Multimodal imaging of the dynamic brain tumor microenvironment during glioblastoma progression and in response to treatment

Zomer, Anoek; Croci, Davide; Kowal, Joanna; Gurp, Léon van; Joyce, Johanna A.

doi:10.1016/j.isci.2022.104570

Cited by 17 publications

(25 citation statements)

References 56 publications

(92 reference statements)

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“…We then sought to longitudinally assess the kinetics of rhodamine-PFCE-NP distribution by taking advantage of a recently established intravital microscopy (IVM)–MRI pipeline in living animals ( 41 ). We induced GFP + tumors in the PDG-Ink4a/Arf KO GEMM, where a cranial imaging window (CIW) was surgically implanted in the skull at the site of tumor induction.…”

Section: Resultsmentioning

confidence: 99%

Multispectral fluorine-19 MRI enables longitudinal and noninvasive monitoring of tumor-associated macrophages

et al. 2022

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High-grade gliomas, the most common and aggressive primary brain tumors, are characterized by a complex tumor microenvironment (TME). Among the immune cells infiltrating the glioma TME, tumor-associated microglia and macrophages (TAMs) constitute the major compartment. In patients with gliomas, increased TAM abundance is associated with more aggressive disease. Alterations in TAM phenotypes and functions have been reported in preclinical models of multiple cancers during tumor development and after therapeutic interventions, including radiotherapy and molecular targeted therapies. These findings indicate that it is crucial to evaluate TAM abundance and dynamics over time. Current techniques to quantify TAMs in patients rely mainly on histological staining of tumor biopsies. Although informative, these techniques require an invasive procedure to harvest the tissue sample and typically only result in a snapshot of a small region at a single point in time. Fluorine isotope 19 MRI ( 19 F MRI) represents a powerful means to noninvasively and longitudinally monitor myeloid cells in pathological conditions by intravenously injecting perfluorocarbon-containing nanoparticles (PFC-NP). In this study, we demonstrated the feasibility and power of 19 F MRI in preclinical models of gliomagenesis, breast-to-brain metastasis, and breast cancer and showed that the major cellular source of 19 F signal consists of TAMs. Moreover, multispectral 19 F MRI with two different PFC-NP allowed us to identify spatially and temporally distinct TAM niches in radiotherapy-recurrent murine gliomas. Together, we have imaged TAMs noninvasively and longitudinally with integrated cellular, spatial, and temporal resolution, thus revealing important biological insights into the critical functions of TAMs, including in disease recurrence.

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Section: Resultsmentioning

confidence: 99%

Multispectral fluorine-19 MRI enables longitudinal and noninvasive monitoring of tumor-associated macrophages

et al. 2022

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“…Measuring the mechanical properties of cells and the tumor microenvironment in live animals or patients is a formidable task, but several groups have devised techniques to understand GBM-ECM interactions in-vivo (15,(290)(291)(292)(293). We recently demonstrated the intravital multiphoton imaging to study glioma cell dynamics deep into the brain with high-resolution and low photobleaching (15).…”

Section: Probing Ecm-gbm Cell Interactions In-vivomentioning

confidence: 99%

“…We recently demonstrated the intravital multiphoton imaging to study glioma cell dynamics deep into the brain with high-resolution and low photobleaching (15). Joyce et al also used two-photon microscopy as well as magnetic resonance imaging (MRI) to longitudinally image glioblastoma tumor initiation and development (293). Using both methods, the authors could measure overall tumor growth or regression with different therapeutic measures and also probe the TME at a single-cell level.…”

Section: Probing Ecm-gbm Cell Interactions In-vivomentioning

confidence: 99%

“…Joyce et al. also used two-photon microscopy as well as magnetic resonance imaging (MRI) to longitudinally image glioblastoma tumor initiation and development ( 293 ). Using both methods, the authors could measure overall tumor growth or regression with different therapeutic measures and also probe the TME at a single-cell level.…”

Section: Exploring the Physical Effects And Multi-dimensionality Of T...mentioning

confidence: 99%

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The complex interactions between the cellular and non-cellular components of the brain tumor microenvironmental landscape and their therapeutic implications

et al. 2022

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Glioblastoma (GBM), an aggressive high-grade glial tumor, is resistant to therapy and has a poor prognosis due to its universal recurrence rate. GBM cells interact with the non-cellular components in the tumor microenvironment (TME), facilitating their rapid growth, evolution, and invasion into the normal brain. Herein we discuss the complexity of the interactions between the cellular and non-cellular components of the TME and advances in the field as a whole. While the stroma of non-central nervous system (CNS) tissues is abundant in fibrillary collagens, laminins, and fibronectin, the normal brain extracellular matrix (ECM) predominantly includes proteoglycans, glycoproteins, and glycosaminoglycans, with fibrillary components typically found only in association with the vasculature. However, recent studies have found that in GBMs, the microenvironment evolves into a more complex array of components, with upregulated collagen gene expression and aligned fibrillary ECM networks. The interactions of glioma cells with the ECM and the degradation of matrix barriers are crucial for both single-cell and collective invasion into neighboring brain tissue. ECM-regulated mechanisms also contribute to immune exclusion, resulting in a major challenge to immunotherapy delivery and efficacy. Glioma cells chemically and physically control the function of their environment, co-opting complex signaling networks for their own benefit, resulting in radio- and chemo-resistance, tumor recurrence, and cancer progression. Targeting these interactions is an attractive strategy for overcoming therapy resistance, and we will discuss recent advances in preclinical studies, current clinical trials, and potential future clinical applications. In this review, we also provide a comprehensive discussion of the complexities of the interconnected cellular and non-cellular components of the microenvironmental landscape of brain tumors to guide the development of safe and effective therapeutic strategies against brain cancer.

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“…The TME is undeniably complex and studying it is a major challenge ( 1 ). But techniques are improving all the time where notable advances such as intravital microscopy ( 2 , 3 ), single cell sequencing ( 4 ) and cell-location techniques borrowed from astronomy can inform us about the complicated workings of the TME ( 5 ). Once better informed, we can expect new interventions that improve therapeutic responses.…”

Section: Introductionmentioning

confidence: 99%

Managing the TME to improve the efficacy of cancer therapy

2022

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The tumor microenvironment (TME) influences tumor growth, metastatic spread and response to treatment. Often immunosuppression, mediated by the TME, impairs a beneficial response. The complexity of the tumor composition challenges our abilities to design new and more effective therapies. Going forward we will need to ‘manage’ the content and or functionality of the TME to improve treatment outcomes. Currently, several different kinds of treatments are available to patients with cancer: there are the traditional approaches of chemotherapy, radiation and surgery; there are targeted agents that inhibit kinases associated with oncogenic pathways; there are monoclonal antibodies that target surface antigens often delivering toxic payloads or cells and finally there are antibodies and biologics that seek to overcome the immunosuppression caused by elements within the TME. How each of these therapies interact with the TME is currently under intense and widespread investigation. In this review we describe how the TME and its immunosuppressive components can influence both tumor progression and response to treatment focusing on three particular tumor types, classic Hodgkin Lymphoma (cHL), Pancreatic Ductal Adenocarcinoma (PDAC) and Glioblastoma Multiforme (GBM). And, finally, we offer five approaches to manipulate or manage the TME to improve outcomes for cancer patients.

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Multimodal imaging of the dynamic brain tumor microenvironment during glioblastoma progression and in response to treatment

Cited by 17 publications

References 56 publications

Multispectral fluorine-19 MRI enables longitudinal and noninvasive monitoring of tumor-associated macrophages

Multispectral fluorine-19 MRI enables longitudinal and noninvasive monitoring of tumor-associated macrophages

The complex interactions between the cellular and non-cellular components of the brain tumor microenvironmental landscape and their therapeutic implications

Managing the TME to improve the efficacy of cancer therapy

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