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Beyond genetics: driving cancer with the tumour microenvironment behind the wheel

Nature Reviews Cancer volume 24, pages 274–286 (2024)Cite this article

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Abstract

Cancer has long been viewed as a genetic disease of cumulative mutations. This notion is fuelled by studies showing that ageing tissues are often riddled with clones of complex oncogenic backgrounds coexisting in seeming harmony with their normal tissue counterparts. Equally puzzling, however, is how cancer cells harbouring high mutational burden contribute to normal, tumour-free mice when allowed to develop within the confines of healthy embryos. Conversely, recent evidence suggests that adult tissue cells expressing only one or a few oncogenes can, in some contexts, generate tumours exhibiting many of the features of a malignant, invasive cancer. These disparate observations are difficult to reconcile without invoking environmental cues triggering epigenetic changes that can either dampen or drive malignant transformation. In this Review, we focus on how certain oncogenes can launch a two-way dialogue of miscommunication between a stem cell and its environment that can rewire downstream events non-genetically and skew the morphogenetic course of the tissue. We review the cells and molecules of and the physical forces acting in the resulting tumour microenvironments that can profoundly affect the behaviours of transformed cells. Finally, we discuss possible explanations for the remarkable diversity in the relative importance of mutational burden versus tumour microenvironment and its clinical relevance.

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Fig. 1: Crosstalk between transformed cells and the microenvironment induces the cancer stem cell state.
Fig. 2: Epigenetic changes drive tumorigenesis and progression.
Fig. 3: The balance between mutations and the tumour microenvironment drives tumorigenesis and progression.

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Acknowledgements

S.Y. is the recipient of an F31 Ruth L. Kirschstein Predoctoral Individual National Research Service fellowship from the National Cancer Institute and a Pilot Award from the Shapiro-Silverberg Fund at The Rockefeller University. J.A. is a MacMillan Family Foundation Awardee of the Life Sciences Research Foundation. E.F. is a Howard Hughes Medical Investigator and is supported by grants from the National Institutes of Health (R01-AR050452, R01-AR31737 and R37-AR27883), the Starr Foundation and the Stavros Niarchos Foundation.

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  1. These authors contributed equally: Shaopeng Yuan, Jorge Almagro.

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  1. Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY, USA

    Shaopeng Yuan, Jorge Almagro & Elaine Fuchs

  2. Howard Hughes Medical Institute, New York, NY, USA

    Elaine Fuchs

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Glossary

Axonogenic factors

Soluble molecules that induce axon elongation.

Caerulein

A ten-amino-acid peptide that induces pancreatic secretion and acute pancreatitis.

Cancer stem cell

(CSC). A subset of tumour-initiating progenitors that mimic some stem cell behaviours and obtain increased resistance to chemotherapy and immunotherapy.

Cre driver

Cell-type-specific recombinase.

Dextran sodium sulfate

(DSS). Sulphated polysaccharide, toxic to colonic epithelial cells and used to induce colitis.

Epigenetic rewiring

Environment-induced changes in chromatin accessibility that affect the biology of cells.

Extracellular matrix

(ECM). Network of fibrous macromolecules between cells.

Organotropism

Preferential invasion of specific distant organs by metastatic cells.

T cell exhaustion

Acquired state of T cell dysfunction.

Tissue architecture

Three-dimensional spatial organization of biological tissues.

Transformed cell

A cell afflicted by an oncogenic genetic alteration, resulting in the development of a neoplastic phenotype.

Translational machinery

Macromolecules (proteins and ribosomal RNA) involved in protein biosynthesis.

Vagotomy

Surgical cauterization of vagus nerve.

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Yuan, S., Almagro, J. & Fuchs, E. Beyond genetics: driving cancer with the tumour microenvironment behind the wheel. Nat Rev Cancer 24, 274–286 (2024). https://doi.org/10.1038/s41568-023-00660-9

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