Bridging live-cell imaging and next-generation cancer treatment

Alieva, Maria; Wezenaar, Amber K. L.; Wehrens, Ellen J.; Rios, Anne C.

doi:10.1038/s41568-023-00610-5

Cited by 16 publications

(6 citation statements)

References 158 publications

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“…However, the metaphenotype as a dynamic spatiotemporal metric is a challenge to measure ( 47 ), since most spatially resolved methods of interrogating a tumor in vivo are either destructive or of low resolution, and therefore lack the needed temporal component. Novel in vivo live-imaging technologies are one possible route to investigate how the different cellular phenotypes in the tumor environment change over time in response to emergent physiological changes and to therapeutic interventions ( 48 ). Another option would be the use of organoid cultures(e.g.…”

Section: Discussionmentioning

confidence: 99%

Tumor-immune metaphenotypes orchestrate an evolutionary bottleneck that promotes metabolic transformation

West,

Rentzeperis,

Adam

et al. 2024

Front. Immunol.

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IntroductionMetabolism plays a complex role in the evolution of cancerous tumors, including inducing a multifaceted effect on the immune system to aid immune escape. Immune escape is, by definition, a collective phenomenon by requiring the presence of two cell types interacting in close proximity: tumor and immune. The microenvironmental context of these interactions is influenced by the dynamic process of blood vessel growth and remodelling, creating heterogeneous patches of well-vascularized tumor or acidic niches.MethodsHere, we present a multiscale mathematical model that captures the phenotypic, vascular, microenvironmental, and spatial heterogeneity which shapes acid-mediated invasion and immune escape over a biologically-realistic time scale. The model explores several immune escape mechanisms such as i) acid inactivation of immune cells, ii) competition for glucose, and iii) inhibitory immune checkpoint receptor expression (PD-L1). We also explore the efficacy of anti-PD-L1 and sodium bicarbonate buffer agents for treatment. To aid in understanding immune escape as a collective cellular phenomenon, we define immune escape in the context of six collective phenotypes (termed “meta-phenotypes”): Self-Acidify, Mooch Acid, PD-L1 Attack, Mooch PD-L1, Proliferate Fast, and Starve Glucose.ResultsFomenting a stronger immune response leads to initial benefits (additional cytotoxicity), but this advantage is offset by increased cell turnover that leads to accelerated evolution and the emergence of aggressive phenotypes. This creates a bimodal therapy landscape: either the immune system should be maximized for complete cure, or kept in check to avoid rapid evolution of invasive cells. These constraints are dependent on heterogeneity in vascular context, microenvironmental acidification, and the strength of immune response.DiscussionThis model helps to untangle the key constraints on evolutionary costs and benefits of three key phenotypic axes on tumor invasion and treatment: acid-resistance, glycolysis, and PD-L1 expression. The benefits of concomitant anti-PD-L1 and buffer treatments is a promising treatment strategy to limit the adverse effects of immune escape.

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Section: Discussionmentioning

confidence: 99%

Tumor-immune metaphenotypes orchestrate an evolutionary bottleneck that promotes metabolic transformation

West,

Rentzeperis,

Adam

et al. 2024

Front. Immunol.

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“…While ATP-based assays have been widely used in functional precision medicine, our comparative studies suggest that imaging presents a superior readout. Imaging offers several advantages in function precision oncology, including low cost, the ability for multiplexing, providing spatial information, and supporting label free, kinetic analysis 26 . BF imaging excels in tracking dynamic cellular processes over time, facilitating longitudinal studies, whereas fluorescence imaging is limited to providing snapshots of cells at specific instances.…”

Section: Discussionmentioning

confidence: 99%

Combining Scalable Organ Chip Platform with Deep Learning-Based Imaging Analysis for Cancer Therapeutic Screening

Yuan,

Xu,

McCormack

et al. 2024

Preprint

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Functional precision oncology represents an emerging approach to genomic approaches by testing treatment options directly on patient-derived models. Current assays, including the use of patient-derived xenograft (PDX) and patient-derived organoid (PDOs), faces major barriers in clinical use due to technical challenges, such as standardization, cost, assay time, scalability, and faithful mimicry of patient tumor microenvironment (TME). Here, we introduce an Organ Chip (OC) device constructed entirely from thermoplastic materials, free of porous membrane or other barrier structures, and optimized for high-content imaging (HCI). This automation-compatible device supports tissue-specific extracellular matrices and coculture for a wide spectrum of organ and disease types, including the TME. As a proof-of-concept, we demonstrate the growth of pancreatic, lung, and colon cancer cell lines and primary lung cancer cells and the testing of cancer drugs in these models. HCI-based phenotypic profiling enabled accurate quantification of drug response, with better performance than traditional biochemical assays. Moreover, we developed a deep-learning method for assessing drug responses using bright field images. The integration of a low-cost, scalable, and faithful OC models with automatic high-content image analysis represents a significant stride towards functional precision oncology and cancer drug discovery.

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“…In summary, some elegant, recent examples of using BSLB in combination with cell-cell synapse models are indeed preferred approaches that have profoundly changed our view of synaptic architecture and the contribution of microvilli and EV derived from microvilli to IS function ( 62 , 63 , 100 ). The development and incorporation of high-temporal resolution, super-resolution imaging techniques ( 28 , 37 , 54 , 65 , 70 ) to synapse studies, such as those recently published in CAR synapses ( 129 , 132 ), will indeed improve our knowledge of the IS structure and function.…”

Section: Future Directions and Concluding Remarksmentioning

confidence: 99%

Extracellular vesicles and microvilli in the immune synapse

Ruiz-Navarro,

Calvo,

Izquierdo

2024

Front. Immunol.

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T cell receptor (TCR) binding to cognate antigen on the plasma membrane of an antigen-presenting cell (APC) triggers the immune synapse (IS) formation. The IS constitutes a dedicated contact region between different cells that comprises a signaling platform where several cues evoked by TCR and accessory molecules are integrated, ultimately leading to an effective TCR signal transmission that guarantees intercellular message communication. This eventually leads to T lymphocyte activation and the efficient execution of different T lymphocyte effector tasks, including cytotoxicity and subsequent target cell death. Recent evidence demonstrates that the transmission of information between immune cells forming synapses is produced, to a significant extent, by the generation and secretion of distinct extracellular vesicles (EV) from both the effector T lymphocyte and the APC. These EV carry biologically active molecules that transfer cues among immune cells leading to a broad range of biological responses in the recipient cells. Included among these bioactive molecules are regulatory miRNAs, pro-apoptotic molecules implicated in target cell apoptosis, or molecules triggering cell activation. In this study we deal with the different EV classes detected at the IS, placing emphasis on the most recent findings on microvilli/lamellipodium-produced EV. The signals leading to polarized secretion of EV at the synaptic cleft will be discussed, showing that the IS architecture fulfills a fundamental task during this route.

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Bridging live-cell imaging and next-generation cancer treatment

Cited by 16 publications

References 158 publications

Tumor-immune metaphenotypes orchestrate an evolutionary bottleneck that promotes metabolic transformation

Tumor-immune metaphenotypes orchestrate an evolutionary bottleneck that promotes metabolic transformation

Combining Scalable Organ Chip Platform with Deep Learning-Based Imaging Analysis for Cancer Therapeutic Screening

Extracellular vesicles and microvilli in the immune synapse

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