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Specialized microenvironments (or “niches”) are essential for metastasis, but how cancer cells and host cells contribute to their establishment remains poorly understood. Our study reveals that platelets and granulocytes are sequentially recruited to disseminated tumor cells to form “early metastatic niches” that promote metastatic progression. Importantly, the recruitment of granulocytes is not primarily due to tumor cell-derived signals but rather relies on platelet-derived CXCL5/7 chemokines. Prevention of granulocyte recruitment via inhibition of the CXCL5/7 receptor CXCR2, or depletion of either platelets or granulocytes inhibits metastasis, thereby uncovering a key role for platelet-to-granulocyte signaling in the establishment of metastases. Specific inhibition of platelet-to-granulocyte interactions may thus represent a valuable antimetastatic therapy in addition to cancer cell-centered treatments. During metastasis, host cells are recruited to disseminated tumor cells to form specialized microenvironments (“niches”) that promote metastatic progression, but the mechanisms guiding the assembly of these niches are largely unknown. Tumor cells may autonomously recruit host cells or, alternatively, host cell-to-host cell interactions may guide the formation of these prometastatic microenvironments. Here, we show that platelet-derived rather than tumor cell-derived signals are required for the rapid recruitment of granulocytes to tumor cells to form “early metastatic niches.” Granulocyte recruitment relies on the secretion of CXCL5 and CXCL7 chemokines by platelets upon contact with tumor cells. Blockade of the CXCL5/7 receptor CXCR2, or transient depletion of either platelets or granulocytes prevents the formation of early metastatic niches and significantly reduces metastatic seeding and progression. Thus, platelets recruit granulocytes and guide the formation of early metastatic niches, which are crucial for metastasis.

Extracellular matrix (ECM) proteins constitute >1% of the proteome and interact with many modifiers and growth factors to affect most aspects of cellular behaviour during development and normal physiology, as well as in diseases such as fibroses, cancer and many genetic disorders. In addition to biochemical signals provided to cells by ECM proteins, important cell–ECM interactions involve bidirectional mechanotransduction influences, which are dependent on the physical structure and organization of the ECM. These are beginning to be understood using twenty-first-century approaches, including biophysics, nanotechnology, biological engineering and modern microscopy. Articles in this issue of Nature Reviews Molecular Cell Biology review progress in our understanding of the ECM.

SignificanceCancers, fibroses, and inflammatory disorders are characterized by increased deposition of the extracellular matrix (ECM). ECM biomarkers that are selectively expressed at these disease sites are attractive targets for imaging and therapeutic approaches. Nanobodies against these biomarkers would be pertinent vehicles for the accumulation of imaging and therapeutic cargo at disease sites, potentially increasing specificity and reducing background. We demonstrate the specificity of one such anti-ECM nanobody by using immuno-PET/CT and show that it detects multiple models of cancer, including early lesions and metastases, and also fibroses, with excellent specificity and clarity. Thus, novel strategies for delivering imaging and therapeutic probes specifically to the ECM in disease sites may prove particularly valuable for detection and treatment of cancer in patients. Extracellular matrix (ECM) deposition is a hallmark of many diseases, including cancer and fibroses. To exploit the ECM as an imaging and therapeutic target, we developed alpaca-derived libraries of “nanobodies” against disease-associated ECM proteins. We describe here one such nanobody, NJB2, specific for an alternatively spliced domain of fibronectin expressed in disease ECM and neovasculature. We showed by noninvasive in vivo immuno-PET/CT imaging that NJB2 detects primary tumors and metastatic sites with excellent specificity in multiple models of breast cancer, including human and mouse triple-negative breast cancer, and in melanoma. We also imaged mice with pancreatic ductal adenocarcinoma (PDAC) in which NJB2 was able to detect not only PDAC tumors but also early pancreatic lesions called pancreatic intraepithelial neoplasias, which are challenging to detect by any current imaging modalities, with excellent clarity and signal-to-noise ratios that outperformed conventional 2-fluorodeoxyglucose PET/CT imaging. NJB2 also detected pulmonary fibrosis in a bleomycin-induced fibrosis model. We propose NJB2 and similar anti-ECM nanobodies as powerful tools for noninvasive detection of tumors, metastatic lesions, and fibroses. Furthermore, the selective recognition of disease tissues makes NJB2 a promising candidate for nanobody-based therapeutic applications.

Systemic inflammation occurring around the course of tumor progression and treatment are often correlatedwith adverse oncological outcomes. As such, it is suspected that neutrophils, the first line of defense against infection, may play important roles in linking inflammation and metastatic seeding. To decipher the dynamic roles of inflamed neutrophils during hematogenous dissemination, we employ a multiplexed microfluidic model of the human microvasculature enabling physiologically relevant transport of circulating cells combined with real-time, high spatial resolution observation of heterotypic cell–cell interactions. LPS-stimulated neutrophils (PMNs) and tumor cells (TCs) form heterotypic aggregates under flow, and arrest due to both mechanical trapping and neutrophil–endothelial adhesions. Surprisingly, PMNs are not static following aggregation, but exhibit a confined migration pattern near TC–PMN clusters. We discover that PMNs are chemotactically confined by self-secreted IL-8 and tumor-derived CXCL-1, which are immobilized by the endothelial glycocalyx. This results in significant neutrophil sequestration with arrested tumor cells, leading to the spatial localization of neutrophil-derived IL-8, which also contributes to increasing the extravasation potential of adjacent tumor cells through modulation of the endothelial barrier. Strikingly similar migration patterns and extravasation behaviors were also observed in an in vivo zebrafish model upon PMN–tumor cell coinjection into the embryo vasculature. These insights into the temporal dynamics of intravascular tumor–PMN interactions elucidate the mechanisms through which inflamed neutrophils can exert proextravasation effects at the distant metastatic site.

The transcriptional coactivator Yes-associated protein (YAP) is a major regulator of organ size and proliferation in vertebrates. As such, YAP can act as an oncogene in several tissue types if its activity is increased aberrantly. Although no activating mutations in the yap1 gene have been identified in human cancer, yap1 is located on the 11q22 amplicon, which is amplified in several human tumors. In addition, mutations or epigenetic silencing of members of the Hippo pathway, which represses YAP function, have been identified in human cancers. Here we demonstrate that, in addition to increasing tumor growth, increased YAP activity is potently prometastatic in breast cancer and melanoma cells. Using a Luminex-based approach to multiplex in vivo assays, we determined that the domain of YAP that interacts with the TEAD/TEF family of transcription factors but not the WW domains or PDZ-binding motif, is essential for YAP-mediated tumor growth and metastasis. We further demonstrate that, through its TEAD-interaction domain, YAP enhances multiple processes known to be important for tumor progression and metastasis, including cellular proliferation, transformation, migration, and invasion. Finally, we found that the metastatic potential of breast cancer and melanoma cells is strongly correlated with increased TEAD transcriptional activity. Together, our results suggest that increased YAP/TEAD activity plays a causal role in cancer progression and metastasis.

Pancreatic ductal adenocarcinoma (PDAC) has a collagen-rich dense extracellular matrix (ECM) that promotes malignancy of cancer cells and presents a barrier for drug delivery. Data analysis of our published mass spectrometry (MS)-based studies on enriched ECM from samples of progressive PDAC stages reveal that the C-terminal prodomains of fibrillar collagens are partially uncleaved in PDAC ECM, suggesting reduced procollagen C-proteinase activity. We further show that the enzyme responsible for procollagen C-proteinase activity, bone morphogenetic protein1 (BMP1), selectively suppresses tumor growth and metastasis in cells expressing high levels of COL1A1. Although BMP1, as a secreted proteinase, promotes fibrillar collagen deposition from both cancer cells and stromal cells, only cancer-cell-derived procollagen cleavage and deposition suppresses tumor malignancy. These studies reveal a role for cancer-cell-derived fibrillar collagen in selectively restraining tumor growth and suggest stratification of patients based on their tumor epithelial collagen I expression when considering treatments related to perturbation of fibrillar collagens. Pancreatic ductal adenocarcinoma has a collagen-rich dense extracellular matrix that promotes malignancy of cancer cells. Here, the authors show that fibrillar collagen that is cancer-cell-derived, but not stroma-derived, selectively restrains tumor growth under control of their pC-proteinase, BMP1.

Direct injection of therapies into tumors has emerged as an administration route capable of achieving high local drug exposure and strong anti-tumor response. A diverse array of immune agonists ranging in size and target are under development as local immunotherapies. However, due to the relatively recent adoption of intratumoral administration, the pharmacokinetics of locally-injected biologics remains poorly defined, limiting rational design of tumor-localized immunotherapies. Here we define a pharmacokinetic framework for biologics injected intratumorally that can predict tumor exposure and effectiveness. We find empirically and computationally that extending the tumor exposure of locally-injected interleukin-2 by increasing molecular size and/or improving matrix-targeting affinity improves therapeutic efficacy in mice. By tracking the distribution of intratumorally-injected proteins using positron emission tomography, we observe size-dependent enhancement in tumor exposure occurs by slowing the rate of diffusive escape from the tumor and by increasing partitioning to an apparent viscous region of the tumor. In elucidating how molecular weight and matrix binding interplay to determine tumor exposure, our model can aid in the design of intratumoral therapies to exert maximal therapeutic effect. Understanding the pharmacokinetics of locally-injected drugs could aid in the design of immunotherapies to maximize their therapeutic effect. Here, by evaluating different IL-2 fusion proteins, the authors show that molecular weight and matrix binding affect anti-tumor immune response and report a pharmacokinetic framework to predict response to intratumoral IL-2 therapy.

The extracellular matrix (ECM) and ECM proteins are important in phenomena as diverse as developmental patterning, stem cell niches, cancer, and genetic diseases. The ECM has many effects beyond providing structural support. ECM proteins typically include multiple, independently folded domains whose sequences and arrangement are highly conserved. Some of these domains bind adhesion receptors such as integrins that mediate cell-matrix adhesion and also transduce signals into cells. However, ECM proteins also bind soluble growth factors and regulate their distribution, activation, and presentation to cells. As organized, solid-phase ligands, ECM proteins can integrate complex, multivalent signals to cells in a spatially patterned and regulated fashion. These properties need to be incorporated into considerations of the functions of the ECM.

Binding of α5β1 and αvβ3/β5 integrin receptors on the endothelium to their fibronectin substrate in the extracellular matrix has been targeted as a possible means of blocking tumor angiogenesis and tumor growth. However, clinical trials of blocking antibodies and peptides have been disappointing despite promising preclinical results, leading to questions about the mechanism of the inhibitors and the reasons for their failure. Here, using tissue-specific and inducible genetics to delete the α5 and αv receptors in the endothelium or their fibronectin substrate, either in the endothelium or globally, we show that both are dispensable for tumor growth, in transplanted tumors as well as spontaneous and angiogenesis-dependent RIP-Tag-driven pancreatic adenocarcinomas. In the nearly complete absence of fibronectin, no differences in vascular density or the deposition of basement membrane laminins, ColIV, Nid1, Nid2, or the TGFβ binding matrix proteins, fibrillin-1 and -2, could be observed. Our results reveal that fibronectin and the endothelial fibronectin receptor subunits, α5 and αv, are dispensable for tumor angiogenesis, suggesting that the inhibition of angiogenesis induced by antibodies or small molecules may occur through a dominant negative effect, rather than a simple functional block.

The extracellular matrix (ECM) is a major component of tumors and a significant contributor to cancer progression. In this study, we use proteomics to investigate the ECM of human mammary carcinoma xenografts and show that primary tumors of differing metastatic potential differ in ECM composition. Both tumor cells and stromal cells contribute to the tumor matrix and tumors of differing metastatic ability differ in both tumor- and stroma-derived ECM components. We define ECM signatures of poorly and highly metastatic mammary carcinomas and these signatures reveal up-regulation of signaling pathways including TGFβ and VEGF. We further demonstrate that several proteins characteristic of highly metastatic tumors (LTBP3, SNED1, EGLN1, and S100A2) play causal roles in metastasis, albeit at different steps. Finally we show that high expression of LTBP3 and SNED1 correlates with poor outcome for ER − /PR − breast cancer patients. This study thus identifies novel biomarkers that may serve as prognostic and diagnostic tools. Metastasis is the process whereby tumor cells spread within the body and is the cause of most deaths from cancer. This complex process involves several steps: first the cancer cells invade the tissues that surround the tumor; second, the cancer cells enter the blood stream and travel throughout the body; and third, the cancer cells seed the growth of new tumors in distant organs. Within tissues, the extracellular matrix forms a complex scaffold of proteins that surrounds cells, to support and organize them: it also provides signals that control how much cells can multiply, how likely cells are to stick together or migrate, and even a cell’s chances of survival. Pathologists have used an accumulation of extracellular matrix proteins in tumors as a sign that the outcome of the disease will likely be unfavorable for a patient, and that treatment will be challenging. However, we still do not have a clear picture of the composition of the tumor extracellular matrix and we do not know all the details of how it affects tumor growth and metastasis. Now, Naba et al. have explored these questions by injecting different types of human breast tumor cells into mice. Some of the cells were capable of spreading throughout the body and were said to have a high ‘metastatic potential’; others were less capable of spreading and were said to have a low metastatic potential. Naba et al. then analyzed the proteins that made up the extracellular matrix of the tumors that grew in the mice. Some proteins were found in both types of tumor; whereas some proteins were only found in the tumors with low metastatic potential and some were only found in the highly metastatic tumors. Naba et al. also demonstrated that both cancer cells and non-cancer cells—which are also found within the tumors—contributed to the production of the extracellular matrix in the tumor. Moreover, and somewhat surprisingly, the contributions from the non-cancer cells in the two types of tumors were also different. Computational analysis predicted that the production of several extracellular matrix proteins in the highly metastatic tumors was under the control of signaling pathways that are involved in cancer progression. Furthermore, Naba et al. also demonstrated that several of the extracellular matrix proteins specific to highly metastatic tumors were required for the cancer to spread. These proteins are involved in different stages of the metastatic process, and some of them are commonly over-produced in tumors from patients with some of the worst chances of recovery. If similar results are consistently observed in clinical samples from humans, the work of Naba et al. could help doctors to discriminate between tumors that will spread and those that will not, which should lead to improved patient care. The proteins and pathways associated with the highly metastatic tumors could be also investigated as potential drug targets.