Pub Date : 2026-01-12DOI: 10.1158/2159-8290.cd-25-1586
W H Adrian Tsui,Y M Dennis Lo
Pancreatic cancer is known as the "king of cancers" due to its aggressive progression and poor prognosis. Wang, Wang, Zhang, and colleagues develop a promising liquid biopsy approach that uses features derived from a single run of low-pass whole-genome cell-free DNA sequencing to predict pancreatic cancer years before diagnosis in a large asymptomatic high-risk cohort, markedly outperforming existing biomarkers and projecting survival gains. See related article by Wang et al., p. 66.
{"title":"Checking Up on the King of Cancers.","authors":"W H Adrian Tsui,Y M Dennis Lo","doi":"10.1158/2159-8290.cd-25-1586","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-1586","url":null,"abstract":"Pancreatic cancer is known as the \"king of cancers\" due to its aggressive progression and poor prognosis. Wang, Wang, Zhang, and colleagues develop a promising liquid biopsy approach that uses features derived from a single run of low-pass whole-genome cell-free DNA sequencing to predict pancreatic cancer years before diagnosis in a large asymptomatic high-risk cohort, markedly outperforming existing biomarkers and projecting survival gains. See related article by Wang et al., p. 66.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"30 1","pages":"10-12"},"PeriodicalIF":28.2,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anti-PD1 therapy benefits a subset of brain metastasis (BrM) patients; however, heterogeneous responses imply an incomplete understanding of the brain-immune ecosystem. To elucidate host-driven determinants of this variability, we performed single-cell RNA sequencing to characterize the brain microenvironment. While anti-PD1 induced robust anti-tumor immune activation, it uniquely, among all ICIs tested, compromised blood-brain barrier (BBB) integrity. This permeabilization was mediated by DKK1-expressing activated CD8⁺ T cells through the induction of β-catenin/TCF and FOXM1 pathways, contributing to endothelial cell destabilization. Depleting plasma-DKK1 restored BBB integrity and reduced experimental BrM formation. Clinically, lung cancer patients receiving anti-PD1 exhibited increased MRI contrast enhancement in the brain, suggestive of BBB perturbations, and increasing plasma DKK1 levels correlated with higher BrM incidence in non-responders. Sequencing anti-PD1 followed by cisplatin improved intracranial cisplatin delivery and therapeutic efficacy in ICI-resistant BrM. These findings identify anti-PD1-induced BBB modulation as a tractable vulnerability in BrM management.
{"title":"PD1 blockade-induced DKK1 expression by CD8+ T cells promotes blood-brain barrier permeabilization","authors":"Abhilash Deo, Sapir Levin, Chen Buxbaum, Madeleine Benguigui, Bar Manobla, Galit Saar, Noam Bosak, Eyal Bergmann, Ayelet Eran, Anat Grinfeld, Michal Harel, Coren Lahav, Ziv Raviv, Sameh Daher, Alona Zer, Julia Helena. Reuter, Claus Peter. Heuβel, Petros Christopoulos, Keren Yizhak, Yuval Shaked","doi":"10.1158/2159-8290.cd-25-1222","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-1222","url":null,"abstract":"Anti-PD1 therapy benefits a subset of brain metastasis (BrM) patients; however, heterogeneous responses imply an incomplete understanding of the brain-immune ecosystem. To elucidate host-driven determinants of this variability, we performed single-cell RNA sequencing to characterize the brain microenvironment. While anti-PD1 induced robust anti-tumor immune activation, it uniquely, among all ICIs tested, compromised blood-brain barrier (BBB) integrity. This permeabilization was mediated by DKK1-expressing activated CD8⁺ T cells through the induction of β-catenin/TCF and FOXM1 pathways, contributing to endothelial cell destabilization. Depleting plasma-DKK1 restored BBB integrity and reduced experimental BrM formation. Clinically, lung cancer patients receiving anti-PD1 exhibited increased MRI contrast enhancement in the brain, suggestive of BBB perturbations, and increasing plasma DKK1 levels correlated with higher BrM incidence in non-responders. Sequencing anti-PD1 followed by cisplatin improved intracranial cisplatin delivery and therapeutic efficacy in ICI-resistant BrM. These findings identify anti-PD1-induced BBB modulation as a tractable vulnerability in BrM management.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"30 1","pages":""},"PeriodicalIF":28.2,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145955125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-12DOI: 10.1158/2159-8290.CD-RW2025-103
{"title":"Circulating Tumor Cell Infiltration of Major Vessels Influences Cancer Prognosis.","authors":"","doi":"10.1158/2159-8290.CD-RW2025-103","DOIUrl":"10.1158/2159-8290.CD-RW2025-103","url":null,"abstract":"","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":" ","pages":"OF1"},"PeriodicalIF":33.3,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145767293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2026-01-12DOI: 10.1158/2159-8290.cd-25-1836
Amy M Boddy,Lisa M Abegglen
Although mice develop lung cancer from a single Eml4-Alk driver fusion, Shepard, Lester, and colleagues show that naked mole rats require three simultaneous oncogenic events: Eml4-Alk, Tp53 loss, and Rb1 loss, achieving only 30% tumor penetrance. This inducible cancer model in naked mole rats offers a unique platform for uncovering mechanisms of cancer resistance and modeling rare pleomorphic lung carcinomas. See related article by Shepard et al., p. 35.
{"title":"Testing Nature's Defenses: Inducing Cancer in the Naked Mole Rat.","authors":"Amy M Boddy,Lisa M Abegglen","doi":"10.1158/2159-8290.cd-25-1836","DOIUrl":"https://doi.org/10.1158/2159-8290.cd-25-1836","url":null,"abstract":"Although mice develop lung cancer from a single Eml4-Alk driver fusion, Shepard, Lester, and colleagues show that naked mole rats require three simultaneous oncogenic events: Eml4-Alk, Tp53 loss, and Rb1 loss, achieving only 30% tumor penetrance. This inducible cancer model in naked mole rats offers a unique platform for uncovering mechanisms of cancer resistance and modeling rare pleomorphic lung carcinomas. See related article by Shepard et al., p. 35.","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":"48 1","pages":"7-9"},"PeriodicalIF":28.2,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145949625","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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