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Towards targeting of shared mechanisms of cancer metastasis and therapy resistance

Nature Reviews Cancer volume 22, pages 157–173 (2022)Cite this article

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Abstract

Resistance to therapeutic treatment and metastatic progression jointly determine a fatal outcome of cancer. Cancer metastasis and therapeutic resistance are traditionally studied as separate fields using non-overlapping strategies. However, emerging evidence, including from in vivo imaging and in vitro organotypic culture, now suggests that both programmes cooperate and reinforce each other in the invasion niche and persist upon metastatic evasion. As a consequence, cancer cell subpopulations exhibiting metastatic invasion undergo multistep reprogramming that — beyond migration signalling — supports repair programmes, anti-apoptosis processes, metabolic adaptation, stemness and survival. Shared metastasis and therapy resistance signalling are mediated by multiple mechanisms, such as engagement of integrins and other context receptors, cell–cell communication, stress responses and metabolic reprogramming, which cooperate with effects elicited by autocrine and paracrine chemokine and growth factor cues present in the activated tumour microenvironment. These signals empower metastatic cells to cope with therapeutic assault and survive. Identifying nodes shared in metastasis and therapy resistance signalling networks should offer new opportunities to improve anticancer therapy beyond current strategies, to eliminate both nodular lesions and cells in metastatic transit.

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Fig. 1: Invasion-associated reprogramming.
Fig. 2: Invasion-associated reprogramming from the extracellular matrix.
Fig. 3: Mechanisms of repair and cell survival.
Fig. 4: Cooperation and redundancy of survival signalling in single-cell and collective invasion during metastasis.
Fig. 5: Targeting metastasis-associated therapy resistance programmes.

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Acknowledgements

The original work underlying this article in the authors’ laboratories was supported by the Netherlands Science Organization (NWO-VICI 918.11.626), the European Research Council (617430-DEEPINSIGHT), NIH U54 CA210184-01 and U54 CA261694-01, and the Dutch Cancer Genomics Center (cancergenomics.nl).

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Authors and Affiliations

  1. Department of Cell Biology, RIMLS, Radboud University Medical Center, Nijmegen, Netherlands

    Felix Weiss & Peter Friedl

  2. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA

    Douglas Lauffenburger

  3. Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA

    Douglas Lauffenburger

  4. David H. Koch Center for Applied Research of Genitourinary Cancers, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Peter Friedl

  5. Cancer Genomics Center, Utrecht, Netherlands

    Peter Friedl

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Correspondence to Peter Friedl.

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Supplementary information

Glossary

Adaptive resistance

Resistance resulting from stress programmes induced in cancer cells by a range of external triggers, including therapy stress, metabolic perturbation, and cytokine-mediated stemness or epithelial-to-mesenchymal transition.

Anoikis

A form of programmed cell death of anchorage-dependent cells that is activated upon detachment from the extracellular matrix due to the lack of growth and survival signals provided from the matrix interaction.

Autophagy

A controlled pathway in which autophagosomes engulf and degrade cellular organelles as an alternative source for energy production and cell survival.

Cell detritus

Interstitial cell fragments, including cell membranes, organelles and DNA.

Chromatin organization

The 3D structure of DNA, under the control of histone proteins. The density of chromatin packaging determines the accessibility of the genome to transcription factors.

Context receptors

A heterogeneous group of cell surface receptors that provide intracellular signals in response to binding extracellular matrix, matrix-associated growth factors and adjacent cell-surface receptors.

DNA methyltransferases

(DNMTs). A group of enzymes that introduce methylation of cytosine and guanine-rich regions of the DNA and repress transcription by recruitment of methyl-CpG-binding proteins.

Endosomal sorting complexes required for transport III

(ESCRTIII). A complex of cytosolic proteins forming a machinery able to remodel and repair cell membranes.

Epithelial-to-mesenchymal transition

(EMT). The conversion of polarized, adherent epithelial cells into motile mesenchymal cells that lack apicobasal polarity and possess decreased cell–cell adhesion strength and acquire stem cell-like traits.

Hippo pathway

A mechanosensitive pathway that controls cell size, division and apoptosis. In morphogenesis, Hippo pathway activation limits growth and induces apoptosis, whereas in cancer cells it enhances oncogenic signalling.

Histone acetyltransferases

(HATs). A group of enzymes that add acetyl groups to the histone tail; this weakens the strength of binding to DNA, reduces chromatin density and facilitates access of transcription factors to DNA.

Histone deacetylases

(HDACs). A group of enzymes that remove acetyl groups from the histone tail; this strengthens the histone–DNA interaction, leads to chromatin condensation and reduces transcription.

Histone demethylases

(HDMs). A group of enzymes that remove methyl groups from the histone tail, which reduces chromatin density.

Histone methyltransferases

(HMTs). A group of enzymes that add methyl groups to the histone tail, which favours heterochromatization by recruitment of chromatin-binding proteins, which increases chromatin density, decreases DNA accessibility and silences transcription.

Histone-modifying enzymes

Enzymes that induce reversible acetylation and methylation of histones, which regulates the chromatin structure and density, and thereby the local accessibility of DNA for transcription factors and DNA damage response proteins.

Integrin

Adhesion receptor, which engages with extracellular matrix and other ligands and mechanically connects to the actin cytoskeleton for cell anchorage and migration.

Lipid mediators

Metabolites of polyunsaturated fatty acids, including leukotrienes and prostaglandins, which are acutely released by leukocytes to induce and regulate local inflammation.

Matrix metalloproteinases

(MMPs). A large family of proteolytic secreted or membrane-bound enzymes that degrade a broad range of substrates, including extracellular matrix, growth factors and surface receptors.

Nanolumenal release

Extracellular secretion of vesicle content into very tight spaces between cell–cell junctions, which limits dilution of released cytokines and enables particularly strong autocrine and juxtacrine signalling.

Senescence

A cellular state of sustained growth arrest in response to stress. It is associated with increased resistance to cell death.

Shear stress

The physical force exerted on circulating tumour cells by blood flow.

Survivin

Belongs to the inhibitor of apoptosis (IAP) protein family, which inhibits caspases and thereby suppresses apoptosis.

Tissue inhibitor of metalloproteinases 3

(TIMP3). An important broad-spectrum inhibitor of matrix metalloproteinases produced by tumour and stromal cells that inhibits epithelial-to-mesenchymal transition and metastatic progression.

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Weiss, F., Lauffenburger, D. & Friedl, P. Towards targeting of shared mechanisms of cancer metastasis and therapy resistance. Nat Rev Cancer 22, 157–173 (2022). https://doi.org/10.1038/s41568-021-00427-0

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