Publications by authors named "Andrea R Lim"

4 Publications

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Thorny ground, rocky soil: Tissue-specific mechanisms of tumor dormancy and relapse.

Semin Cancer Biol 2021 May 9. Epub 2021 May 9.

Public Health Sciences Division/Translational Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Electronic address:

Disseminated tumor cells (DTCs) spread systemically yet distinct patterns of metastasis indicate a range of tissue susceptibility to metastatic colonization. Distinctions between permissive and suppressive tissues are still being elucidated at cellular and molecular levels. Although there is a growing appreciation for the role of the microenvironment in regulating metastatic success, we have a limited understanding of how diverse tissues regulate DTC dormancy, the state of reversible quiescence and subsequent awakening thought to contribute to delayed relapse. Several themes of microenvironmental regulation of dormancy are beginning to emerge, including vascular association, co-option of pre-existing niches, metabolic adaptation, and immune evasion, with tissue-specific nuances. Conversely, DTC awakening is often associated with injury or inflammation-induced activation of the stroma, promoting a proliferative environment with DTCs following suit. We review what is known about tissue-specific regulation of tumor dormancy on a tissue-by-tissue basis, profiling major metastatic organs including the bone, lung, brain, liver, and lymph node. An aerial view of the barriers to metastatic growth may reveal common targets and dependencies to inform the therapeutic prevention of relapse.
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http://dx.doi.org/10.1016/j.semcancer.2021.05.007DOI Listing
May 2021

N-methyladenosine mRNA marking promotes selective translation of regulons required for human erythropoiesis.

Nat Commun 2019 10 10;10(1):4596. Epub 2019 Oct 10.

Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.

Many of the regulatory features governing erythrocyte specification, maturation, and associated disorders remain enigmatic. To identify new regulators of erythropoiesis, we utilize a functional genomic screen for genes affecting expression of the erythroid marker CD235a/GYPA. Among validating hits are genes coding for the N-methyladenosine (mA) mRNA methyltransferase (MTase) complex, including, METTL14, METTL3, and WTAP. We demonstrate that mA MTase activity promotes erythroid gene expression programs through selective translation of ~300 mA marked mRNAs, including those coding for SETD histone methyltransferases, ribosomal components, and polyA RNA binding proteins. Remarkably, loss of mA marks results in dramatic loss of H3K4me3 marks across key erythroid-specific KLF1 transcriptional targets (e.g., Heme biosynthesis genes). Further, each mA MTase subunit and a subset of their mRNAs targets are required for human erythroid specification in primary bone-marrow derived progenitors. Thus, mA mRNA marks promote the translation of a network of genes required for human erythropoiesis.
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http://dx.doi.org/10.1038/s41467-019-12518-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6787028PMC
October 2019

Targeting the perivascular niche sensitizes disseminated tumour cells to chemotherapy.

Nat Cell Biol 2019 02 21;21(2):238-250. Epub 2019 Jan 21.

Public Health Sciences Division/Translational Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

The presence of disseminated tumour cells (DTCs) in bone marrow is predictive of poor metastasis-free survival of patients with breast cancer with localized disease. DTCs persist in distant tissues despite systemic administration of adjuvant chemotherapy. Many assume that this is because the majority of DTCs are quiescent. Here, we challenge this notion and provide evidence that the microenvironment of DTCs protects them from chemotherapy, independent of cell cycle status. We show that chemoresistant DTCs occupy the perivascular niche (PVN) of distant tissues, where they are protected from therapy by vascular endothelium. Inhibiting integrin-mediated interactions between DTCs and the PVN, driven partly by endothelial-derived von Willebrand factor and vascular cell adhesion molecule 1, sensitizes DTCs to chemotherapy. Importantly, chemosensitization is achieved without inducing DTC proliferation or exacerbating chemotherapy-associated toxicities, and ultimately results in prevention of bone metastasis. This suggests that prefacing adjuvant therapy with integrin inhibitors is a viable clinical strategy to eradicate DTCs and prevent metastasis.
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http://dx.doi.org/10.1038/s41556-018-0267-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6948102PMC
February 2019

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

Mol Oncol 2017 01;11(1):40-61

Public Health Sciences Division/Translational Research Program and Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.

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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http://dx.doi.org/10.1002/1878-0261.12022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5423226PMC
January 2017