The BMP Inhibitor Coco Reactivates Breast Cancer Cells at Lung Metastatic Sites

Gao, Hua; Chakraborty, Goutam; Lee-Lim, Ai Ping; Mo, Qianxing; Decker, Markus; Vonica, Alin; Shen, Ronglai; Brogi, Edi; Brivanlou, Ali H.; Giancotti, Filippo G.

doi:10.1016/j.cell.2012.06.035

Cited by 373 publications

(357 citation statements)

References 59 publications

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“…In contrast, the 4TO7 cells infected with the 4T1 libraries produced a total of nine lung nodules in multiple mice within 60 d (Fig. S2A) (12). Thirty mice injected with 4TO7 cells infected with empty vector did not produce macroscopic lung metastases, indicating that insertional mutagenesis does not contribute to metastasis in this system.…”

Section: Significancementioning

confidence: 97%

“…The remaining three cDNAs were able to promote lung metastasis upon reintroduction in 4TO7 cells (12). One of these cDNAs was recovered from two distinct lesions and found to encode for an N-terminally truncated form of the secreted TGF-β ligand inhibitor Coco (encoded by Dand5) (Fig.…”

Section: Significancementioning

confidence: 99%

“…Second, the completion of each of the steps of metastasis requires the acquisition of multiple capabilities, suggesting the possible involvement of several genes. We have recently identified a mouse xenograft model that effectively mimics metastatic dormancy and reactivation of breast cancer (12). Here, we describe a flexible and highthroughput functional genomic platform that enables the identification of single genes that enforce dormancy or mediate metastatic reactivation of breast cancer.…”

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confidence: 99%

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Forward genetic screens in mice uncover mediators and suppressors of metastatic reactivation

Gao

Chakraborty²,

Lee-Lim³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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We have developed a screening platform for the isolation of genetic entities involved in metastatic reactivation. Retroviral libraries of cDNAs from fully metastatic breast-cancer cells or pooled microRNAs were transduced into breast-cancer cells that become dormant upon infiltrating the lung. Upon inoculation in the tail vein of mice, the cells that had acquired the ability to undergo reactivation generated metastatic lesions. Integrated retroviral vectors were recovered from these lesions, sequenced, and subjected to a second round of validation. By using this strategy, we isolated canonical genes and microRNAs that mediate metastatic reactivation in the lung. To identify genes that oppose reactivation, we screened an expression library encoding shRNAs, and we identified target genes that encode potential enforcers of dormancy. Our screening strategy enables the identification and rapid biological validation of single genetic entities that are necessary to maintain dormancy or to induce reactivation. This technology should facilitate the elucidation of the molecular underpinnings of these processes.forward genetic screens | metastatic reactivation | cDNA library screen | shRNA library screen | microRNA library screen T he majority of cancer-related deaths are caused by metastatic relapse (1). The process through which cancer cells acquire metastatic capacity is complex. Unrestrained proliferation, resistance to proapoptotic insults, and invasion through tissue boundaries are not sufficient for metastasis. To colonize distant organs, cancer cells must also adapt to the local microenvironment of the target organ and finally outgrow (2, 3). Mathematical modeling of clinical data and experiments in mouse models suggest that cancer cells disseminating from prevalent cancers, such as those of the breast and prostate, undergo an extended period of dormancy at premetastatic sites (4). Insights into the mechanisms that enable disseminated cancer cells to survive during dormancy and then outgrow into life-threatening lesions may lead to the identification of novel therapeutic targets for the prevention or treatment of metastatic disease.Advances in genomics and mouse modeling have fostered a renaissance of studies on metastasis (2, 3). Current approaches to the study of metastasis can be divided in two categories. In the first, genetic methods are used to modify the function of a candidate gene in intact mice or in cells that are subsequently transplanted in mice (5, 6). In the second, genomic methods, such as DNA microarray analysis or array comparative genomic hybridization (aCGH), are used to identify a restricted number of candidate genes, which are then tested in appropriate mouse models (7,8). Although these approaches have been extremely successful, they are very laborious and do not necessarily yield biologically potent mediators of metastasis. Functional genetic screens can lead to the rapid identification of strong mediators of a selectable phenotype (9, 10). In agreement with this notion, recent studies have ...

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Section: Significancementioning

confidence: 97%

Section: Significancementioning

confidence: 99%

mentioning

confidence: 99%

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Forward genetic screens in mice uncover mediators and suppressors of metastatic reactivation

Gao

Chakraborty²,

Lee-Lim³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…To our knowledge, these are the first VHHs that can effectively inhibit BMP4 function, while leaving important homeostatic functions of the other BMPs intact. Unselective inhibition of BMP signaling in mice has been shown to increase tumor burden (26) and activation of metastatic dormancy of breast cancer cells (25). Thus, Experiments were repeated at least 3 times with experimental triplicates each.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, the clinical use of current BMP inhibitors is questionable (24). For instance, in vivo treatment with the natural antagonist Coco or the chemical inhibitor LDN-193189 results in reactivation of breast cancer (25) or colon tumor burden (26) in mice with a particular mutational phenotype, respectively. Therefore, these off-target effects could lead to undesirable side effects if used in the clinic.…”

Section: Introductionmentioning

confidence: 99%

Effective Inhibition of Bone Morphogenetic Protein Function by Highly Specific Llama-Derived Antibodies

Calpe

Wagner

Khattabi³

et al. 2015

Molecular Cancer Therapeutics

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Bone morphogenetic proteins (BMP) have important but distinct roles in tissue homeostasis and disease, including carcinogenesis and tumor progression. A large number of BMP inhibitors are available to study BMP function; however, as most of these antagonists are promiscuous, evaluating specific effects of individual BMPs is not feasible. Because the oncogenic role of the different BMPs varies for each neoplasm, highly selective BMP inhibitors are required. Here, we describe the generation of three types of llama-derived heavy chain variable domains (VHH) that selectively bind to either BMP4, to BMP2 and 4, or to BMP2, 4, 5, and 6. These generated VHHs have high affinity to their targets and are able to inhibit BMP signaling. Epitope binning and docking modeling have shed light into the basis for their BMP specificity. As opposed to the wide structural reach of natural inhibitors, these small molecules target the grooves and pockets of BMPs involved in receptor binding. In organoid experiments, specific inhibition of BMP4 does not affect the activation of normal stem cells. Furthermore, in vitro inhibition of cancer-derived BMP4 noncanonical signals results in an increase of chemosensitivity in a colorectal cancer cell line. Therefore, because of their high specificity and low off-target effects, these VHHs could represent a therapeutic alternative for BMP4 þ malignancies.

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Circulating and disseminated tumor cells: harbingers or initiators of metastasis?

2017

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Tumor cells leave the primary tumor and enter the circulation. Once there, they are called circulating tumor cells (CTCs). A fraction of CTCs are capable of entering distant sites and persisting as disseminated tumor cells (DTCs). An even smaller fraction of DTCs are capable of progressing toward metastases. It is known that the DTC microenvironment plays an important role in sustaining their survival, regulating their growth, and conferring resistance to therapy. But we still have much to learn about the nature of these rare cell populations to predict which will progress and what exactly should cause concern for future relapse. Although recent technological advances in our ability to detect and molecularly and functionally characterize CTCs and DTCs promise to unravel this ambiguity, the timing of dissemination and the precise source of CTCs and DTCs profiled will impact the conclusions that can be made from these endeavors. In this review, we discuss the biology of CTCs and DTCs; the technologies to detect, isolate, and profile these cells; and the exceptions we must apply to our understanding of what role these cells play in the metastatic process. We conclude that a greater effort to understand the unique biology of these cells in context will positively impact our ability to use these cells to predict outcome, monitor treatment efficacy, and reveal therapeutically relevant targets to deplete these populations and ultimately prevent metastasis.

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The BMP Inhibitor Coco Reactivates Breast Cancer Cells at Lung Metastatic Sites

Cited by 373 publications

References 59 publications

Forward genetic screens in mice uncover mediators and suppressors of metastatic reactivation

Forward genetic screens in mice uncover mediators and suppressors of metastatic reactivation

Effective Inhibition of Bone Morphogenetic Protein Function by Highly Specific Llama-Derived Antibodies

Circulating and disseminated tumor cells: harbingers or initiators of metastasis?

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