626378
Abstract: Breast cancer is the most prevalent type of cancer amongst women worldwide. The mortality rate for patients with early-stage breast cancer has been decreasing, however, the 5-year survival rate for patients with metastatic disease remains poor, currently at 27%. Here, we have reviewed the current understanding of the role of bone morphogenetic protein (BMP) signaling in breast cancer progression, and have highlighted the discordant results that are reported in different studies. We propose that some of these contradictory outcomes may result from signaling through either the canonical or non-canonical pathways in different cell lines and tumors, or from different tumor-stromal interactions that occur
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424152
Abstract: Supplementary methods
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424155
Abstract: Legends for the four supplementary figures.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424158.V1
Abstract: Figure S4 demonstrates a role for SMAD7 in mediating the inhibition of metastasis by BMP4.
Publisher: Springer Science and Business Media LLC
Date: 15-12-2015
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424155.V1
Abstract: Legends for the four supplementary figures.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/0008-5472.22424161.V1
Abstract: Figure S3 shows that BMP4 does not alter migration or invasion in vitro and that BMP7 can also inhibit metastasis.
Publisher: Routledge
Date: 05-08-2016
No related grants have been discovered for Andreas Pyka.