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  • Review Article
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Measuring and modelling tumour heterogeneity across scales

Nature Reviews Bioengineering volume 1, pages 712–730 (2023)Cite this article

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Abstract

Cancer development, progression and therapy response are heterogeneous and patient-specific. The biological and physical properties of tumour cells and their surrounding tissue microenvironments are critical regulators of these outcomes. How biological and physical properties integrate across length scales to shape disease heterogeneity is poorly understood, because few methods can measure, recapitulate and deconvolve these complex factors. In this Review, we classify regulators of cancer into three categories based on scale: tumour-cell-intrinsic, tissue-microenvironment and organism-level sources. For each length scale, we review the current state of the field, describe how engineering strategies can advance our understanding of these phenomena and assess potential avenues for clinical translation. Engineering strategies include analytical methods of measuring the physical properties of cells and their surroundings, biomimetic culture systems and the integration of these approaches with recent advances such as omics and patient-derived organoids. We further discuss epidemiological and training considerations to improve equity in cancer research. Ultimately, bioengineering approaches will help to generate scientific insights and advance precision-medicine-inspired treatments for patients with cancer.

Key points

  • Tumour heterogeneity comes in different forms across length scales and affects patient outcomes. Many of the factors affecting tumour heterogeneity still need to be taken into account to improve treatment.

  • Physical heterogeneity is an underestimated but major contributor to cancer. Clinically, there is a need to rethink how to identify and target these physical drivers as well as traditional molecular targets.

  • Many organism-level variables (age, race, diet) affect disease progression and therapy response for an individual patient, yet are not considered in most preclinical research.

  • Bioengineering strategies provide toolsets with which to analyse and model individual parameters that contribute to disease heterogeneity and affect tumour development, progression and therapy response.

  • Recruiting cancer researchers across disciplines and fostering interactions between cancer researchers, patients and clinicians will broaden trainee perspectives and foster insights to improve cancer care.

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Fig. 1: Key molecular effectors integrating biological and physical cues to modulate tumour-cell heterogeneity.
Fig. 2: Non-uniform tumor-associated solid stress and fluid pressure mediate spatial heterogeneity.
Fig. 3: Combining patient-derived materials with technologies to model and measure tumour heterogeneity.
Fig. 4: Sources of cancer heterogeneity across length scales.

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Acknowledgements

The authors acknowledge support from the National Cancer Institute through the Center on the Physics of Cancer Metabolism (1U54CA210184) and the National Science Foundation through the National Nanotechnology Coordinated Infrastructure Program (NNCI-2025233) and the Graduate Research Fellowship Program (DGE-1650441 to G.F.B. and A.A.S). Moreover, C.F. acknowledges support by a Rosalind Franklin Fellowship from the Max Planck Institute for the Science of Light. The authors apologize that not all relevant work could be cited owing to space constraints.

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  1. These authors contributed equally: Garrett F. Beeghly, Adrian A. Shimpi.

Authors and Affiliations

  1. Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA

    Garrett F. Beeghly, Adrian A. Shimpi & Claudia Fischbach

  2. Physical Sciences Oncology Center, Cornell University, Ithaca, NY, USA

    Garrett F. Beeghly, Adrian A. Shimpi, Robert N. Riter & Claudia Fischbach

  3. Kavli Institute at Cornell for Nanoscale Science, Cornell University, Ithaca, NY, USA

    Claudia Fischbach

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G.F.B., A.A.S. and C.F. contributed to the conceptualization, writing, revision and figure design of the article. R.N.R. wrote the text and contributed his expertise regarding community engagement in the training of cancer scientists.

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Beeghly, G.F., Shimpi, A.A., Riter, R.N. et al. Measuring and modelling tumour heterogeneity across scales. Nat Rev Bioeng 1, 712–730 (2023). https://doi.org/10.1038/s44222-023-00087-9

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