Abstract Non-genetic intratumor heterogeneity underlies therapeutic failure in cancer, yet how resistant tumor states are encoded in patients remains unclear. In this study, we show that chemoresistant evolution in high-grade serous ovarian cancer (HGSOC) is prefigured by epigenetically primed tumor cell states present before therapy. Using multimodal single-nucleus approaches, we profile transcriptional programs and histone modifications from longitudinal frozen biopsies of 16 patients with HGSOC. Tumors comprise a limited set of functional states that evolve reproducibly under chemotherapy: proliferative and IFN-responsive states are depleted, whereas TNFα-associated and epithelial-mesenchymal transition–associated programs persist or expand. Chromatin profiling reveals that these resistant programs are broadly enriched for histone H3 lysine 4 monomethylation (H3K4me1) prior to treatment, indicating that features of resistance are epigenomically primed. Baseline tumor composition is associated with survival, and fibroblast remodeling accompanies malignant adaptation. Together, these findings identify epigenomic priming as a feature of chemoresistant tumor cell states and provide a scalable framework for anticipating resistance from biopsies. Significance: Using a clinically compatible multimodal single-nucleus approach, the authors show that chemoresistant evolution in HGSOC is prefigured by epigenetically primed tumor cell states present before therapy.
Abstract Breast cancer that arises in the postpartum period often carries a poor prognosis and urgently requires chemoprevention strategies, particularly for women at elevated risk. Here, we report that a single post-lactation dose of cabergoline, a dopaminergic agonist that blocks prolactin secretion, delays the onset and reduces the incidence of postpartum mammary cancer in K14-Cre; Brca1F/F, Trp53F/F mice. In these mice, cabergoline treatment remodels the mammary gland by potentiating involution, reducing ductal area and proliferation, and reversing T cell exhaustion, potentially through modulation of ion channel expression. Notably, independent retrospective studies in two large cohorts of European women showed that cabergoline treatment was associated with a lower incidence of postpartum breast cancer, with a meta-analysis indicating an approximate 69% reduction in risk. Our work underscores the importance of targeting postlactational involution as a strategy for the prevention of postpartum breast cancer and positions cabergoline as a novel, low-risk chemoprevention strategy.
Abstract To evaluate the functional relevance of mutations newly detected in breast cancer metastases, we analyzed genomic data from 662 paired and ~6,000 unpaired primary and metastatic tumors. These analyses indicate that metastasis-specific mutations are frequently acquired post-dissemination, with a disproportionate contribution from APOBEC-mediated mutagenesis. Metastasis-specific mutations converged on a set of pathways that were highly recurrent, distinct from those altered in primary tumors, and dependent on metastatic site. 95% of patients harbored metastasis-specific mutations within a minimum set of 10 pathways. Remarkably, more than half the variation in metastatic latency across patients was explained by the relative timing of mutation acquisition within implicated pathways before versus after dissemination. These findings support a “mutability-dependent” model of metastasis in which functionally consequential mutations accumulate after primary tumor dissemination and contribute to metastatic outgrowth, with latency reflecting the time required for DTCs to acquire the remaining driver mutations needed to achieve metastatic competence.
Abstract Age at diagnosis among patients with cancer is a predictor of pathogenic germline variant prevalence, yet age thresholds often misclassify genetic risk. We performed germline sequencing of 39,184 unselected patients with solid malignancies spanning 32 tumor types, interrogating >90 cancer predisposition genes independent of clinical suspicion. Patients were stratified into early-, average-, and late-onset groups based on standard deviations from tumor-specific mean age at diagnosis. Pathogenic variant prevalence inversely correlated with age at diagnosis: 18.4% in early-onset tumors, 15.6% in average-onset tumors, and 12.3% in late-onset tumors (P < 0.001). Variants in high/moderate-penetrance genes accounted for the enrichment in early-onset cases (12.4%, early-onset; 8.9%, average-onset; 5.1%, late-onset; P < 0.001). Restricting hereditary cancer testing to patients diagnosed before age 50, as is typically done, would miss 4,601 pathogenic variant carriers, 72% of all variants detected. These findings support broad-based germline testing beyond conventional age-based criteria, reflecting the burden of hereditary risk even among late-onset cases. Significance: Across 32 solid tumor types in a pan-cancer cohort, we found enrichment of germline pathogenic variants among patients with subtype-specific early-onset cancer. Using age 50 as a testing cutoff misses most patients with inherited predisposition, supporting universal germline genetic testing for all individuals diagnosed with cancer.
The nuclear pore complex (NPC) and its building-block proteins, nucleoporins (NUP), play fundamental roles in maintaining cellular fitness by regulating nucleocytoplasmic transport, chromatin and transcriptional activity, and genome stability. These core biological processes are critical for cancer cells, and thus, tumor-driven co-option of NUP-regulated functions has emerged as an important mechanism contributing to the pathogenesis of multiple malignancies. This review discusses how NUP dysregulation mechanistically contributes to tumor initiation and progression and how these insights open opportunities for innovative anticancer therapies, including using clinical-grade molecular glues that induce selective NUP degradation and pharmacologically inhibiting NPC-regulated epigenomic/transcriptomic signaling and nucleocytoplasmic transport. SIGNIFICANCE:Recent studies demonstrate that NUPs play fundamental roles in cancer pathogenesis by dysregulating key NPC functions and driving tumorigenesis and disease progression. NUPs and NPC-regulated mechanisms can be pharmacologically targeted, providing a strong rationale for developing much-needed innovative therapeutic strategies to combat cancer.
