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  • In this Perspective, Wahida et al. consider six riddles in precision oncology that must be solved to achieve better clinical responses to molecular targeted therapies.

    • Adam Wahida
    • Lars Buschhorn
    • Razelle Kurzrock
  • The gut microbiota has been shown to regulate responses to various cancer therapies, and the microbial species involved and their underlying mechanisms have begun to be unravelled. In this Perspective, Fernandes and colleagues present this evidence and then outline how it could be used to develop microbiota-based therapies for patients with cancer.

    • Miriam R. Fernandes
    • Poonam Aggarwal
    • Giorgio Trinchieri
  • Malignant cells show uninhibited proliferation and cellular plasticity, features also reminiscent of embryogenesis. In this Perspective, Sharma and colleagues present their oncofetal ecosystem concept, discuss evidence of oncofetal reprogramming in malignant and non-malignant cells, and debate the therapeutic relevance of these findings.

    • Ankur Sharma
    • Camille Blériot
    • Florent Ginhoux
  • Structural variations (SVs), which comprise genome-level aneuploidies and rearrangements, result in both copy number changes and novel interactions between formerly distant genomic elements. This Perspective discusses how the folding of the 3D genome, and differences in its folding across cell types, affect the formation of SVs and their impact on cancer cell fitness in different cancer types.

    • Frank Dubois
    • Nikos Sidiropoulos
    • Rameen Beroukhim
  • This Perspective discusses the role of multicellular tumour networks, formed by tumour microtubes and tunnelling nanotubes, in brain tumours. It also discusses their relevance to therapy resistance and how these networks might be therapeutically targeted, and their potential relevance in other cancer types.

    • Varun Venkataramani
    • Matthias Schneider
    • Frank Winkler
  • This Perspective discusses how polyamines, polyamine metabolism, the microbiota and the diet interconnect to establish a tumour microenvironment that facilitates the initiation and progression of cancer. It also details ways in which polyamine metabolism and function can be targeted for therapeutic benefit, including specifically enhancing the antitumour immune response.

    • Cassandra E. Holbert
    • Michael T. Cullen
    • Tracy Murray Stewart
  • Liquid–liquid phase separation (LLPS) has been revealed as a widespread mechanism underlying the spatiotemporal coordination of biological activities in cells. This Perspective discusses how LLPS shapes the biochemical landscape of cancer cells, providing insight into emerging findings of dysregulated LLPS promoting cancer pathology.

    • Sohum Mehta
    • Jin Zhang
  • Cancer cell-intrinsic PDL1 signals present novel drug discovery targets and also have potential as treatment response biomarkers. This Perspective discusses our understanding of cancer cell-intrinsic PDL1 signals, mechanisms for signal controls and immunopathological consequences including resistance to cytotoxic agents, targeted small molecules and immunotherapies.

    • Anand V. R. Kornepati
    • Ratna K. Vadlamudi
    • Tyler J. Curiel
  • This Perspective outlines how the signalling pathways enabling metastasis are often shared with those supporting resistance to cancer therapies. Identifying nodes within these shared signalling networks that could be targeted might result in more effective therapies for the treatment of rapidly growing solid tumours.

    • Felix Weiss
    • Douglas Lauffenburger
    • Peter Friedl
  • This Perspective explores the connection between copper and cancer and how challenges in the field could be addressed, and is a synthesis of discussions from the Copper Cancer Consortium, a meeting of experts in the field that took place in March 2020.

    • Eva J. Ge
    • Ashley I. Bush
    • Christopher J. Chang
  • This Perspective proposes that data from multiple modalities, including molecular diagnostics, radiological and histological imaging and codified clinical data, should be integrated by multimodal machine learning models to advance the prognosis and treatment management of patients with cancer.

    • Kevin M. Boehm
    • Pegah Khosravi
    • Sohrab P. Shah
  • This Perspective discusses the main themes in cancer metabolism research that are currently under investigation in the context of in vivo tumour metabolism, specifically emphasizing emerging aspects and questions that remain unanswered.

    • Inmaculada Martínez-Reyes
    • Navdeep S. Chandel
  • Collective cancer cell invasion with leader–follower organization is a key mechanism of metastasis, but a consensus definition of leader cell characteristics is lacking. This Perspective outlines a conceptual framework for understanding how leader cells coordinate the invasion process using a multitude of cellular and molecular programmes.

    • Samuel A. Vilchez Mercedes
    • Federico Bocci
    • Pak Kin Wong
  • This Perspective highlights the importance of protein–protein interactions for the oncogenic functions of MYC and discusses how the MYC protein interactome might be exploited therapeutically.

    • Corey Lourenco
    • Diana Resetca
    • Linda Z. Penn
  • This Perspective discusses the signalling programmes and biological factors that simultaneously induce cancer stem cells and reprogramme the immune response to facilitate tumour immune evasion. It also highlights therapeutic opportunities for simultaneous targeting of the cancer stem cell niche and immunosurveillance.

    • Defne Bayik
    • Justin D. Lathia
  • Disseminated leukaemia cells share many characteristics with metastasizing solid tumour cells. This Perspective discusses the key molecular processes that facilitate leukaemia metastasis, drawing comparisons with leukocyte trafficking and features of solid tumour invasion. Current and future strategies to target leukaemia metastasis are also discussed.

    • Andrew E. Whiteley
    • Trevor T. Price
    • Dorothy A. Sipkins
  • This Perspective highlights the evidence from basic and translational research that genetic sex influences multiple factors that can contribute to cancer development and treatment responses, and suggests that including genetic sex considerations in treatments for patients with cancer will improve outcomes.

    • Sue Haupt
    • Franco Caramia
    • Ygal Haupt
  • This Perspective outlines the connections of epithelial–mesenchymal transition programmes to the stem cell state in both normal and cancer stem cells and discusses emerging concepts related to the heterogeneous and plastic cell states generated by an epithelial–mesenchymal transition that influence our understanding of cancer stem cell biology and cancer metastasis.

    • Arthur W. Lambert
    • Robert A. Weinberg
  • The number of publications on deep learning for cancer diagnostics is rapidly increasing, but clinical translation is slow. This Perspective advocates performance estimation in external cohorts and strongly advises that a primary analysis is predefined in a standardized protocol preferentially stored in an online repository.

    • Andreas Kleppe
    • Ole-Johan Skrede
    • Håvard E. Danielsen