Biology subjects

Pisanic, T.

Publications and source records attributed to Pisanic, T..

3 recordsLinked to original sources

bioRxiv2026

Polycomb Marked Promoter Methylation Gains in Aging and Cancer are Independent of Replication

DNA methylation alterations are hallmark features of aging and cancer, occurring early during tumor initiation. Yet how these changes evolve during early tumorigenesis, and whether oncogenic signaling actively drives them, remains poorly understood due to limitations in resolving this at the longitudinal and clonal level. Here we developed a genome-wide DNA methylation profiling method for low DNA amounts and applied it to single stem cell-derived clones from a BRAFV600E -inducible mouse colon organoid model, tracking nucleotide-level methylation heterogeneity over time. BRAFV600E induction produced stepwise methylation divergence consistent with progressive clonal takeover, in contrast to gradual epigenetic drift in uninduced controls. Strikingly, while the specific CpG sites altered differed between BRAFV600E and control lineages, they converged on the same genomic elements. Particularly, Polycomb-marked promoter CpG-island methylation gains were not induced or accelerated by BRAFV600E, challenging models in which oncogenic signaling or cell proliferation actively instructs de novo methylation of Polycomb-targeted promoters. Instead, these gains tracked with "biological aging" independent of replication, which was validated across independent aging, cancer, and cell-line datasets. BRAFV600E -induced clones additionally showed progressive loss of intestinal lineage-specification transcription factor programs, consistent with selection for cells adapted to oncogenic stress. Together, these findings show that epigenetic trajectories during early tumor development, are rooted in baseline, age-dependent drivers of epigenetic alterations, and that oncogenic signaling acts primarily by selecting and expanding clones bearing pre-existing, age-associated epigenetic drift rather than instructing new methylation. Our findings have implications for how promoter methylation is interpreted as a cancer biomarker and for identifying upstream aging-associated processes as targets for early intervention.

cancer biology↗

bioRxiv2025

Integrated Spatial Analysis of Ovarian Precancerous Lesions

Studying precancerous lesions is essential for improving early detection and prevention, particularly in aggressive cancers such as ovarian carcinoma. Here, we conducted integrated and spatial analyses of transcriptomes, aneuploidy, and clinic-pathological features in 166 ovarian precancerous lesions. Four pre-cancerous subtypes were identified transcriptomically: proliferative, immunoreactive, dormant, and mixed. These subtypes varied in their frequency of germline-BRCA1/2 mutations, aneuploidy, CCNE1/MYC amplification, proliferative activity, immune-regulatory gene expression, and histological features. Notably, the immunoreactive subtype upregulated immune-regulatory genes, exhibited chronic inflammation, and was enriched in cases with germline-BRCA1/2 mutations, deletions of chromosomes 17 (harboring TP53 and BRCA1) and 13 (harboring BRCA2), leading to a double "two-hit" involving TP53 and BRCA1/2. Tumor invasion was associated with the activation of interferon response pathways, epithelial-mesenchymal transition, and extracellular matrix remodeling. In summary, our results elucidate the earliest molecular landscape of ovarian precancerous lesions, serving as the foundation for future risk stratification to identify aggressive pre-cancerous lesions.

molecular biology↗

bioRxiv2020

Epigenetic reprogramming towards mesenchymal-epithelial transition in ovarian cancer-associated mesenchymal stem cells drives metastasis

Ovarian cancer develops early intra-peritoneal metastasis establishing a supportive tumor microenvironment (TME) through reprogramming normal mesenchymal stem cells into carcinoma-associated mesenchymal stem cells (CA-MSCs). CA-MSCs are the stromal stem cell of the TME, supporting cancer growth, increasing desmoplasia, angiogenesis and chemotherapy resistance. We demonstrate epigenetic reprogramming drives CA-MSC formation via enhancer-enriched DNA hypermethylation, altered chromatin accessibility and differential histone modifications inducing a partial mesenchymal to epithelial transition (MET) increasing adhesion to tumor cells. Direct CA-MSC:tumor cell interactions, confirmed in patient ascites, facilitate ovarian cancer metastasis through co-migration. WT1, a developmental mediator of MET, and EZH2, mediate CA-MSC epigenetic reprogramming. WT1 overexpression induces CA-MSC conversion while WT1 knock-down, along with EZH2 inhibition, blocks CA-MSC formation. EZH2 inhibition subsequently decreases intra-abdominal metastasis. SignificanceThis work presents a new paradigm of stromal reprogramming involving a partial mesenchymal to epithelial transition. Rather than a classic tumor cell epithelial to mesenchymal transition, metastasis relies on epigenetic rewiring of a CA-MSC allowing enhanced tumor cell binding and co-migration with tumor cells to form metastasis. Indeed, CA-MSCs in complex with tumor cells are abundant in patient ascites. Reversion of CA-MSCs to normal MSCs is observed in patients achieving complete response with neoadjuvant therapy. Identification of WT1 and EZH2 as mediators of the epigenetic reprogramming of CA-MSCs present potential targets to block the formation of CA-MSCs thus disrupting the TME and limiting ovarian cancer metastasis.

cancer biology↗