Axl is required for TGF-β2-induced dormancy of prostate cancer cells in the bone marrow

Yumoto, Kenji; Eber, Matthew R.; Wang, Jingcheng; Cackowski, Frank C.; Decker, Ann M.; Lee, Eunsohl; Nobre, Ana Rita; Aguirre‐Ghiso, Julio A.; Jung, Younghun; Taichman, Russell S.

doi:10.1038/srep36520

Cited by 144 publications

(138 citation statements)

References 46 publications

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“…In retrospect, it would have been useful in include MERTK in these studies. Our most recent work, currently in press, confirms the earlier hypothesis regarding AXL and shows that AXL is required for TGF-β2 induced prostate cancer dormancy(Yumoto 2016). However, prior to the current work, the contribution of MERTK to prostate cancer dormancy remained completely unclear.…”

Section: Discussionsupporting

confidence: 87%

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Mer Tyrosine Kinase Regulates Disseminated Prostate Cancer Cellular Dormancy

Cackowski

Eber

Rhee

et al. 2016

J of Cellular Biochemistry

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Many prostate cancer (PCa) recurrences are thought to be due to reactivation of disseminated tumor cells (DTCs). We previously found a role of the TAM family of receptor tyrosine kinases TYRO3, AXL and MERTK in PCa dormancy regulation. However, the mechanism and contributions of the individual TAM receptors is largely unknown. Knockdown of MERTK, but not AXL or TYRO3 by shRNA in PCa cells induced a decreased ratio of P-Erk1/2 to P-p38, increased expression of p27, NR2F1, SOX2, and NANOG, induced higher levels of histone H3K9me3 and H3K27me3, and induced a G1/G0 arrest, all of which are associated with dormancy. Similar effects were also observed with siRNA. Most importantly, knock down of MERTK in PCa cells increased metastasis free survival in an intra-cardiac injection mouse xenograft model. MERTK knockdown also failed to inhibit PCa growth in vitro and subcutaneous growth in vivo, which suggests that MERTK has specificity for dormancy regulation or requires a signal from the PCa microenvironment. The effects of MERTK on the cell cycle and histone methylation were reversed by p38 inhibitor SB203580, which indicates the importance of MAP kinases for MERTK dormancy regulation. Overall, this study shows that MERTK stimulates prostate cancer dormancy escape through a MAP kinase dependent mechanism, also involving p27, pluripotency transcription factors, and histone methylation.

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Section: Discussionsupporting

confidence: 87%

“…However, these studies did not include experiments to test this hypothesis further than gene expression. Most recently, in work that is currently in press, we reported that AXL is required for TGF2 to induce prostate cancer dormancy (Yumoto 2016). However, the contributions of MERTK and TYRO3 remain unclear.…”

mentioning

confidence: 99%

Mer Tyrosine Kinase Regulates Disseminated Prostate Cancer Cellular Dormancy

Cackowski

Eber

Rhee

et al. 2016

J of Cellular Biochemistry

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“…Previously we have observed that GAS6 expression by osteoblasts regulates PCa dormancy through interactions with MERTK (8,29,30,33). First, we sought to confirm the GAS6 mRNA results at the protein level.…”

Section: Resultsmentioning

confidence: 97%

“…Previously we determined that when PCa cells become proliferatively quiescent when co-cultured with osteoblasts (8,29,30). To determine whether NE is able to alter the quiescence of PCa cells induced by osteoblasts, co-culture experiments were performed where in the human PCa cells were selectively analyzed using antibodies specific for human HLA.…”

Section: Resultsmentioning

confidence: 99%

“…One mechanism suggested to be involved in PCa dormancy includes osteoblastic secretion of BMP7, which activates p38/MAPK signaling pathway signaling of PCa cells (7). It has also been demonstrated that expression of paracrine TGF-β (from local osteoblasts) and autocrine expression of TGF-β (from PCa cells) in turn can induce PCa dormancy (8). TGF-β2 signaling initiates a dormant state in DTCs through up-regulation of p27, a ubiquitous cell cycle inhibitor through phosphorylation of p38 and downstream activation of Smad2 and Smad 1/5 with a resultant phenotype of TGF-β2 high , (ERK/p38) low , DEC2 high , p53 high , p27 high and P-H3 low (9).…”

Section: Introductionmentioning

confidence: 99%

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Sympathetic Signaling Reactivates Quiescent Disseminated Prostate Cancer Cells in the Bone Marrow

Decker

Jung

Cackowski

et al. 2017

Molecular Cancer Research

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Clinical observations have identified an association between psychological stress and cancer relapse; suggesting that the sympathetic nervous system/norepinephrine (NE) plays a role in reactivation of dormant disseminated tumor cells (DTCs) in the bone marrow niche. Here, the mechanism by which NE regulates prostate cancer (PCa) DTCs in the marrow is explored. NE directly stimulated PCa cell proliferation through β2-adrenergic receptors (ADRB2). NE also altered PCa proliferation in the marrow niche by indirectly by downregulating the secretion of the dormancy inducing molecule growth arrest specific-6 (GAS6) expressed by osteoblasts. These observations were confirmed in co-cultures of PCa cells expressing the fluorescent ubiquitination-based cell cycle reporters (FUCCI) and osteoblasts isolated from GAS6-deficient (GAS6−/−) animals. A novel ex vivo model system, using femurs harvested from GAS6+/+ or GAS6−/− mice, was used to confirm these results. As in co-culture, when PCa cells were injected into the marrow cavities of GAS6+/+ femurs, NE altered the PCa cell cycle. However, NE had less of an impact on PCa cells in femur explants isolated from GAS6−/− mice. Together, this study demonstrate that NE reactivates PCa cell-cycling through both a direct action on PCa cells and indirectly on adjacent niche cells

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Tumor dormancy in bone

Mayhew¹,

Omokehinde²,

Johnson

2019

Cancer Reports

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Background Bone marrow is a common site of metastasis for a number of tumor types, including breast, prostate, and lung cancer, but the mechanisms controlling tumor dormancy in bone are poorly understood. In breast cancer, while advances in drug development, screening practices, and surgical techniques have dramatically improved survival rates in recent decades, metastatic recurrence in the bone remains common and can develop years or decades after elimination of the primary tumor. Recent Findings It is now understood that tumor cells disseminate to distant metastatic sites at early stages of tumor progression, leaving cancer survivors at a high risk of recurrence. This review will discuss mechanisms of bone lesion development and current theories of how dormant cancer cells behave in bone, as well as a number of processes suspected to be involved in the maintenance of and exit from dormancy in the bone microenvironment. Conclusions The bone is a complex microenvironment with a multitude of cell types and processes. Many of these factors, including angiogenesis, immune surveillance, and hypoxia, are thought to regulate tumor cell entry and exit from dormancy in different bone marrow niches.

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Axl is required for TGF-β2-induced dormancy of prostate cancer cells in the bone marrow

Cited by 144 publications

References 46 publications

Mer Tyrosine Kinase Regulates Disseminated Prostate Cancer Cellular Dormancy

Mer Tyrosine Kinase Regulates Disseminated Prostate Cancer Cellular Dormancy

Sympathetic Signaling Reactivates Quiescent Disseminated Prostate Cancer Cells in the Bone Marrow

Tumor dormancy in bone

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