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Spatial omics and multiplexed imaging to explore cancer biology

Abstract

Understanding intratumoral heterogeneity—the molecular variation among cells within a tumor—promises to address outstanding questions in cancer biology and improve the diagnosis and treatment of specific cancer subtypes. Single-cell analyses, especially RNA sequencing and other genomics modalities, have been transformative in revealing novel biomarkers and molecular regulators associated with tumor growth, metastasis and drug resistance. However, these approaches fail to provide a complete picture of tumor biology, as information on cellular location within the tumor microenvironment is lost. New technologies leveraging multiplexed fluorescence, DNA, RNA and isotope labeling enable the detection of tens to thousands of cancer subclones or molecular biomarkers within their native spatial context. The expeditious growth in these techniques, along with methods for multiomics data integration, promises to yield a more comprehensive understanding of cell-to-cell variation within and between individual tumors. Here we provide the current state and future perspectives on the spatial technologies expected to drive the next generation of research and diagnostic and therapeutic strategies for cancer.

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Fig. 1: Outstanding questions in the field of spatial cancer biology.
Fig. 2: Spatial technologies.
Fig. 3: Spatial proteomic approaches.
Fig. 4: FISH-based spatial transcriptomic methods.
Fig. 5: Sequencing-based spatial transcriptomic methods.
Fig. 6: Timeline of clonal, spatial transcriptomics and proteomics methods.

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Acknowledgements

For Fig. 2, we thank L. Cai for contributing seqFISH data; S. Lakhani and P. Kalita de Croft for clinical annotation of breast cancer tissue; and Ionpath for assisting with tissue staining and generation of MIBI data. We thank D. Brown and T. Weber for critical feedback. M.-L.A.-L. is supported by funding from the Viertel Foundation Senior Medical Research Fellowship, NHMRC grant GNT1182155 and the Harry Secomb Foundation, managed by Perpetual. Q.N. is supported by Australian Research Council DECRA fellowship DE190100116 and NHMRC grant GNT2001514. D.M. is supported by Susan G. Komen and Cancer Australia, CCR19606878, a grant from the National Breast Cancer Foundation, Australia, IIRS-19-082 and the Grant-in-Aid Scheme administered by Cancer Council Victoria. The Olivia Newton-John Cancer Research Institute gratefully acknowledges the generous support of the Love Your Sister Foundation. S.H.N. is supported by NHMRC grants GNT1062820, GNT1100033, GNT1101378, GNT1124812 and GNT1145184. We also acknowledge support from the ACRF Centre for Imaging the Tumour Environment at the Olivia Newton-John Cancer Research Institute, the ACRF Program for Resolving Cancer Complexity and Therapeutic Resistance at WEHI and the Operational Infrastructure Support Program provided by the Victorian government and the NHMRC Independent Research Institutes Infrastructure Support Scheme (IRIISS) grant. The contents of the published material are solely the responsibility of the individual authors and do not reflect the views of Cancer Australia, NHMRC or other funding agencies.

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All authors contributed to the writing of the manuscript, with all figures generated by S.M.L. along with X.T. for Fig. 6b. Primary data for Fig. 2 were contributed by V.C.W., J.B., K.L.R. and D.M. (Fig. 2a), M.-L.A.-L. (Fig. 2b), and X.T. and Q.N. (Fig. 2d).

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Correspondence to Kelly L. Rogers or Shalin H. Naik.

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Lewis, S.M., Asselin-Labat, ML., Nguyen, Q. et al. Spatial omics and multiplexed imaging to explore cancer biology. Nat Methods 18, 997–1012 (2021). https://doi.org/10.1038/s41592-021-01203-6

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