Goodwin RJA, Barry ST, Weatherall J
… +2 more, Platz SJ, Reis-Filho JS
Cancer Discov
· 2026 May · PMID 41999665
·
Publisher ↗
The use of integrated large-scale, multidomain datasets with artificial intelligence (AI) is now essential in drug discovery and development. Organizations that strategically invest in robust data infrastructure and fit-...The use of integrated large-scale, multidomain datasets with artificial intelligence (AI) is now essential in drug discovery and development. Organizations that strategically invest in robust data infrastructure and fit-for-purpose AI solutions will accelerate the delivery of precision oncology therapeutics globally.
Detecting chromosomal copy-number alterations together with protein-defined cell states in intact tissue is critical for understanding early clonal evolution and microenvironmental interactions in cancer. We developed OR...Detecting chromosomal copy-number alterations together with protein-defined cell states in intact tissue is critical for understanding early clonal evolution and microenvironmental interactions in cancer. We developed ORION-FISH, which integrates high-plex tissue imaging with a morphology-preserving DNA-FISH workflow and single-cell registration, yielding measurements concordant with clinical FISH. In High Grade Serous Ovarian Carcinoma (HGSOC), ORION-FISH recapitulated known chromosomal changes while revealing subclonal heterogeneity missed by targeted sequencing. Applied to serous tubal intraepithelial carcinomas (STICs), precursors of HGSOC, ORION-FISH identified intermixed epithelial cells with MYC or CCNE1 copy-number gains, as well as concurrent alterations associated with distinct immune microenvironments. In addition, epithelial cells with MYC and CCNE1 copy-number gains were detected in morphologically normal fallopian tube epithelium, along with rare MDM4 increases across epithelial lineages. Together, ORION-FISH provides a framework linking chromosomal copy number states to protein-defined phenotypes within preserved tissue architecture, enabling context-aware interrogation of early copy-number diversification at single-cell resolution.
Cancer Discov
· 2026 Apr · PMID 41997583
·
Full text
Transposable elements (TEs), mobile DNA sequences that can move independently about the genome, make up about half of the human genome and are mostly silenced by epigenetic modifications in healthy differentiated cells....Transposable elements (TEs), mobile DNA sequences that can move independently about the genome, make up about half of the human genome and are mostly silenced by epigenetic modifications in healthy differentiated cells. Global epigenetic dysregulation during oncogenic transformation causes TE expression, contributing to transcriptional rewiring and TE activity as insertional mutagens. TE nucleic acids are sensed in the cytoplasm, initiating inflammation that can be therapeutically manipulated to activate anti-tumor immune responses. Here we detail how TEs contribute to six of the classic hallmarks of cancer and propose widespread TE expression and activation as a new hallmark of cancer.
During cancer evolution, de-repressed repetitive elements (REs) can trigger innate immune responses via "viral mimicry", imposing selective immune pressure on emerging tumor cells. We propose that RE mimics mediate trans...During cancer evolution, de-repressed repetitive elements (REs) can trigger innate immune responses via "viral mimicry", imposing selective immune pressure on emerging tumor cells. We propose that RE mimics mediate transitions from initial anti-tumorigenic immune selection to a tolerized equilibrium shaped by trade-offs that can ultimately be predicted and exploited therapeutically.
Breast and prostate cancers are both hormone-driven adenocarcinomas that undergo analogous invasion programs. Using lightsheet microscopy on intact tumors, we identified transitional junctions between precancerous and in...Breast and prostate cancers are both hormone-driven adenocarcinomas that undergo analogous invasion programs. Using lightsheet microscopy on intact tumors, we identified transitional junctions between precancerous and invasive regions. We then developed a multimodal serial-section workflow integrating volumetric reconstruction with spatial transcriptomics. Analysis of 319 spatial assays from 51 cases revealed gene-expression features and novel structural insights defining the shift from precancer to invasive disease. In breast cancer, loss of MGP and PLAT was associated with invasive transition and promoted tumorigenesis in functional assays. In prostate cancer, GDF15, ALDH1A3, ANPEP, and FASN were upregulated along invasive progression, and their knockdown in PC-3 cells suppressed proliferation and migration. Enrichment of tumor-associated macrophages (SPP1⁺, MS4A6A⁺) along non-TNBC breast cancer transitions highlights immune involvement as a potential driver of invasiveness.
Cancer Discov
· 2026 Jun · PMID 41995580
·
Publisher ↗
Results from the DRUP trial suggest that off-label targeted cancer therapies produce meaningful benefit primarily in tumors with well-validated biomarkers, such as MSI-H, echoing findings from prior basket studies. The s...Results from the DRUP trial suggest that off-label targeted cancer therapies produce meaningful benefit primarily in tumors with well-validated biomarkers, such as MSI-H, echoing findings from prior basket studies. The study also demonstrates how systematically collected real-world outcomes data can inform reimbursement decisions and help determine which tumor-agnostic strategies are both clinically useful and economically justified.
Cancer Discov
· 2026 Jun · PMID 41983773
·
Publisher ↗
Dennis Lo, DM, DPhil, known as the "father" of noninvasive prenatal testing, discusses how his discovery of fetal DNA in maternal blood led to his groundbreaking work on liquid biopsy, as well as new methods for detectin...Dennis Lo, DM, DPhil, known as the "father" of noninvasive prenatal testing, discusses how his discovery of fetal DNA in maternal blood led to his groundbreaking work on liquid biopsy, as well as new methods for detecting and analyzing circulating tumor DNA.
Liu X, Tan J, Wu C
… +23 more, Huang G, Cheng Y, Hu J, Zhang B, Zhao M, Zhao B, Lian J, Zheng S, Zeng L, Xu M, Xu Y, Zeng S, Yu H, Yang H, Zuo Z, Liu C, Feng W, Guo W, Li C, Liu SL, Liu Q, Wen F, Hong X
UNLABELLED: Brain metastasis remains a devastating disease with dismal prognosis. How circulating tumor cells (CTC) penetrate the blood-brain barrier (BBB) and reprogram the brain microenvironment remains unclear. Using...UNLABELLED: Brain metastasis remains a devastating disease with dismal prognosis. How circulating tumor cells (CTC) penetrate the blood-brain barrier (BBB) and reprogram the brain microenvironment remains unclear. Using spatially resolved multi-omics profiling of CTCs and brain metastases, integrated with experimental and clinical analyses, we identified glycoprotein nonmetastatic melanoma protein B (GPNMB) as a CTC-secreted driver of vascular disruption and brain colonization. CBX3 upregulation induced GPNMB expression, which bound endothelial EGFR, triggering CBL-mediated ubiquitination and degradation. Attenuated EGFR signaling suppressed FTO and disrupted endothelial junctions via YTHDF2-dependent TJP1 m6A methylation. Remarkably, GPNMB-induced BBB remodeling promoted immune infiltration via the CXCL12-CXCR4 axis and induced time-course-dependent T-cell exhaustion within the brain microenvironment. Clinically, elevated CBX3+GPNMB+ CTCs and plasma CXCL12 were significantly associated with brain metastasis progression in lung cancer and melanoma. Therapeutically, dual blockade of GPNMB and PD1 enhanced anti-brain metastasis efficacy in mice, unveiling GPNMB as a promising target for precision immunotherapy. SIGNIFICANCE: GPNMB is a CTC-secreted driver of BBB disruption and brain colonization via the CBX3-GPNMB-EGFR-FTO-TJP1 axis. GPNMB-induced BBB remodeling promotes CXCL12-CXCR4-mediated immune infiltration and enhances T-cell exhaustion, sensitizing brain metastasis tumors to GPNMB/PD1 dual blockade. CBX3+GPNMB+ CTCs and plasma CXCL12 may serve as noninvasive biomarkers for brain metastasis management.
Zhang HF, De Dreuzy E, Huang YZ
… +39 more, Shin S, Huang QF, Delaidelli A, Yang X, Adamiak V, Lytle A, Arzoo A, Lizardo MM, Lin Q, Sanadi S, Rouleau M, Liu LX, Xu LY, Li EM, Lai R, Primus C, Reda El Sayed S, Bourhis L, Genin D, Demontrond L, Bouquet L, Démolis L, Barberot A, Lameynardie S, Delabrière A, Hua H, Yang J, Ishima R, Imle R, Banito A, Slack GW, Savage KJ, Maris JM, Bosse KR, Dimitrov DS, Steidl C, Li W, Sainson RCA, Sorensen PH
Gene fusions generated by chromosomal rearrangements function as oncogenic drivers in human cancers. We previously showed that EWSR1-ETS oncofusions of Ewing sarcoma (EwS) directly induce surface expression of IL1 recept...Gene fusions generated by chromosomal rearrangements function as oncogenic drivers in human cancers. We previously showed that EWSR1-ETS oncofusions of Ewing sarcoma (EwS) directly induce surface expression of IL1 receptor accessory protein (IL1RAP), which along with limited expression in healthy tissues except placenta nominate IL1RAP as a promising EwS immunotherapy target. We therefore engineered antibody-drug conjugates (ADCs) with different cytotoxic payloads to target IL1RAP. ADCs potently blocked tumor growth and induced durable regression of EwS xenografts in mice, and diminished metastatic dissemination in vivo. Moreover, we show that other oncofusions also induce IL1RAP expression in diverse cancers, including NPM-ALK in anaplastic large cell lymphoma (ALCL), and ETV6-NTRK3 in multiple tumor types. IL1RAP expression rendered these malignancies similarly vulnerable to IL1RAP-targeting ADCs, which effectively blocked growth of ALCL xenografts and syngeneic ETV6-NTRK3+ sarcomas. Lack of detectable normal tissue toxicity, including in non-human primates, support the further clinical translation of IL1RAP-targeting ADCs.
Cancer Discov
· 2026 May · PMID 41972778
·
Publisher ↗
Despite unprecedented opportunities at the convergence of artificial intelligence (AI) and cancer research, few scientists possess fluency in both domains. We propose a six-principle framework for training "AI-oncology b...Despite unprecedented opportunities at the convergence of artificial intelligence (AI) and cancer research, few scientists possess fluency in both domains. We propose a six-principle framework for training "AI-oncology bilingual" scientists who can bridge this gap and translate AI-driven discoveries into improved patient outcomes.
Ji M, Zhang L, Zitnik M
… +3 more, Hripcsak G, Buenrostro JD, Cao Y
Cancer Discov
· 2026 May · PMID 41972758
·
Publisher ↗
Advances in multimodal longitudinal data and artificial intelligence (AI) create new opportunities for cancer etiology research. We envision an AI-powered discovery workflow integrating an interoperable epidemiologic dat...Advances in multimodal longitudinal data and artificial intelligence (AI) create new opportunities for cancer etiology research. We envision an AI-powered discovery workflow integrating an interoperable epidemiologic data ecosystem and causal inference frameworks to accelerate the identification of both cancer causes and the converging biological states for prevention.
Cancer Discov
· 2026 Jun · PMID 41961996
·
Publisher ↗
Under the Trump Administration's proposed budget for fiscal year 2027, and if enacted, the NIH would receive $41.2 billion, down from $47.22 in fiscal year 2026, and NCI would receive $7.353 billion, an increase of $8.9...Under the Trump Administration's proposed budget for fiscal year 2027, and if enacted, the NIH would receive $41.2 billion, down from $47.22 in fiscal year 2026, and NCI would receive $7.353 billion, an increase of $8.9 million, or 0.1%. Research advocacy organizations are calling upon Congress, which has the final say on federal spending, for increased funding.
Cancer Discov
· 2026 Jun · PMID 41961988
·
Publisher ↗
Renier Brentjens, MD, PhD, a pioneer of chimeric antigen receptor (CAR) T-cell therapy, speaks about his early work in the field, the current limitations of CAR T cells, and how researchers might advance the technology i...Renier Brentjens, MD, PhD, a pioneer of chimeric antigen receptor (CAR) T-cell therapy, speaks about his early work in the field, the current limitations of CAR T cells, and how researchers might advance the technology in the coming years.
Metabolic reprogramming within the tumor microenvironment impairs antitumor immunity and compromises the efficacy of immunotherapy. Through multi-omics-based metabolic subtyping in intrahepatic cholangiocarcinoma (iCCA),...Metabolic reprogramming within the tumor microenvironment impairs antitumor immunity and compromises the efficacy of immunotherapy. Through multi-omics-based metabolic subtyping in intrahepatic cholangiocarcinoma (iCCA), we identified a subgroup with the worst prognosis that demonstrates significant enrichment in both Cyclooxygenase/Arachidonic acid (COX/AA) metabolism and KRAS mutations. Mechanistically, KRAS mutation-mediated NF-κB pathway activation upregulates CXCL5 expression, thereby recruiting CXCR2+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) into the tumor microenvironment. Concurrently, KRAS mutation drives prostaglandin E2 (PGE2) production in tumor cells, and PGE2 in turn enhances arachidonic acid uptake and COX-2 expression in PMN-MDSCs, establishing an amplifying loop between tumor cells and PMN-MDSCs that exacerbates PGE2 production. PGE2 accumulation potently suppresses the antitumor activity of CD8+ T cells via prostaglandin E receptor 4 (EP4). Therapeutic targeting of the COX-2-PGE2-EP4 axis, combined with anti-PD-1 immunotherapy, demonstrates profound synergistic efficacy in both KRAS-mutant murine models and patient-derived tumor fragments harboring KRAS mutations.
Despite successful immuno-oncology therapies in other cancers, they largely failed in glioblastoma(GBM). Here, natural killer (NK) cells from glioma patients show impaired oxidative phosphorylation and mitochondrial comp...Despite successful immuno-oncology therapies in other cancers, they largely failed in glioblastoma(GBM). Here, natural killer (NK) cells from glioma patients show impaired oxidative phosphorylation and mitochondrial complex I activity. Multiomics profiling identified complex I subunit NDUFA9 as a critical mediator of NK cell metabolic fitness. Abundance of NDUFA9+ NK cells informed patient outcome. Ndufa9 knockout in NK cells compromised mitochondrial function, anti-tumor efficacy, and memory-like phenotype of NK cells by triggering a metabolic reprogramming toward glutamine dependence. Decreased α-ketoglutarate(α-KG)/succinate ratio in Ndufa9-deficient NK cells mediated widespread epigenetic reprogramming through inducing transcriptionally repressive histone mark H3K27me3 on key immune function genes. Resveratrol-mediated NDUFA9 activation or its overexpression enhanced NK cell anti-GBM function by restoring complex I activity. Together, these findings reveal the critical role of mitochondrial complex I activity in NK cells and highlight its potential as an actionable target to enhance NK cell-based immunotherapy for GBM patients.
Cancer Discov
· 2026 May · PMID 41940795
·
Publisher ↗
Researchers utilized a two-vector system, consisting of an enveloped delivery vehicle and an adeno-associated virus to deliver CRISPR tools and a large DNA payload, to achieve stable and cell-specific expression of chime...Researchers utilized a two-vector system, consisting of an enveloped delivery vehicle and an adeno-associated virus to deliver CRISPR tools and a large DNA payload, to achieve stable and cell-specific expression of chimeric antigen receptor (CAR) T cells. This study demonstrates the first in vivo engineering of CAR T cells at a therapeutic level for both hematologic and solid cancers, and opens the door for more efficient, precise, and affordable CAR T-cell therapies.