Targeting the perivascular niche sensitizes disseminated tumour cells to chemotherapy

Carlson, Patrick; Dasgupta, Arko; Grzelak, Candice Alexandra; Kim, Jeanna; Barrett, Alexander S.; Coleman, Ilsa M.; Shor, Ryann E; Goddard, Erica T.; Dai, Jinxiang; Schweitzer, Emma M; Lim, Andrea R.; Crist, Sarah B.; Cheresh, David A.; Nelson, Peter S.; Hansen, Kirk C.; Ghajar, Cyrus M.

doi:10.1038/s41556-018-0267-0

Cited by 220 publications

(213 citation statements)

References 68 publications

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“…Another camp promotes a regimen that would keep cells in a dormant state, but this could be costly, lengthy, and unnecessary if a patient does not have micrometastases. A more exciting possibility is the recent revelation that dormant cells may in fact be sensitized to chemotherapy in an ECM-dependent manner [5,71]. This agrees with our suggestion that targeting survival signaling from cell-ECM adhesion could be a valuable treatment option.…”

Section: Discussionsupporting

confidence: 86%

Tumor cell-organized fibronectin is required to maintain a dormant breast cancer population

Barney¹,

Hall²,

Schwartz³

et al. 2019

Preprint

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Tumors can undergo long periods of dormancy, with cancer cells entering a largely quiescent, nonproliferative state before reactivation and outgrowth. For a patient, these post-remission tumors are often drug resistant and highly aggressive, resulting in poor prognosis. To understand the role of the extracellular matrix (ECM) in regulating tumor dormancy, we created an in vitro cell culture system that combines carefully controlled ECM substrates with nutrient deprivation to observe entrance into and exit from dormancy with live imaging. We saw that cell populations capable of surviving entrance into long-term dormancy were heterogeneous, containing quiescent, cell cycle arrested, and actively proliferating cells. Cell populations that endured extended periods of serum-deprivation-induced dormancy formed an organized, fibrillar fibronectin matrix via avb3 and a5b1 integrin adhesion, ROCK-generated tension, and TGFβ2 stimulation. We surmised that the fibronectin matrix was primarily a mediator of cell survival, not proliferation, during the serum-deprivation stress, bacause cancer cell outgrowth after dormancy required MMP-2-mediated fibronectin degradation. Given the difficulty of animal models in observing entrance and exit from dormancy in real-time, we propose this approach as a new, in vitro method to study factors important in regulating dormancy, and we used it here to elucidate a role for fibronectin deposition and MMP activation.

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Section: Discussionsupporting

confidence: 86%

Tumor cell-organized fibronectin is required to maintain a dormant breast cancer population

Barney¹,

Hall²,

Schwartz³

et al. 2019

Preprint

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“…Separately, a wide range of studies have focused on developing microphysiological models of the perivascular environment to interrogate processes associated with disease progression, 9,29,54,55 cancer invasion or metastasis, 4,37,50,51,66 and even dormancy of cancer stem cells. 10,24 These studies provide an illustrative example of the power of the perivascular environment and motivate our study of the role of perivascular signals on murine HSC culture.…”

Section: Discussionmentioning

confidence: 86%

Perivascular Secretome Influences Hematopoietic Stem Cell Maintenance in a Gelatin Hydrogel

Barnhouse

Petrikas

Crosby

et al. 2020

Preprint

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Adult hematopoietic stem cells (HSCs) produce the body's full complement of blood and immune cells. They reside in specialized microenvironments, or niches, within the bone marrow. The perivascular niche near blood vessels is believed to help maintain primitive HSCs in an undifferentiated state but demonstration of this effect is difficult. In vivo studies make it challenging to determine the direct effect of the endosteal and perivascular niches as they can be in close proximity, and two-dimensional in vitro cultures often lack an instructive extracellular matrix environment. We describe a tissue engineering approach to develop and characterize a three-dimensional perivascular tissue model to investigate the influence of the perivascular secretome on HSC behavior. We generate 3D endothelial networks in methacrylamide-functionalized gelatin hydrogels using human umbilical vein endothelial cells (HUVECs) and mesenchymal stromal cells (MSCs). We identify a subset of secreted factors important for HSC function, and examine the response of primary murine HSCs in hydrogels to the perivascular secretome. Within 4 days of culture, perivascular conditioned media promoted maintenance of a greater fraction of hematopoietic stem and progenitor cells. This work represents an important first-generation perivascular model to investigate the role of niche secreted factors on the maintenance of primary HSCs.

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“…As a result, ongoing efforts are examining if the other proteins identified in this study are individual mediators of temozolomide resistance in order to identify underlying signaling mechanisms that lead to this response. Potential mechanisms include modulation of MGMT and mismatch repair functionality, as well as integrin-mediated resistance [13].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, recent studies in regenerative, stem cell, and cancer biology suggest that vasculature can instruct the behavior of surrounding cells via signaling cues derived from the cells that make up vasculature, namely endothelial cells and supporting mural cells (e.g. pericytes, smooth muscle cells) [12][13][14][15]. Understanding how signaling cues from vasculature affect tumor cell behavior and the underlying mechanisms that govern the crosstalk between vasculature and tumor cells can provide insights into new therapeutic strategies, particularly because the PVN has been associated with the maintenance of stem-like and therapeutically-resistant GBM cells that facilitate disease recurrence [6,[16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Multidimensional hydrogel models reveal endothelial network angiocrine signals increase glioblastoma cell number, invasion, and temozolomide resistance

Ngo

Karvelis

Harley

2020

Preprint

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Glioblastoma is the most common primary malignant brain tumor. The tissue microenvironment adjacent to vasculature, termed the perivascular niche, has been implicated in promoting biological processes involved in glioblastoma progression such as invasion, proliferation, and therapeutic resistance. However, the exact nature of the cues that support tumor cell aggression in this niche are largely unknown. Soluble angiocrine factors secreted by tumor-associated vasculature have been shown to support such behaviors in other cancer types. Here, we exploit macroscopic and microfluidic gelatin hydrogel platforms to profile angiocrine factors secreted by self-assembled endothelial networks and evaluate their relevance to glioblastoma biology.Aggregate angiocrine factors support U87-MG proliferation, migration, and therapeutic resistance to temozolomide. We also identify a novel role for TIMP1 in facilitating glioblastoma tumor cell migration. Overall, this work highlights the use of multidimensional hydrogel models to evaluate the role of angiocrine signals in glioblastoma progression. Glioblastoma progression is linked to interactions between tumor and vascular cells, which caninfluence invasion and therapeutic response. In co-culture studies to investigate tumor-vascular crosstalk, endothelial cells often are not presented in three-dimensional structures mimicking vasculature and the exact identity of secreted factors is not explored. Here, we use tissue engineering strategies to generate three-dimensional endothelial networks from which to collect soluble angiocrine signals and assess the impact of these signals on glioblastoma behavior. Furthermore, we use secretomic analysis to identify specific factors influencing glioblastoma

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Targeting the perivascular niche sensitizes disseminated tumour cells to chemotherapy

Cited by 220 publications

References 68 publications

Tumor cell-organized fibronectin is required to maintain a dormant breast cancer population

Tumor cell-organized fibronectin is required to maintain a dormant breast cancer population

Perivascular Secretome Influences Hematopoietic Stem Cell Maintenance in a Gelatin Hydrogel

Multidimensional hydrogel models reveal endothelial network angiocrine signals increase glioblastoma cell number, invasion, and temozolomide resistance

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