Yunfan Sun, Pin Wu, Zefan Zhang, Zejian Wang, Kaiqian Zhou, Minfang Song, Yuan Ji, Fenglin Zang, Limu Lou, Keqiang Rao, Pengxiang Wang, Yutong Gu, Jie Gu, Binbin Lu, Limeng Chen, Xiuqi Pan, Xiaojing Zhao, Lihua Peng, Dongbing Liu, Xiaofang Chen, Kui Wu, Penghui Lin, Liang Wu, Yulin Su, Min Du, Yingyong Hou, Xinrong Yang, Shuangjian Qiu, Yinghong Shi, Huichuan Sun, Jian Zhou, Xingxu Huang, David H Peng, Liye Zhang, Jia Fan <<<

Comprehensive molecular analyses of metastatic hepatocellular carcinoma (HCC) are lacking. Here, we generate multi-omic profiling of 257 primary and 176 metastatic regions from 182 HCC patients. Primary tumors rich in hypoxia signatures facilitated polyclonal dissemination. Genomic divergence between primary and metastatic HCC is high, and early dissemination is prevalent. The remarkable neoantigen intratumor heterogeneity observed in metastases is associated with decreased T cell reactivity, resulting from disruptions to neoantigen presentation. We identify somatic copy number alterations as highly selected events driving metastasis. Subclones without Wnt mutations show a stronger selective advantage for metastasis than those with Wnt mutations and are characterized by a microenvironment rich in activated fibroblasts favoring a pro-metastatic phenotype. Finally, metastases without Wnt mutations exhibit higher enrichment of immunosuppressive B cells that mediate terminal exhaustion of CD8 T cells via HLA-E:CD94-NKG2A checkpoint axis. Collectively, our results provide a multi-dimensional dissection of the complex evolutionary process of metastasis. <<<

Anthony P Y Liu, Kyle S Smith, Rahul Kumar, Leena Paul, Laure Bihannic, Tong Lin, Kendra K Maass, Kristian W Pajtler, Murali Chintagumpala, Jack M Su, Eric Bouffet, Michael J Fisher, Sridharan Gururangan, Richard Cohn, Tim Hassall, Jordan R Hansford, Paul Klimo, Frederick A Boop, Clinton F Stewart, Julie H Harreld, Thomas E Merchant, Ruth G Tatevossian, Geoffrey Neale, Matthew Lear, Jeffery M Klco, Brent A Orr, David W Ellison, Richard J Gilbertson, Arzu Onar-Thomas, Amar Gajjar, Giles W Robinson, Paul A Northcott <<<

Nearly one-third of children with medulloblastoma, a malignant embryonal tumor of the cerebellum, succumb to their disease. Conventional response monitoring by imaging and cerebrospinal fluid (CSF) cytology remains challenging, and a marker for measurable residual disease (MRD) is lacking. Here, we show the clinical utility of CSF-derived cell-free DNA (cfDNA) as a biomarker of MRD in serial samples collected from children with medulloblastoma (123 patients, 476 samples) enrolled on a prospective trial. Using low-coverage whole-genome sequencing, tumor-associated copy-number variations in CSF-derived cfDNA are investigated as an MRD surrogate. MRD is detected at baseline in 85% and 54% of patients with metastatic and localized disease, respectively. The number of MRD-positive patients declines with therapy, yet those with persistent MRD have significantly higher risk of progression. Importantly, MRD detection precedes radiographic progression in half who relapse. Our findings advocate for the prospective assessment of CSF-derived liquid biopsies in future trials for medulloblastoma. <<<

Alexandra Mousset, Enora Lecorgne, Isabelle Bourget, Pascal Lopez, Kitti Jenovai, Julien Cherfils-Vicini, Chloé Dominici, Géraldine Rios, Cédric Girard-Riboulleau, Bodu Liu, David L Spector, Sidse Ehmsen, Shufang Renault, Caroline Hego, Fatima Mechta-Grigoriou, François-Clément Bidard, Mikkel Green Terp, Mikala Egeblad, Cédric Gaggioli, Jean Albrengues <<<

Metastasis is the major cause of cancer death, and the development of therapy resistance is common. The tumor microenvironment can confer chemotherapy resistance (chemoresistance), but little is known about how specific host cells influence therapy outcome. We show that chemotherapy induces neutrophil recruitment and neutrophil extracellular trap (NET) formation, which reduces therapy response in mouse models of breast cancer lung metastasis. We reveal that chemotherapy-treated cancer cells secrete IL-1β, which in turn triggers NET formation. Two NET-associated proteins are required to induce chemoresistance: integrin-αvβ1, which traps latent TGF-β, and matrix metalloproteinase 9, which cleaves and activates the trapped latent TGF-β. TGF-β activation causes cancer cells to undergo epithelial-to-mesenchymal transition and correlates with chemoresistance. Our work demonstrates that NETs regulate the activities of neighboring cells by trapping and activating cytokines and suggests that chemoresistance in the metastatic setting can be reduced or prevented by targeting the IL-1β-NET-TGF-β axis. <<<

Andrew Chow, Sara Schad, Michael D Green, Matthew D Hellmann, Viola Allaj, Nicholas Ceglia, Giulia Zago, Nisargbhai S Shah, Sai Kiran Sharma, Marissa Mattar, Joseph Chan, Hira Rizvi, Hong Zhong, Cailian Liu, Yonina Bykov, Dmitriy Zamarin, Hongyu Shi, Sadna Budhu, Corrin Wohlhieter, Fathema Uddin, Aditi Gupta, Inna Khodos, Jessica J Waninger, Angel Qin, Geoffrey J Markowitz, Vivek Mittal, Vinod Balachandran, Jennifer N Durham, Dung T Le, Weiping Zou, Sohrab P Shah, Andrew McPherson, Katherine Panageas, Jason S Lewis, Justin S A Perry, Elisa de Stanchina, Triparna Sen, John T Poirier, Jedd D Wolchok, Charles M Rudin, Taha Merghoub <<<

Immune checkpoint blockade (ICB) has been a remarkable clinical advance for cancer; however, the majority of patients do not respond to ICB therapy. We show that metastatic disease in the pleural and peritoneal cavities is associated with poor clinical outcomes after ICB therapy. Cavity-resident macrophages express high levels of Tim-4, a receptor for phosphatidylserine (PS), and this is associated with reduced numbers of CD8 T cells with tumor-reactive features in pleural effusions and peritoneal ascites from patients with cancer. We mechanistically demonstrate that viable and cytotoxic anti-tumor CD8 T cells upregulate PS and this renders them susceptible to sequestration away from tumor targets and proliferation suppression by Tim-4 macrophages. Tim-4 blockade abrogates this sequestration and proliferation suppression and enhances anti-tumor efficacy in models of anti-PD-1 therapy and adoptive T cell therapy in mice. Thus, Tim-4 cavity-resident macrophages limit the efficacy of immunotherapies in these microenvironments. <<<

Peng Liao, Weimin Wang, Weichao Wang, Ilona Kryczek, Xiong Li, Yingjie Bian, Amanda Sell, Shuang Wei, Sara Grove, Jeffrey K Johnson, Paul D Kennedy, Miguel Gijón, Yatrik M Shah, Weiping Zou <<<

Tumor cell intrinsic ferroptosis-initiating mechanisms are unknown. Here, we discover that T cell-derived interferon (IFN)γ in combination with arachidonic acid (AA) induces immunogenic tumor ferroptosis, serving as a mode of action for CD8 T cell (CTL)-mediated tumor killing. Mechanistically, IFNγ stimulates ACSL4 and alters tumor cell lipid pattern, thereby increasing incorporations of AA into C16 and C18 acyl chain-containing phospholipids. Palmitoleic acid and oleic acid, two common C16 and C18 fatty acids in blood, promote ACSL4-dependent tumor ferroptosis induced by IFNγ plus AA. Moreover, tumor ACSL4 deficiency accelerates tumor progression. Low-dose AA enhances tumor ferroptosis and elevates spontaneous and immune checkpoint blockade (ICB)-induced anti-tumor immunity. Clinically, tumor ACSL4 correlates with T cell signatures and improved survival in ICB-treated cancer patients. Thus, IFNγ signaling paired with selective fatty acids is a natural tumor ferroptosis-promoting mechanism and a mode of action of CTLs. Targeting the ACSL4 pathway is a potential anti-cancer approach. <<<

Arash Jamshidi, Minetta C Liu, Eric A Klein, Oliver Venn, Earl Hubbell, John F Beausang, Samuel Gross, Collin Melton, Alexander P Fields, Qinwen Liu, Nan Zhang, Eric T Fung, Kathryn N Kurtzman, Hamed Amini, Craig Betts, Daniel Civello, Peter Freese, Robert Calef, Konstantin Davydov, Saniya Fayzullina, Chenlu Hou, Roger Jiang, Byoungsok Jung, Susan Tang, Vasiliki Demas, Joshua Newman, Onur Sakarya, Eric Scott, Archana Shenoy, Seyedmehdi Shojaee, Kristan K Steffen, Virgil Nicula, Tom C Chien, Siddhartha Bagaria, Nathan Hunkapiller, Mohini Desai, Zhao Dong, Donald A Richards, Timothy J Yeatman, Allen L Cohn, David D Thiel, Donald A Berry, Mohan K Tummala, Kristi McIntyre, Mikkael A Sekeres, Alan Bryce, Alexander M Aravanis, Michael V Seiden, Charles Swanton <<<

In the Circulating Cell-free Genome Atlas (NCT02889978) substudy 1, we evaluate several approaches for a circulating cell-free DNA (cfDNA)-based multi-cancer early detection (MCED) test by defining clinical limit of detection (LOD) based on circulating tumor allele fraction (cTAF), enabling performance comparisons. Among 10 machine-learning classifiers trained on the same samples and independently validated, when evaluated at 98% specificity, those using whole-genome (WG) methylation, single nucleotide variants with paired white blood cell background removal, and combined scores from classifiers evaluated in this study show the highest cancer signal detection sensitivities. Compared with clinical stage and tumor type, cTAF is a more significant predictor of classifier performance and may more closely reflect tumor biology. Clinical LODs mirror relative sensitivities for all approaches. The WG methylation feature best predicts cancer signal origin. WG methylation is the most promising technology for MCED and informs development of a targeted methylation MCED test. <<<

Sjors G J G In 't Veld, Mohammad Arkani, Edward Post, Mafalda Antunes-Ferreira, Silvia D'Ambrosi, Daan C L Vessies, Lisa Vermunt, Adrienne Vancura, Mirte Muller, Anna-Larissa N Niemeijer, Jihane Tannous, Laura L Meijer, Tessa Y S Le Large, Giulia Mantini, Niels E Wondergem, Kimberley M Heinhuis, Sandra van Wilpe, A Josien Smits, Esther E E Drees, Eva Roos, Cyra E Leurs, Lee-Ann Tjon Kon Fat, Ewoud J van der Lelij, Govert Dwarshuis, Maarten J Kamphuis, Lisanne E Visser, Romee Harting, Annemijn Gregory, Markus W Schweiger, Laurine E Wedekind, Jip Ramaker, Kenn Zwaan, Heleen Verschueren, Idris Bahce, Adrianus J de Langen, Egbert F Smit, Michel M van den Heuvel, Koen J Hartemink, Marijke J E Kuijpers, Mirjam G A Oude Egbrink, Arjan W Griffioen, Rafael Rossel, T Jeroen N Hiltermann, Elizabeth Lee-Lewandrowski, Kent B Lewandrowski, Philip C De Witt Hamer, Mathilde Kouwenhoven, Jaap C Reijneveld, William P J Leenders, Ann Hoeben, Irma M Verdonck-de Leeuw, C René Leemans, Robert J Baatenburg de Jong, Chris H J Terhaard, Robert P Takes, Johannes A Langendijk, Saskia C de Jager, Adriaan O Kraaijeveld, Gerard Pasterkamp, Minke Smits, Jack A Schalken, Sylwia Łapińska-Szumczyk, Anna Łojkowska, Anna J Żaczek, Henk Lokhorst, Niels W C J van de Donk, Inger Nijhof, Henk-Jan Prins, Josée M Zijlstra, Sander Idema, Johannes C Baayen, Charlotte E Teunissen, Joep Killestein, Marc G Besselink, Lindsay Brammen, Thomas Bachleitner-Hofmann, Farrah Mateen, John T M Plukker, Michal Heger, Quirijn de Mast, Ton Lisman, D Michiel Pegtel, Harm-Jan Bogaard, Jacek Jassem, Anna Supernat, Niven Mehra, Winald Gerritsen, Cornelis D de Kroon, Christianne A R Lok, Jurgen M J Piek, Neeltje Steeghs, Winan J van Houdt, Ruud H Brakenhoff, Gabe S Sonke, Henk M Verheul, Elisa Giovannetti, Geert Kazemier, Siamack Sabrkhany, Ed Schuuring, Erik A Sistermans, Rob Wolthuis, Hanne Meijers-Heijboer, Josephine Dorsman, Cees Oudejans, Bauke Ylstra, Bart A Westerman, Daan van den Broek, Danijela Koppers-Lalic, Pieter Wesseling, R Jonas A Nilsson, W Peter Vandertop, David P Noske, Bakhos A Tannous, Nik Sol, Myron G Best, Thomas Wurdinger <<<

Cancer patients benefit from early tumor detection since treatment outcomes are more favorable for less advanced cancers. Platelets are involved in cancer progression and are considered a promising biosource for cancer detection, as they alter their RNA content upon local and systemic cues. We show that tumor-educated platelet (TEP) RNA-based blood tests enable the detection of 18 cancer types. With 99% specificity in asymptomatic controls, thromboSeq correctly detected the presence of cancer in two-thirds of 1,096 blood samples from stage I-IV cancer patients and in half of 352 stage I-III tumors. Symptomatic controls, including inflammatory and cardiovascular diseases, and benign tumors had increased false-positive test results with an average specificity of 78%. Moreover, thromboSeq determined the tumor site of origin in five different tumor types correctly in over 80% of the cancer patients. These results highlight the potential properties of TEP-derived RNA panels to supplement current approaches for blood-based cancer screening. <<<

Daniel Bottomly, Nicola Long, Anna Reister Schultz, Stephen E Kurtz, Cristina E Tognon, Kara Johnson, Melissa Abel, Anupriya Agarwal, Sammantha Avaylon, Erik Benton, Aurora Blucher, Uma Borate, Theodore P Braun, Jordana Brown, Jade Bryant, Russell Burke, Amy Carlos, Bill H Chang, Hyun Jun Cho, Stephen Christy, Cody Coblentz, Aaron M Cohen, Amanda d'Almeida, Rachel Cook, Alexey Danilov, Kim-Hien T Dao, Michie Degnin, James Dibb, Christopher A Eide, Isabel English, Stuart Hagler, Heath Harrelson, Rachel Henson, Hibery Ho, Sunil K Joshi, Brian Junio, Andy Kaempf, Yoko Kosaka, Ted Laderas, Matt Lawhead, Hyunjung Lee, Jessica T Leonard, Chenwei Lin, Evan F Lind, Selina Qiuying Liu, Pierrette Lo, Marc M Loriaux, Samuel Luty, Julia E Maxson, Tara Macey, Jacqueline Martinez, Jessica Minnier, Andrea Monteblanco, Motomi Mori, Quinlan Morrow, Dylan Nelson, Justin Ramsdill, Angela Rofelty, Alexandra Rogers, Kyle A Romine, Peter Ryabinin, Jennifer N Saultz, David A Sampson, Samantha L Savage, Robert Schuff, Robert Searles, Rebecca L Smith, Stephen E Spurgeon, Tyler Sweeney, Ronan T Swords, Aashis Thapa, Karina Thiel-Klare, Elie Traer, Jake Wagner, Beth Wilmot, Joelle Wolf, Guanming Wu, Amy Yates, Haijiao Zhang, Christopher R Cogle, Robert H Collins, Michael W Deininger, Christopher S Hourigan, Craig T Jordan, Tara L Lin, Micaela E Martinez, Rachel R Pallapati, Daniel A Pollyea, Anthony D Pomicter, Justin M Watts, Scott J Weir, Brian J Druker, Shannon K McWeeney, Jeffrey W Tyner <<<

Acute myeloid leukemia (AML) is a cancer of myeloid-lineage cells with limited therapeutic options. We previously combined ex vivo drug sensitivity with genomic, transcriptomic, and clinical annotations for a large cohort of AML patients, which facilitated discovery of functional genomic correlates. Here, we present a dataset that has been harmonized with our initial report to yield a cumulative cohort of 805 patients (942 specimens). We show strong cross-cohort concordance and identify features of drug response. Further, deconvoluting transcriptomic data shows that drug sensitivity is governed broadly by AML cell differentiation state, sometimes conditionally affecting other correlates of response. Finally, modeling of clinical outcome reveals a single gene, PEAR1, to be among the strongest predictors of patient survival, especially for young patients. Collectively, this report expands a large functional genomic resource, offers avenues for mechanistic exploration and drug development, and reveals tools for predicting outcome in AML. <<<

Myron G Best, Nik Sol, Irsan Kooi, Jihane Tannous, Bart A Westerman, François Rustenburg, Pepijn Schellen, Heleen Verschueren, Edward Post, Jan Koster, Bauke Ylstra, Najim Ameziane, Josephine Dorsman, Egbert F Smit, Henk M Verheul, David P Noske, Jaap C Reijneveld, R Jonas A Nilsson, Bakhos A Tannous, Pieter Wesseling, Thomas Wurdinger <<<

Tumor-educated blood platelets (TEPs) are implicated as central players in the systemic and local responses to tumor growth, thereby altering their RNA profile. We determined the diagnostic potential of TEPs by mRNA sequencing of 283 platelet samples. We distinguished 228 patients with localized and metastasized tumors from 55 healthy individuals with 96% accuracy. Across six different tumor types, the location of the primary tumor was correctly identified with 71% accuracy. Also, MET or HER2-positive, and mutant KRAS, EGFR, or PIK3CA tumors were accurately distinguished using surrogate TEP mRNA profiles. Our results indicate that blood platelets provide a valuable platform for pan-cancer, multiclass cancer, and companion diagnostics, possibly enabling clinical advances in blood-based "liquid biopsies". <<<

Transposable elements (TEs), which make up almost half of the human genome, often display altered expression in cancers. Here, we review recent progress in elucidating the role of TEs as mediators of immune responses in cancer and discuss how novel therapeutic strategies can harness TE immunogenicity for cancer immunotherapy. <<<

Denise M Wolf, Christina Yau, Julia Wulfkuhle, Lamorna Brown-Swigart, Rosa I Gallagher, Pei Rong Evelyn Lee, Zelos Zhu, Mark J Magbanua, Rosalyn Sayaman, Nicholas O'Grady, Amrita Basu, Amy Delson, Jean Philippe Coppé, Ruixiao Lu, Jerome Braun, I-SPY2 Investigators, Smita M Asare, Laura Sit, Jeffrey B Matthews, Jane Perlmutter, Nola Hylton, Minetta C Liu, Paula Pohlmann, W Fraser Symmans, Hope S Rugo, Claudine Isaacs, Angela M DeMichele, Douglas Yee, Donald A Berry, Lajos Pusztai, Emanuel F Petricoin, Gillian L Hirst, Laura J Esserman, Laura J van 't Veer <<<

Using pre-treatment gene expression, protein/phosphoprotein, and clinical data from the I-SPY2 neoadjuvant platform trial (NCT01042379), we create alternative breast cancer subtypes incorporating tumor biology beyond clinical hormone receptor (HR) and human epidermal growth factor receptor-2 (HER2) status to better predict drug responses. We assess the predictive performance of mechanism-of-action biomarkers from ∼990 patients treated with 10 regimens targeting diverse biology. We explore >11 subtyping schemas and identify treatment-subtype pairs maximizing the pathologic complete response (pCR) rate over the population. The best performing schemas incorporate Immune, DNA repair, and HER2/Luminal phenotypes. Subsequent treatment allocation increases the overall pCR rate to 63% from 51% using HR/HER2-based treatment selection. pCR gains from reclassification and improved patient selection are highest in HR subsets (>15%). As new treatments are introduced, the subtyping schema determines the minimum response needed to show efficacy. This data platform provides an unprecedented resource and supports the usage of response-based subtypes to guide future treatment prioritization. <<<

The translational challenges in the field of precision oncology are in part related to the biological complexity and diversity of this disease. Technological advances in genomics have facilitated large sequencing efforts and discoveries that have further supported this notion. In this review, we reflect on the impact of these discoveries on our understanding of several concepts: cancer initiation, cancer prevention, early detection, adjuvant therapy and minimal residual disease monitoring, cancer drug resistance, and cancer evolution in metastasis. We discuss key areas of focus for improving cancer outcomes, from biological insights to clinical application, and suggest where the development of these technologies will lead us. Finally, we discuss practical challenges to the wider adoption of molecular profiling in the clinic and the need for robust translational infrastructure. <<<

Shen Zhao, Dong Wang, Hongyun Zhao, Jifang Gong, Jian Zhang, Wenfeng Fang, Fei Ma, Binghe Xu, Jin Li, Xichun Hu, Yi Ba, Xiaoyuan Chen, Zhimin Yang, Lin Shen, Jianhua Jiang, Li Zhang, Chinese Phase 1 Oncology Trial Consortium <<<

Alexander Bagaev, Nikita Kotlov, Krystle Nomie, Viktor Svekolkin, Azamat Gafurov, Olga Isaeva, Nikita Osokin, Ivan Kozlov, Felix Frenkel, Olga Gancharova, Nava Almog, Maria Tsiper, Ravshan Ataullakhanov, Nathan Fowler <<<

The clinical use of molecular targeted therapy is rapidly evolving but has primarily focused on genomic alterations. Transcriptomic analysis offers an opportunity to dissect the complexity of tumors, including the tumor microenvironment (TME), a crucial mediator of cancer progression and therapeutic outcome. TME classification by transcriptomic analysis of >10,000 cancer patients identifies four distinct TME subtypes conserved across 20 different cancers. The TME subtypes correlate with patient response to immunotherapy in multiple cancers, with patients possessing immune-favorable TME subtypes benefiting the most from immunotherapy. Thus, the TME subtypes act as a generalized immunotherapy biomarker across many cancer types due to the inclusion of malignant and microenvironment components. A visual tool integrating transcriptomic and genomic data provides a global tumor portrait, describing the tumor framework, mutational load, immune composition, anti-tumor immunity, and immunosuppressive escape mechanisms. Integrative analyses plus visualization may aid in biomarker discovery and the personalization of therapeutic regimens. <<<