Host-microbe-cancer interactions on-a-chip

Abstract

The tumor microbiota has emerged as a pivotal contributor to a variety of cancers, impacting disease development, progression, and therapeutic resistance. Due to the complexity of the tumor microenvironment, reproducing the interactions between the microbes, tumor cells, and the immune system remains a great challenge for both in vitro and in vivo studies. To this end, significant progress has been made toward leveraging tumor-on-a-chip model systems to replicate critical hallmarks of the native disease in vitro. These microfluidic platforms offer the ability to mimic essential components of the tumor microenvironment, including controllable fluid flow conditions, manipulable extracellular matrix dynamics, and intricate 3D multi-cellular communication. The primary objective of this review is to discuss recent challenges and advances in engineering host-microbiota and tumor interactions on-a-chip. Ultimately, overcoming these obstacles will help us gain deeper insights into tumor-microbe interactions and enhance avenues for developing more effective cancer therapies.

Keywords: host-microbes; microbes; microfluidic devices; tissue engineering; tumor on-a-chip.

FIGURE 1

Tumor on-a-chip as platforms to emulate the host-microbe interactions in early oncogenesis and inflammation. These models can be used to emulate essential hallmarks of the tumor microenvironment, such as shear stress, hypoxia, a 3D matrix, different cell types, and interactions with several bacteria, fungi, viruses, archaea, parasites, and their sub-products (A). In (B) reproduced from Min et al. (2022) a polydimethylsiloxane (PDMS) chip was used to understand the role of probiotics in reestablishing gut homeostasis. Chips that were treated with Lactobacillus rhamnosus (LLG) or a complex mixture VSL#3 could reduce inflammatory and carcinogenic signaling pathways (p65 – magenta, pSTAT3 - cyan, and MYD88) after 3 days [(C, D) scale bar – 50 µm]. In (E, F), reproduced from de Gregorio et al. (2022), the authors developed a device that features an open central chamber accommodating a transwell membrane separating the lumen and serosal sides to emulate a human intestine on-a-chip (hi-oC) (E). The authors observed that lipopolysaccharide (hl-oCLPS) would stimulate a higher inflammatory response compared to the hi-oC (F), and the probiotics (Mihl-oCLPS) improved tight junction formation and mucus production (G). Scales bars in (F, G) represent 100 µm. Parts of this figure were created with biorender.com. This figure was licensed under a common creative attribution [CC by 4.0 Spring Nature–(B–D) and Elsevier (E–G)].

FIGURE 2

Applications of on-chip models to understand host-microbe interactions in cancer for colorectal cancer (A, B), breast cancer (C, D), and oral mucosa/head and neck (E, F). In (A), Penarete-Acosta et al. (2024) developed a colorectal tumor on-a-chip to evaluate the effect of F. nucleatum in modulating the microbiome. They found that this microorganism is responsible for increasing the abundance of pro-inflammatory microorganisms (B). In (C), reproduced from Brasino et al., developed microfluidic devices that can keep patient-derived organoid viability (C) while communicating with the gut microbiome (D). These polycarbonate chips allow researchers to study hypoxic environments (gut) while connecting those systems with other distal tissues (D). In (E, F), reproduced from Rahimi et al. (2018), a PDMS device was designed to mimic the oral mucosa interaction with microorganisms. These devices have a central chamber containing gingival fibroblasts (HGFs) in collagen and a layer of keratinocytes (E). Although the authors just evaluated the species S. mutans (F), this platform can be used to study how oral pathobiont microorganisms can interact with head and neck cancers. This figure was licensed under a common creative attribution (CC by 4.0 Royal Chemical Society, Wiley and Elsevier). (E, F) was reproduced from [Christopher Rahimi, Benjamin Rahimi, Dominic Padova, Seyed A. Rooholghodos, Diane R. Bienek, Xiaolong Luo, Gili Kaufman, Christopher B. Raub; Oral mucosa-on-a-chip to assess layer-specific responses to bacteria and dental materials. Biomicrofluidics 1 September 2018; 12 (5): 054106. https://doi.org/10.1063/1.5048938], with the permission of AIP Publishing.