{"entity":{"id":"paper-hallmarks-new-dimensions-cancer-discov-2022","kind":"paper","name":"Hallmarks of Cancer 2022: adding phenotypic plasticity, epigenetic reprogramming, microbiomes and senescent cells","aka":[],"tldr":"The third hallmarks paper proposed two new hallmarks (unlocking phenotypic plasticity, senescent cells) and two new enabling characteristics (non-mutational epigenetic reprogramming, polymorphic microbiomes), bringing the framework to fourteen elements.","summary":"Twenty-two years after the original, Douglas Hanahan reviewed developments that the 2000 and 2011 frameworks did not accommodate. He proposed unlocking phenotypic plasticity (dedifferentiation, blocked differentiation and transdifferentiation, as in neuroendocrine transformation of prostate and lung cancers) as a hallmark, and senescent cells as a distinct cell type contributing to tumour progression.\n\nHe added non-mutational epigenetic reprogramming and polymorphic microbiomes as enabling characteristics: mechanisms by which cells acquire hallmark capabilities without new mutations, and ways in which microbial communities in gut and tumour modulate cancer risk, progression and therapy response.\n\nThe paper reflects how much lineage plasticity, epigenetics and the microbiome now feature in drug development, including for resistance to targeted therapy and immunotherapy.","asOf":"2026-09-08","links":[{"label":"DOI","url":"https://doi.org/10.1158/2159-8290.CD-21-1059"}],"tags":[],"related":["paper-hallmarks-of-cancer-cell-2000","unlocking-phenotypic-plasticity","nonmutational-epigenetic-reprogramming","polymorphic-microbiomes","senescent-cells"],"cancers":[],"sections":["drug-discovery","epigenetics"],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":["epigenetic-reprogramming","senescence","microbiome-tumour","cancer-stem-cells-plasticity"],"terms":["hallmarks-of-cancer"],"trials":[],"people":[],"bottlenecks":["b-resistance","b-knowledge-diffusion"],"keyPapers":[],"journals":["cancer-discovery"],"dependsOn":[],"notes":[],"journal":"Cancer Discovery","year":2022,"doi":"10.1158/2159-8290.CD-21-1059","pmid":"35022204","authors":"Hanahan D","paperType":"review","findings":["New hallmark: unlocking phenotypic plasticity (dedifferentiation, blocked differentiation, transdifferentiation)","New hallmark: senescent cells, whose secretory phenotype can promote proliferation, invasion and immune suppression","New enabling characteristic: non-mutational epigenetic reprogramming, including microenvironment-driven states","New enabling characteristic: polymorphic microbiomes affecting carcinogenesis and therapy response","Reaffirmed the 2011 set of eight hallmarks and two enabling characteristics"],"whatItMeans":"Cancer is now understood to change its identity and behaviour without new mutations, to be shaped by bacteria inside and around it, and to be helped along by ageing cells. This explains why some tumours escape targeted drugs by changing cell type and why gut bacteria affect immunotherapy response.","caveats":["Single-author perspective; some proposed additions remain contested as hallmarks rather than mechanisms","Evidence for microbiome causality in human tumours is uneven and confounded","Senolytic therapy in cancer is early and unproven","The framework has grown to 14 elements, reducing the parsimony that made the original influential"],"changedPractice":false},"route":"/key-papers/paper-hallmarks-new-dimensions-cancer-discov-2022/","neighbours":{"paper":[{"id":"paper-hallmarks-of-cancer-cell-2000","kind":"paper","name":"The Hallmarks of Cancer: six capabilities every tumour must acquire","route":"/key-papers/paper-hallmarks-of-cancer-cell-2000/"}],"term":[{"id":"nonmutational-epigenetic-reprogramming","kind":"term","name":"Hallmark (2022): non-mutational epigenetic reprogramming","route":"/terms/nonmutational-epigenetic-reprogramming/"},{"id":"polymorphic-microbiomes","kind":"term","name":"Hallmark (2022): polymorphic microbiomes","route":"/terms/polymorphic-microbiomes/"},{"id":"senescent-cells","kind":"term","name":"Hallmark (2022): senescent cells","route":"/terms/senescent-cells/"},{"id":"unlocking-phenotypic-plasticity","kind":"term","name":"Hallmark (2022): unlocking phenotypic plasticity","route":"/terms/unlocking-phenotypic-plasticity/"},{"id":"hallmarks-of-cancer","kind":"term","name":"Hallmarks of Cancer","route":"/terms/hallmarks-of-cancer/"},{"id":"hallmarks-synthesis","kind":"term","name":"Hallmarks of cancer as a synthesis of the theories","route":"/terms/hallmarks-synthesis/"}],"section":[{"id":"drug-discovery","kind":"section","name":"Drug Discovery Platforms","route":"/fronts/drug-discovery/"},{"id":"epigenetics","kind":"section","name":"Epigenetic & Transcriptional Therapy","route":"/fronts/epigenetics/"}],"pathway":[{"id":"cancer-stem-cells-plasticity","kind":"pathway","name":"Cancer stem cells & phenotypic plasticity","route":"/pathways/cancer-stem-cells-plasticity/"},{"id":"senescence","kind":"pathway","name":"Cellular senescence","route":"/pathways/senescence/"},{"id":"epigenetic-reprogramming","kind":"pathway","name":"Epigenetic reprogramming","route":"/pathways/epigenetic-reprogramming/"},{"id":"microbiome-tumour","kind":"pathway","name":"Microbiome-tumour interactions","route":"/pathways/microbiome-tumour/"},{"id":"theories-of-cancer","kind":"pathway","name":"Theories of cancer: how the ideas connect","route":"/pathways/theories-of-cancer/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"},{"id":"b-knowledge-diffusion","kind":"bottleneck","name":"Knowledge reaches practice too slowly","route":"/bottlenecks/b-knowledge-diffusion/"}],"journal":[{"id":"cancer-discovery","kind":"journal","name":"Cancer Discovery","route":"/journals/cancer-discovery/"}],"roadmap":[{"id":"epigenetics-roadmap","kind":"roadmap","name":"Epigenetic therapy roadmap: loosening silenced genes → mutation-specific enzymes → editing the epigenome","route":"/roadmaps/epigenetics-roadmap/"}]}}