Measuring and modelling tumour heterogeneity across scales

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. Heterogeneity constitutes a critical barrier to treating cancer. This Review discusses the biological and physical sources of heterogeneity across length scales, encompassing tumour-cell-intrinsic, tissue-microenvironment and organism-level sources, and how engineering strategies can improve our understanding of these phenomena.