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Micro-engineering and nano-engineering approaches to investigate tumour ecosystems

Nature Reviews Cancer volume 23, pages 581–599 (2023)Cite this article

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Abstract

The interactions among tumour cells, the tumour microenvironment (TME) and non-tumour tissues are of interest to many cancer researchers. Micro-engineering approaches and nanotechnologies are under extensive exploration for modelling these interactions and measuring them in situ and in vivo to investigate therapeutic vulnerabilities in cancer and extend a systemic view of tumour ecosystems. Here we highlight the greatest opportunities for improving the understanding of tumour ecosystems using microfluidic devices, bioprinting or organ-on-a-chip approaches. We also discuss the potential of nanosensors that can transmit information from within the TME or elsewhere in the body to address scientific and clinical questions about changes in chemical gradients, enzymatic activities, metabolic and immune profiles of the TME and circulating analytes. This Review aims to connect the cancer biology and engineering communities, presenting biomedical technologies that may expand the methodologies of the former, while inspiring the latter to develop approaches for interrogating cancer ecosystems.

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Fig. 1: Preclinical models of tumour ecosystems.
Fig. 2: Research tools to investigate hallmark processes and bioanalytes in tumour ecosystems.
Fig. 3: Nanosensor technologies to investigate tumour ecosystems.

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Acknowledgements

This work was supported in part by the NIH (R01-CA215719, R01-NS116353, R01-NS122987, R01-DK129299 and the Cancer Center Support Grant, P30-CA008748), the National Science Foundation CAREER Award (1752506), the American Cancer Society Research Scholar Grant (GC230452), the Ara Parseghian Foundation, the Honorable Tina Brozman Foundation for Ovarian Cancer Research, the Ovarian Cancer Research Alliance (CRDGAI-2023-3-1003), the Pershing Square Sohn Cancer Research Alliance, the Expect Miracles Foundation — Financial Services Against Cancer, Emerson Collective, the Experimental Therapeutics Center, William H. Goodwin and Alice Goodwin and the Commonwealth Foundation for Cancer Research, Burroughs Wellcome Funds, AACR, Stand Up to Cancer. M.K. was supported by the NIH (K99-EB033580) and the Marie-Josée Kravis Women in Science Endeavor Postdoctoral Fellowship. M.P. was supported by an NIH grant (5T32CA062948) and the Tow Foundation Postdoctoral Fellowship. S.B.R. was supported by the MERIT Mandel Fellowship, Memorial Sloan Kettering Cancer Center.

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Authors and Affiliations

  1. Molecular Pharmacology Program, Sloan Kettering Institute, New York, NY, USA

    Mijin Kim, Magdalini Panagiotakopoulou, Chen Chen, Stephen B. Ruiz, Karuna Ganesh & Daniel A. Heller

  2. Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA

    Chen Chen, Stephen B. Ruiz, Karuna Ganesh, Tuomas Tammela & Daniel A. Heller

  3. Tri-Institutional PhD Program in Chemical Biology, Sloan Kettering Institute, New York, NY, USA

    Chen Chen

  4. Cancer Biology and Genetics Program, Sloan Kettering Institute, New York, NY, USA

    Tuomas Tammela

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Contributions

M.K., M.P., C.C. and S.B.R. researched data for the article. M.K., M.P., C.C., K.G., T.T. and D.A.H. contributed substantially to discussion of the content. M.K., M.P., C.C., S.B.R. and D.A.H wrote the article. M.K., K.G., T.T. and D.A.H reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Daniel A. Heller.

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Competing interests

D.A.H. is a co-founder and officer with equity interest in Lime Therapeutics, Inc. and co-founder with equity interest in Selectin Therapeutics Inc. and Resident Diagnostics, Inc. and a member of the scientific advisory board of Concarlo Therapeutics, Inc., Nanorobotics Inc. and Mediphage Bioceuticals, Inc. T.T. has research support from ONO Pharma USA, Inc. (unrelated to this work) and is a member of the scientific advisory board of Lime Therapeutics, Inc. with equity interest. M.K., M.P., C.C., S.B.R. and K.G. declare no competing interests.

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Nature Reviews Cancer thanks Xiaoyuan Chen, Twan Lammers and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Bottleneck effects

An event that drastically reduces the size of a population. Bottlenecks produce a decrease in the gene pool of the population because many alleles, or gene variants, that were present in the original population are lost. Owing to the loss of genetic variation, the new population can become genetically distinct from the original population.

Chemokines

A family of inducible chemoattractant cytokines that regulate the chemotaxis of tumour cells and other cell types. Chemokines also affect processes such as proliferation, migration and invasion.

Cytokines

Small, secreted proteins produced by immune cells that are used in cellular communication.

DNAzyme

Single-stranded DNA oligonucleotides with high catalytic activities towards specific substrates.

Electrospun nanofibres

Fibres with diameters in the nanometre range created using electrospinning. Electrospinning relies on the electrostatic repulsion between surface charges to continuously draw nanofibres from a viscoelastic fluid.

Enhanced permeability and retention effect

Tumours can exhibit increased permeability and retention of large molecular weight molecules or nanoparticles primarily owing to structural abnormality of tumour vasculature.

Enzymatic suicide inactivation

Irreversible inhibition of  the activity of an enzyme.

Gefitinib

The first quinazoline-based reversible small-molecule epidermal growth factor receptor tyrosine kinase inhibitor.

Genetic drift

Changes in the frequency of a genetic variant in a population owing to chance alone.

Hypoxia

A subnormal concentration of oxygen. In cancer tissue, hypoxia is often the result of abnormal vasculature.

Immune checkpoint receptors

Cell-surface molecules that are expressed by T cells and the normal function of which is to maintain self-tolerance and regulate the magnitude and duration of immune responses. Checkpoint receptors, including PD1 and TIM3, can be co-opted by tumours to inhibit antitumour immune responses.

Immunoediting

Describes the complex relationship between a developing tumour under constant pressure from the host immune system. Cancer immunoediting consists of three phases: elimination (that is, cancer immunosurveillance), equilibrium and escape. The immune system not only protects the host against development of primary cancers but also sculpts tumour immunogenicity.

Mechanotransduction

Mechanisms by which cells convert mechanical stimulus into biochemical signals.

Microcontact printed lines

Microcontact printing is a method of transferring patterns of various materials such as polymers, proteins, nanoparticles and so on, onto another surface. Typically, a polydimethylsiloxane stamp is dipped in a solution of a material that has to be patterned and is brought into contact with the surface.

Microfluidic systems

These small ‘plumbing’ systems deal with the accurate control and manipulation of fluids that are confined to micrometre-sized environments. This enables the supply of nutrients, oxygen and the flow of media to be precisely controlled.

Mouse tumour xenograft models

Hetero-transplantation of human tumour cells into immunodeficient mice, in either the orthotopic (same organ) site or ectopic (foreign) site. Mice are typically athymic nu/nu T cell-deficient or severe combined immunodeficient, lacking B cell and T cell functions.

Multicellular spheroids

Multicellular spheroids are either self-assembling or are forced to grow as 3D spherical cell clusters. They can be established from a single cell type or can be multicellular mixtures of tumour, stromal and immune cells. These aggregates can mimic tumour cell behaviour more effectively because they harbour a gradient of cells that are surface-exposed and cells that are deeply buried, thereby also establishing a gradient of nutrient and oxygen availability.

Nanolithography

Set of top-down fabrication techniques that allow patterning materials and building devices with nanoscale resolution.

Nanopipette

A nanoscale pipette that locally collects analytes for mass spectrometry, electrochemical and optical analysis.

Nanoprinted scaffolds

Three-dimensional scaffolds with nanometre-scale features that mimic interstitial tissue or extracellular matrix. They are used either as cell migration or tumour formation platforms.

Organoids

Tissue-like 3D cultures originating from human stem cells, organ-specific progenitor cells or dissociated tumour tissues, grown in a reconstituted extracellular matrix. Organoids mimic primary tissues by retaining some aspects of tissue architecture and function. Tumour-derived organoids retain the diversity and fidelity of mutational landscapes and, when transplanted into mice, reconstitute many of the histopathological features of their tumours of origin.

Plasmonic nanoparticles

Metallic nanoparticles whose electron density can couple with certain wavelengths of light. Plasmonic nanoparticles exhibit interesting scattering, absorbance and coupling properties on the basis of their structures, geometries and relative positions.

Sacrificial bioink

A biomaterial used as ink in 3D printing of biomimetic structures, which has gentle and reversible crosslinking properties and can be easily removed (or ‘sacrificed’) without harming the involved cells and structures.

Self-assembled microvessels

Spontaneously created in vitro vascular networks driven by inherent cellular interactions between endothelial cells and stromal cells to undergo morphogenesis.

Sentinel lymph nodes

The first lymph node that connects to a primary tumour site, also it is likely the first lymph node in which cancer cells spread.

Single-walled carbon nanotubes

sp2-Hybridized carbon-based hollow cylindrical nanostructures that exhibit unique electronic and optical properties for intracellular and in vivo imaging and sensing.

Solvatochromic shift

Phenomenon in which emission wavelength of a fluorophore changes in response to the dielectric constant of its environment.

Surface-enhanced Raman spectroscopy

Highly sensitive technique that enhances the Raman scattering of molecules supported by nanostructured materials.

Synthetic molecular recognition

Recognition of target analytes conferred by synthetic polymers that create a selective molecular recognition site on a nanoparticle for the molecule of interest, leading to sensitive and selective optical response.

Vascular lumen

The inside space of a vessel, composed of a cord of endothelial cells.

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Kim, M., Panagiotakopoulou, M., Chen, C. et al. Micro-engineering and nano-engineering approaches to investigate tumour ecosystems. Nat Rev Cancer 23, 581–599 (2023). https://doi.org/10.1038/s41568-023-00593-3

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