Characterisation of tumour microenvironment remodelling following oncogene inhibition in preclinical studies with imaging mass cytometry

Maldegem, Febe van; Valand, Karishma; Cole, Megan; Patel, Harshil; Angelova, Mihaela; Rana, Sareena; Colliver, Emma; Enfield, Katey S.S.; Bah, Nourdine; Kelly, Gavin; Tsang, Victoria; Mugarza, Edurne; Moore, Christopher; Hobson, Philip; Levi, Dina; Molina‐Arcas, Míriam; Swanton, Charles; Downward, Julian

doi:10.1038/s41467-021-26214-x

Cited by 50 publications

(61 citation statements)

References 48 publications

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“…In cancer research, IMC is used to discover novel phenotypes and biomarkers, or to study TME heterogeneity [22][23][24][25][30][31][32]36,43,44,50]. IMC is also used to predict prognosis and therapy responses in humans or in mice [23,30,51,[65][66][67][68][73][74][75].…”

Section: Imaging Mass Cytometrymentioning

confidence: 99%

Multiplex Tissue Imaging: Spatial Revelations in the Tumor Microenvironment

Dam

Baars

Vercoulen

2022

Cancers

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The tumor microenvironment is a complex ecosystem containing various cell types, such as immune cells, fibroblasts, and endothelial cells, which interact with the tumor cells. In recent decades, the cancer research field has gained insight into the cellular subtypes that are involved in tumor microenvironment heterogeneity. Moreover, it has become evident that cellular interactions in the tumor microenvironment can either promote or inhibit tumor development, progression, and drug resistance, depending on the context. Multiplex spatial analysis methods have recently been developed; these have offered insight into how cellular crosstalk dynamics and heterogeneity affect cancer prognoses and responses to treatment. Multiplex (imaging) technologies and computational analysis methods allow for the spatial visualization and quantification of cell–cell interactions and properties. These technological advances allow for the discovery of cellular interactions within the tumor microenvironment and provide detailed single-cell information on properties that define cellular behavior. Such analyses give insights into the prognosis and mechanisms of therapy resistance, which is still an urgent problem in the treatment of multiple types of cancer. Here, we provide an overview of multiplex imaging technologies and concepts of downstream analysis methods to investigate cell–cell interactions, how these studies have advanced cancer research, and their potential clinical implications.

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Section: Imaging Mass Cytometrymentioning

confidence: 99%

Multiplex Tissue Imaging: Spatial Revelations in the Tumor Microenvironment

Dam

Baars

Vercoulen

2022

Cancers

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“…Those efforts should help us to clarify the target brain regions, immune-cell targets, or pathways for emerging the disease and to ameliorate symptoms with the drug delivery. Highly multiplexed special expression pattern of distinct marker proteins with multi-dimensional data analyses must enable us to interpret the whole embodied schema of immune-triggered plasticity and disease association in the brain microenvironment and tissue architecture, as done in the field of cancer (Fernández-Zapata et al, 2020 ; Chen et al, 2021 ; van Maldegem et al, 2021 ; Kuett et al, 2022 ). Additionally, ion channels significant for the intrinsic excitability plasticity of neurons, such as Ca 2+ -activated K + -channels (i.e., SK-, IK-, and BK-channels) or HCN channels, would be another potential target for the drug administration, while we should note that inflammatory mediators could be modulators of not only fast synaptic transmissions and the intrinsic excitability but also metabotropic receptors of monoamine, mGluRs, GABA B R, and other G protein-coupled receptors, which are also involved in the plasticity induction.…”

Section: Plasticity Triggered By Inflammatory Cytokines and Relevance...mentioning

confidence: 99%

Immune-Triggered Forms of Plasticity Across Brain Regions

Hikosaka

Kawano

Wada

et al. 2022

Front. Cell. Neurosci.

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Immune cells play numerous roles in the host defense against the invasion of microorganisms and pathogens, which induces the release of inflammatory mediators (e.g., cytokines and chemokines). In the CNS, microglia is the major resident immune cell. Recent efforts have revealed the diversity of the cell types and the heterogeneity of their functions. The refinement of the synapse structure was a hallmark feature of the microglia, while they are also involved in the myelination and capillary dynamics. Another promising feature is the modulation of the synaptic transmission as synaptic plasticity and the intrinsic excitability of neurons as non-synaptic plasticity. Those modulations of physiological properties of neurons are considered induced by both transient and chronic exposures to inflammatory mediators, which cause behavioral disorders seen in mental illness. It is plausible for astrocytes and pericytes other than microglia and macrophage to induce the immune-triggered plasticity of neurons. However, current understanding has yet achieved to unveil what inflammatory mediators from what immune cells or glia induce a form of plasticity modulating pre-, post-synaptic functions and intrinsic excitability of neurons. It is still unclear what ion channels and intracellular signaling of what types of neurons in which brain regions of the CNS are involved. In this review, we introduce the ubiquitous modulation of the synaptic efficacy and the intrinsic excitability across the brain by immune cells and related inflammatory cytokines with the mechanism for induction. Specifically, we compare neuro-modulation mechanisms by microglia of the intrinsic excitability of cerebellar Purkinje neurons with cerebral pyramidal neurons, stressing the inverted directionality of the plasticity. We also discuss the suppression and augmentation of the extent of plasticity by inflammatory mediators, as the meta-plasticity by immunity. Lastly, we sum up forms of immune-triggered plasticity in the different brain regions with disease relevance. Together, brain immunity influences our cognition, sense, memory, and behavior via immune-triggered plasticity.

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“…Interestingly, AMG-510 and MRTX1257 were reported to induce a pro-inflammatory microenvironment also, suggesting a synergistic effect between this class of inhibitors and the immune checkpoint inhibitors [9,10]. In fact, both AMG-510 and MRTX1257 provoke a TME remodeling, increasing the density of macrophages, dendritic cells, and T cells (Figure 5) [63,64]. Additionally, those drugs drive a change of macrophages phenotype and, most dramatically, CD8 + T cell infiltration, favoring a pro-inflammatory/anti-tumor immune response [63,64].…”

Section: Therapies Targeting Kras Mutations and The Tumor Microenviro...mentioning

confidence: 99%

“…These alterations impair RAF binding and the activation of the signaling pathway, decreasing cell viability and increasing apoptosis of those cells harboring KRAS G12C mutations [10,57,62,63]. ARS-853, ARS-1620, MRTX1257, AMG-510 (Sotorasib), and MRTX849 (Adagrasib) are KRAS G12C potent inhibitors, AMG-510 and MRTX849 being the first ones to enter in the clinic [57,62,64]. Although KRAS G12C is the most frequent mutation in lung cancer with a frequency of 13%, it is present at low percentages in colorectal cancer (3%) and other solid tumors (2%) [63].…”

Section: Therapies Targeting Kras Mutations and The Tumor Microenviro...mentioning

confidence: 99%

“…In fact, both AMG-510 and MRTX1257 provoke a TME remodeling, increasing the density of macrophages, dendritic cells, and T cells (Figure 5) [63,64]. Additionally, those drugs drive a change of macrophages phenotype and, most dramatically, CD8 + T cell infiltration, favoring a pro-inflammatory/anti-tumor immune response [63,64]. Thus, both treatments prompted a pro-inflammatory microenvironment that could be highly responsive to immune checkpoint inhibitors.…”

Section: Therapies Targeting Kras Mutations and The Tumor Microenviro...mentioning

confidence: 99%

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KRAS as a Modulator of the Inflammatory Tumor Microenvironment: Therapeutic Implications

Pereira

Ferreira

Reis

et al. 2022

Cells

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KRAS mutations are one of the most frequent oncogenic mutations of all human cancers, being more prevalent in pancreatic, colorectal, and lung cancers. Intensive efforts have been encouraged in order to understand the effect of KRAS mutations, not only on tumor cells but also on the dynamic network composed by the tumor microenvironment (TME). The relevance of the TME in cancer biology has been increasing due to its impact on the modulation of cancer cell activities, which can dictate the success of tumor progression. Here, we aimed to clarify the pro- and anti-inflammatory role of KRAS mutations over the TME, detailing the context and the signaling pathways involved. In this review, we expect to open new avenues for investigating the potential of KRAS mutations on inflammatory TME modulation, opening a different vision of therapeutic combined approaches to overcome KRAS-associated therapy inefficacy and resistance in cancer.

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Characterisation of tumour microenvironment remodelling following oncogene inhibition in preclinical studies with imaging mass cytometry

Cited by 50 publications

References 48 publications

Multiplex Tissue Imaging: Spatial Revelations in the Tumor Microenvironment

Multiplex Tissue Imaging: Spatial Revelations in the Tumor Microenvironment

Immune-Triggered Forms of Plasticity Across Brain Regions

KRAS as a Modulator of the Inflammatory Tumor Microenvironment: Therapeutic Implications

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