Search

Many solid cancers metastasize to the bone and bone marrow (BM). This process may occur even before the diagnosis of primary tumors, as evidenced by the discovery of disseminated tumor cells (DTCs) in patients without occult malignancies. The cellular fates and metastatic progression of DTCs are determined by complicated interactions between cancer cells and BM niches. Not surprisingly, these niches also play important roles in normal biology, including homeostasis and turnover of skeletal and hematopoiesis systems. In this Review, we summarize recent findings on functions of BM niches in bone metastasis (BoMet), particularly during the early stage of colonization. In light of the rich knowledge of hematopoiesis and osteogenesis, we highlight how DTCs may progress into overt BoMet by taking advantage of niche cells and their activities in tissue turnover, especially those related to immunomodulation and bone repair., Introduction The bone is a common site of metastasis for many tumor types, particularly those of breast, prostate, lung, and multiple myeloma (1-3). Breast and prostate cancers are the most [...]

Summary In the era where transcriptome profiling moves toward single-cell and spatial resolutions, the traditional co-expression analysis lacks the power to fully utilize such rich information to unravel spatial gene associations. Here, we present a Python package called Spatial Enrichment Analysis of Gene Associations using L -index (SEAGAL) to detect and visualize spatial gene correlations at both single-gene and gene-set levels. Our package takes spatial transcriptomics datasets with gene expression and the aligned spatial coordinates as input. It allows for analyzing and visualizing genes' spatial correlations and cell types' colocalization within the precise spatial context. The output could be visualized as volcano plots and heatmaps with a few lines of code, thus providing an easy-yet-comprehensive tool for mining spatial gene associations. Availability and implementation The Python package SEAGAL can be installed using pip: https://pypi.org/project/seagal/. The source code and step-by-step tutorials are available at: https://github.com/linhuawang/SEAGAL. [ABSTRACT FROM AUTHOR]

MYC (also known as c-MYC) overexpression or hyperactivation is one of the most common drivers of human cancer. Despite intensive study, the MYC oncogene remains recalcitrant to therapeutic inhibition. MYC is a transcription factor, and many of its protumorigenic functions have been attributed to its ability to regulate gene expression programs (1-3). Notably, oncogenic MYC activation has also been shown to increase total RNA and protein production in many tissue and disease contexts (4-7). While such increases in RNA and protein production may endow cancer cells with pro-tumour hallmarks, this increase in synthesis may also generate new or heightened burden on MYC-driven cancer cells to process these macromolecules properly (8). Here we discover that the spliceosome is a new target of oncogenic stress in MYC-driven cancers. We identify BUD31 as a MYC-synthetic lethal gene in human mammary epithelial cells, and demonstrate that BUD31 is a component of the core spliceosome required for its assembly and catalytic activity. Core spliceosomal factors (such as SF3B1 and U2AF1) associated with BUD31 are also required to tolerate oncogenic MYC. Notably, MYC hyperactivation induces an increase in total precursor messenger RNA synthesis, suggesting an increased burden on the core spliceosome to process pre-mRNA. In contrast to normal cells, partial inhibition of the spliceosome in MYC-hyperactivated cells leads to global intron retention, widespread defects in pre-mRNA maturation, and deregulation of many essential cell processes. Notably, genetic or pharmacological inhibition of the spliceosome in vivo impairs survival, tumorigenicity and metastatic proclivity of MYC-dependent breast cancers. Collectively, these data suggest that oncogenic MYC confers a collateral stress on splicing, and that components of the spliceosome may be therapeutic entry points for aggressive MYC-driven cancers., To discover genes and cellular processes required to tolerate oncogenic MYC expression, we previously performed a genome-wide MYC-synthetic lethal screen in human mammary epithelial cells (HMECs) engineered with an inducible [...]

A better understanding of the mechanisms regulating cancer metastasis is critical to develop new therapies and decrease mortality. Emerging evidence suggests that the interactions between tumor cells and the host immune system play important roles in establishing metastasis. Tumor cells are able to recruit immune cells, which in turn promotes tumor cell invasion, intravasation, survival in circulation, extravasation, and colonization in different organs. The tumor-host immunological interactions also generate a premetastatic niche in distant organs which facilitates metastasis. In this review, we summarize the recent findings on how tumor cells and immune cells regulate each other to coevolve and promote the formation of metastases at the major organ sites of metastasis. [ABSTRACT FROM AUTHOR]

We report that breast cancer cells that infiltrate the lungs support their own metastasis-initiating ability by expressing tenascin C (TNC). We find that the expression of TNC, an extracellular matrix protein of stem cell niches, is associated with the aggressiveness of pulmonary metastasis. Cancer cell-derived TNC promotes the survival and outgrowth of pulmonary micrometastases. TNC enhances the expression of stem cell signaling components, musashi homolog 1 (MSI1) and leucinerich repeat-containing G protein-coupled receptor 5 (LGR5). MSI1 is a positive regulator of NOTCH signaling, whereas LGR5 is a target gene of the WNT pathway. TNC modulation of stem cell signaling occurs without affecting the expression of transcriptional enforcers of the stem cell phenotype and pluripotency, namely nanog homeobox (NANOG), POU class 5 homeobox 1 (POU5F1), also known as OCT4, and SRY-box 2 (SOX2). TNC protects MSIl-dependent NOTCH signaling from inhibition by signal transducer and activator of transcription 5 (STAT5), and selectively enhances the expression of LGR5 as a WNT target gene. Cancer cell-derived TNC remains essential for metastasis outgrowth until the tumor stroma takes over as a source of TNC. These findings link TNC to pathways that support the fitness of metastasis-initiating breast cancer cells and highlight the relevance of TNC as an extracellular matrix component of the metastatic niche., Many malignant tumors start releasing cancer cells into the circulation long before diagnosis (1). To create a disseminated population that may eventually progress to overt metastasis, circulating cancer cells must [...]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2009.11.025 Byline: Mi-Young Kim (1), Thordur Oskarsson (1), Swarnali Acharyya (1), Don X. Nguyen (1), Xiang H.-F. Zhang (1), Larry Norton (2), Joan Massague (1)(3) Keywords: HUMDISEASE Abstract: Cancer cells that leave the primary tumor can seed metastases in distant organs, and it is thought that this is a unidirectional process. Here we show that circulating tumor cells (CTCs) can also colonize their tumors of origin, in a process that we call 'tumor self-seeding.' Self-seeding of breast cancer, colon cancer, and melanoma tumors in mice is preferentially mediated by aggressive CTCs, including those with bone, lung, or brain-metastatic tropism. We find that the tumor-derived cytokines IL-6 and IL-8 act as CTC attractants whereas MMP1/collagenase-1 and the actin cytoskeleton component fascin-1 are mediators of CTC infiltration into mammary tumors. We show that self-seeding can accelerate tumor growth, angiogenesis, and stromal recruitment through seed-derived factors including the chemokine CXCL1. Tumor self-seeding could explain the relationships between anaplasia, tumor size, vascularity and prognosis, and local recurrence seeded by disseminated cells following ostensibly complete tumor excision. Author Affiliation: (1) Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA (2) Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA (3) Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA Article History: Received 8 June 2009; Revised 24 September 2009; Accepted 12 November 2009 Article Note: (miscellaneous) Published: December 24, 2009

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.cell.2008.01.046 Byline: David Padua (1), Xiang H.-F. Zhang (1), Qiongqing Wang (1), Cristina Nadal (5), William L. Gerald (2), Roger R. Gomis (4), Joan Massague (1)(3) Keywords: HUMDISEASE; SIGNALING; CELLBIO Abstract: Cells released from primary tumors seed metastases to specific organs by a nonrandom process, implying the involvement of biologically selective mechanisms. Based on clinical, functional, and molecular evidence, we show that the cytokine TGF[beta] in the breast tumor microenvironment primes cancer cells for metastasis to the lungs. Central to this process is the induction of angiopoietin-like 4 (ANGPTL4) by TGF[beta] via the Smad signaling pathway. TGF[beta] induction of Angptl4 in cancer cells that are about to enter the circulation enhances their subsequent retention in the lungs, but not in the bone. Tumor cell-derived Angptl4 disrupts vascular endothelial cell-cell junctions, increases the permeability of lung capillaries, and facilitates the trans-endothelial passage of tumor cells. These results suggest a mechanism for metastasis whereby a cytokine in the primary tumor microenvironment induces the expression of another cytokine in departing tumor cells, empowering these cells to disrupt lung capillary walls and seed pulmonary metastases. Author Affiliation: (1) Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA (2) Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA (3) Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA (4) Oncology Programme, Institute for Research in Biomedicine, 08028 Barcelona, Spain (5) Institut de Malalties Hemato-OncolA[sup.2]giques, Hospital Clinic-IDIBAPS, 08036 Barcelona, Spain Article History: Received 18 October 2007; Revised 11 December 2007; Accepted 30 January 2008 Article Note: (miscellaneous) Published: April 3, 2008

Author(s): Lin Tian [1, 2, 3]; Amit Goldstein [1, 2, 4]; Hai Wang [1, 2, 4]; Hin Ching Lo [1, 2, 5]; Ik Sun Kim [1, 2, 5]; Thomas Welte [...]

Recent studies by our group and others demonstrated a required and conserved role of Stim in store-operated [Ca.sup.2+] influx and [Ca.sup.2+] release-activated [Ca.sup.2+] (CRAC) channel activity. By using an unbiased genome-wide RNA interference screen in Drosophila S2 cells, we now identify 75 hits that strongly inhibited [Ca.sup.2+] influx upon store emptying by thapsigargin. Among these hits are 11 predicted transmembrane proteins, including Stim, and one, olf186-F, that upon RNA interference-mediated knockdown exhibited a profound reduction of thapsigargin-evoked [Ca.sup.2+] entry and CRAC current, and upon overexpression a 3-fold augmentation of CRAC current. CRAC currents were further increased to 8-fold higher than control and developed more rapidly when olf186-F was cotransfected with Stim. olf186-F is a member of a highly conserved family of four-transmembrane spanning proteins with homologs from Caenorhabditis elegans to human. The endoplasmic reticulum (ER) [Ca.sup.2+] pump sarco-/ER calcium ATPase (SERCA) and the single transmembrane-soluble N-ethylmaleimide-sensitive (NSF) attachment receptor (SNARE) protein Syntaxin5 also were required for CRAC channel activity, consistent with a signaling pathway in which Stim senses [Ca.sup.2+] depletion within the ER, translocates to the plasma membrane, and interacts with olf186-F to trigger CRAC channel activity. capacitative calcium entry (CCE) | genome-wide screen | CRAC channel | RNA interference | store-operated calcium (SOC) influx