Volume 1 Issue 1, January 2020

Volume 1 Issue 1

Understanding the complexities of cancer

Our inaugural issue highlights the complexities of cancer, featuring articles on cancer evolution, heterogeneity and population-specific disparities, identifying cancer drivers and the origins of metastasis-initiating cells. Highlighting diverse aspects of immunotherapy are studies on sensitizing tumors to immune-checkpoint blockade, improving predictors of response and devising therapeutic trispecific antibodies.

See Editorial

Image: concept by Lucia Morgado-Palacin. Cover Design: Allen Beattie.

Editorial

  • Editorial |

    Cancer is a multifaceted global health issue that continues to demand action. We are launching Nature Cancer to inform, inspire and convene scientists across the multidisciplinary arena of cancer research, aiming to advance biomedical knowledge and treatment strategies within the greater framework of society.

Comment & Opinion

  • Comment |

    Intratumoral genetic heterogeneity of driver somatic mutations is present in a variety of tumor types, yet the extent of heterogeneity is variable. We propose that this variation is a reflection of the inherent biology of a given tumor type, representing the pace of metastatic dissemination and hence clinical disease course.

    • Christine A. Iacobuzio-Donahue
    • , Kevin Litchfield
    •  & Charles Swanton
  • Q&A |

    Norman E. ‘Ned’ Sharpless became director of the US National Cancer Institute (NCI) in 2017. From April 2019, he served as acting commissioner of the US Food and Drug Administration (FDA), and he returned to the NCI in November. Douglas R. Lowy has been the principal deputy director of the NCI since 2010, having also served as acting director twice, most recently in 2019. Nature Cancer spoke with both last fall to learn more about what makes NCI and its leadership tick.

    • Alexia-Ileana Zaromytidou
  • Viewpoint |

    Cancer research in recent years has been marked by significant developments in understanding disease biology and foundational discoveries that have changed clinical practice. Ten cancer researchers take stock of the field, the advances that excite them, key outstanding questions and breakthroughs they anticipate looking forward.

    • René Bernards
    • , Elizabeth Jaffee
    • , Johanna A. Joyce
    • , Scott W. Lowe
    • , Elaine R. Mardis
    • , Sean J. Morrison
    • , Kornelia Polyak
    • , Cynthia L. Sears
    • , Karen H. Vousden
    •  & Zemin Zhang

News & Views

  • News & Views |

    Immunotherapy resistance is associated with poor T cell infiltration into tumors. Tumor-cell-intrinsic oncogenic events that contribute to this defect include Wnt–β-catenin activation. PAK4 is now identified as an upstream modulator of this pathway, thus suggesting the potential of enhancing the efficacy of immunotherapy by targeting this druggable kinase.

    • Thomas F. Gajewski
    •  & Jessica Fessler
  • News & Views |

    Identifying cancer driver mutations is essential to understand disease biology and devise effective therapies, but remains a complex endeavor. A focused analytical approach is now presented that defines driver mutations affecting ubiquitin-mediated proteolysis through machine learning and mining of cancer multi-omics data.

    • Han Liang
  • News & Views |

    Metastasis competence can be acquired early in tumorigenesis, although its underlying molecular intricacies remain unclear. A recent study provides key information about the function of L1CAM in conferring metastasis-initiation potential and chemoresistance in colorectal cancer by hijacking epithelial regenerative mechanisms.

    • Gloria Pascual
    •  & Salvador A. Benitah

Cancer in Translation

  • Cancer in Translation |

    KRAS mutations are among the most prevalent tumor drivers, but targeting them pharmacologically has been challenging. Recent landmark studies have demonstrated promising clinical results of KRASG12C inhibition by using small molecules. Bar-Sagi, and Knelson and Sequist provide their distinct perspectives on this recent tour de force in targeting KRASG12C alterations.

    • Dafna Bar-Sagi
    • , Erik H. Knelson
    •  & Lecia V. Sequist

Research

  • Article |

    The authors identify a population of L1CAM-positive cells that, following loss of epithelial integrity, promote intestinal tissue regeneration and mediate metastasis initiation and chemoresistance in colorectal cancer.

    • Karuna Ganesh
    • , Harihar Basnet
    • , Yasemin Kaygusuz
    • , Ashley M. Laughney
    • , Lan He
    • , Roshan Sharma
    • , Kevin P. O’Rourke
    • , Vincent P. Reuter
    • , Yun-Han Huang
    • , Mesruh Turkekul
    • , Ekrem Emrah Er
    • , Ignas Masilionis
    • , Katia Manova-Todorova
    • , Martin R. Weiser
    • , Leonard B. Saltz
    • , Julio Garcia-Aguilar
    • , Richard Koche
    • , Scott W. Lowe
    • , Dana Pe’er
    • , Jinru Shia
    •  & Joan Massagué
  • Article |

    Ribas and colleagues report that inhibition of PAK4 improves response to anti-PD-1 immunotherapy by reducing Wnt pathway activation and increasing tumor infiltration by T cells.

    • Gabriel Abril-Rodriguez
    • , Davis Y. Torrejon
    • , Wei Liu
    • , Jesse M. Zaretsky
    • , Theodore S. Nowicki
    • , Jennifer Tsoi
    • , Cristina Puig-Saus
    • , Ignacio Baselga-Carretero
    • , Egmidio Medina
    • , Michael J. Quist
    • , Alejandro J. Garcia
    • , William Senapedis
    • , Erkan Baloglu
    • , Anusha Kalbasi
    • , Gardenia Cheung-Lau
    • , Beata Berent-Maoz
    • , Begoña Comin-Anduix
    • , Siwen Hu-Lieskovan
    • , Cun-Yu Wang
    • , Catherine S. Grasso
    •  & Antoni Ribas
  • Article |

    Iacobuzio-Donahue and colleagues use integrated transcriptomic, histologic and mutational data to analyze squamous features of pancreatic ductal adenocarcinoma (PDAC), further refining the understanding of heterogeneity and evolution in PDAC.

    • Akimasa Hayashi
    • , Jun Fan
    • , Ruoyao Chen
    • , Yu-jui Ho
    • , Alvin P. Makohon-Moore
    • , Nicolas Lecomte
    • , Yi Zhong
    • , Jungeui Hong
    • , Jinlong Huang
    • , Hitomi Sakamoto
    • , Marc A. Attiyeh
    • , Zachary A. Kohutek
    • , Lance Zhang
    • , Aida Boumiza
    • , Rajya Kappagantula
    • , Priscilla Baez
    • , Jessica Bai
    • , Marta Lisi
    • , Kalyani Chadalavada
    • , Jerry P. Melchor
    • , Winston Wong
    • , Gouri J. Nanjangud
    • , Olca Basturk
    • , Eileen M. O’Reilly
    • , David S. Klimstra
    • , Ralph H. Hruban
    • , Laura D. Wood
    • , Michael Overholtzer
    •  & Christine A. Iacobuzio-Donahue
  • Article |

    Ajona and colleagues report that short-term starvation synergizes with anti-PD-1 blockade to reduce lung tumor growth and metastasis. This antitumor effect is mediated through the reduction of plasma IGF-1 levels and IGF-1R levels on tumor cells.

    • Daniel Ajona
    • , Sergio Ortiz-Espinosa
    • , Teresa Lozano
    • , Francisco Exposito
    • , Alfonso Calvo
    • , Karmele Valencia
    • , Miriam Redrado
    • , Ana Remírez
    • , Fernando Lecanda
    • , Diego Alignani
    • , Juan J. Lasarte
    • , Irati Macaya
    • , Yaiza Senent
    • , Cristina Bértolo
    • , Cristina Sainz
    • , Ignacio Gil-Bazo
    • , Iñaki Eguren-Santamaría
    • , Jose M. Lopez-Picazo
    • , Alvaro Gonzalez
    • , Jose L. Perez-Gracia
    • , Carlos E. de Andrea
    • , Silvestre Vicent
    • , Miguel F. Sanmamed
    • , Luis M. Montuenga
    •  & Ruben Pio
  • Article |

    Wu et al. develop trispecific antibodies that recognize CD38, CD3 and CD28 and induce T cell activation and co-signaling. They show in mice and non-human primates that by engaging multiple targets, these antibodies induce enhanced tumor-cell killing.

    • Lan Wu
    • , Edward Seung
    • , Ling Xu
    • , Ercole Rao
    • , Dana M. Lord
    • , Ronnie R. Wei
    • , Virna Cortez-Retamozo
    • , Beatriz Ospina
    • , Valeriya Posternak
    • , Gregory Ulinski
    • , Peter Piepenhagen
    • , Elisa Francesconi
    • , Nizar El-Murr
    • , Christian Beil
    • , Patrick Kirby
    • , Aiqun Li
    • , Jennifer Fretland
    • , Rita Vicente
    • , Gejing Deng
    • , Tarik Dabdoubi
    • , Beatrice Cameron
    • , Thomas Bertrand
    • , Paul Ferrari
    • , Stéphanie Pouzieux
    • , Cendrine Lemoine
    • , Catherine Prades
    • , Anna Park
    • , Huawei Qiu
    • , Zhili Song
    • , Bailin Zhang
    • , Fangxian Sun
    • , Marielle Chiron
    • , Srinivas Rao
    • , Katarina Radošević
    • , Zhi-yong Yang
    •  & Gary J. Nabel
  • Article |

    Anagnostou et al. present an improved predictor of response to immune checkpoint blockade that integrates estimates of tumor mutational burden corrected for tumor purity, RTK genomic alterations, a smoking-related mutational signature and HLA status.

    • Valsamo Anagnostou
    • , Noushin Niknafs
    • , Kristen Marrone
    • , Daniel C. Bruhm
    • , James R. White
    • , Jarushka Naidoo
    • , Karlijn Hummelink
    • , Kim Monkhorst
    • , Ferry Lalezari
    • , Mara Lanis
    • , Samuel Rosner
    • , Joshua E. Reuss
    • , Kellie N. Smith
    • , Vilmos Adleff
    • , Kristen Rodgers
    • , Zineb Belcaid
    • , Lamia Rhymee
    • , Benjamin Levy
    • , Josephine Feliciano
    • , Christine L. Hann
    • , David S. Ettinger
    • , Christos Georgiades
    • , Franco Verde
    • , Peter Illei
    • , Qing Kay Li
    • , Alexander S. Baras
    • , Edward Gabrielson
    • , Malcolm V. Brock
    • , Rachel Karchin
    • , Drew M. Pardoll
    • , Stephen B. Baylin
    • , Julie R. Brahmer
    • , Robert B. Scharpf
    • , Patrick M. Forde
    •  & Victor E. Velculescu
  • Article |

    Ryan and colleagues analyze genomic features in tumors from African Americans and European Americans and find that homologous recombination deficiency is more prevalent in African Americans.

    • Sanju Sinha
    • , Khadijah A. Mitchell
    • , Adriana Zingone
    • , Elise Bowman
    • , Neelam Sinha
    • , Alejandro A. Schäffer
    • , Joo Sang Lee
    • , Eytan Ruppin
    •  & Bríd M. Ryan
  • Analysis |

    Martínez-Jiménez et al. report how disruption of the ubiquitin–proteasome system affects cancer, estimating that >10% of driver mutations involve alterations in genes relevant in ubiquitin-mediated proteolysis, including E3 ligases and their targets.

    • Francisco Martínez-Jiménez
    • , Ferran Muiños
    • , Erika López-Arribillaga
    • , Nuria Lopez-Bigas
    •  & Abel Gonzalez-Perez