The genomic trajectory of ovarian high grade serous carcinoma is determined in STIC lesions

Cheng, Z.; Ennis, D. P.; Lu, B.; Mirza, H. B.; Sokota, C.; Kaur, B.; Singh, N.; Le Saux, O.; Russo, G.; Giannone, G.; Tookman, L. A.; Krell, J.; McDermott, J.; Barnes, C.; McNeish, I. A.

doi:10.1101/2024.03.11.584384

bioRxiv · 10.1101/2024.03.11.584384

The genomic trajectory of ovarian high grade serous carcinoma is determined in STIC lesions

Cheng, Z.·Ennis, D. P.·Lu, B.·Mirza, H. B.·Sokota, C.·Kaur, B.·Singh, N.·Le Saux, O.·Russo, G.·Giannone, G.·Tookman, L. A.·Krell, J.·McDermott, J.·Barnes, C.·McNeish, I. A.

View original source ↗Export metadata ↓

Abstract

Ovarian high-grade serous carcinoma (HGSC) originates in the fallopian tube, with secretory cells carrying a TP53 mutation, known as p53 signatures, identified as potential precursors. p53 signatures evolve into serous tubal intraepithelial carcinomas (STIC) lesions, which, in turn, progress into invasive HGSC that readily spread to the ovary and disseminate around the peritoneal cavity. We recently investigated the genomic landscape of early- and late-stage HGSC and found higher ploidy in late-stage (median 3.1) than early-stage (median 2.0) samples. Here, to explore whether the high ploidy and possible whole genome duplication observed in late-stage disease are determined early in the evolution of HGSC, we analysed archival formalin-fixed paraffin-embedded samples (FFPE) from five HGSC patients. p53 signatures and STIC lesions were laser-capture microdissected and sequenced using shallow whole genome sequencing (sWGS), while invasive ovarian/fallopian tube and metastatic carcinoma samples underwent macrodissection and were profiled using both sWGS and targeted next generation sequencing. Results showed highly similar patterns of global copy number change between STIC lesions and invasive carcinoma samples within each patient. Ploidy changes were evident in STIC lesions, but not p53 signatures, and there was strong correlation between ploidy in STIC lesions and invasive ovarian/fallopian tube and metastatic samples in each patient. The reconstruction of sample phylogeny for each patient from relative copy number indicated that high ploidy, when present, occurred early in the evolution of HGSC, which was further validated by copy number signatures in ovarian and metastatic tumours. These findings suggest that aberrant ploidy, suggestive of whole genome duplication, arises early in HGSC, and is detected in STIC lesions, implying that the trajectory of HGSC may be determined at the earliest stages of tumour development.

Explore related subjects

cancer biology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Cheng, Z., Ennis, D. P., Lu, B., Mirza, H. B., Sokota, C., Kaur, B., Singh, N., Le Saux, O., Russo, G., Giannone, G., Tookman, L. A., Krell, J., McDermott, J., Barnes, C., McNeish, I. A.. 2024-03-13. The genomic trajectory of ovarian high grade serous carcinoma is determined in STIC lesions. https://doi.org/10.1101/2024.03.11.584384

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Epigenetic progression of pancreatic cancer to aggressive subtypes involves alternate routes of lineage reprogramming in subtype-intermediate progenitor cells

Pancreatic ductal adenocarcinoma (PDAC) progression involves malignant cell state plasticity. Epigenetic changes underlie this plasticity, yet the PDAC cis-regulatory landscape remains understudied. To address this, we profiled 33 primary tumors and 7 metastases from 39 patients with single-cell ATAC-seq, paired with 10 single-cell RNA-seq profiles. We found that epigenetic GATA6+/KRT17+ co-accessibility identifies a classical-basal subtype-intermediate progenitor state (SIP) associated with better clinical outcomes. SIP cells display limited epigenetic reprogramming from premalignant epithelium and retain gastric-intestinal differentiation reminiscent of neoplastic precursors. Lineages without GATA6+/KRT17+ co-accessibility exhibit greater lineage and epithelial-mesenchymal plasticity. Classical PDACs that repress basal gene accessibility activate neural-like progenitor (NRP) and tuft lineage enhancers, whereas basal committed tumors display esophageal transdifferentiation. Compared to SIP, classical-NRP and basal committed tumors have poorer outcomes, and show distinct PD-1/PD-L1 immune proteomic phenotypes and prognostic myofibroblast epigenetic states, respectively. Our work reveals links between lineage reprogramming, EMT, and epigenetic progression in human PDAC.

cancer biology↗

bioRxiv2026

Tissue resident CD4+ memory T-cells mark response to immune checkpoint inhibition in high-grade glioma

Background: Immune checkpoint inhibitors (ICI) are efficacious in many solid tumors, but response in glioma is restricted to a small subgroup. The determinants of response and resistance to ICI remain poorly understood. Methods: Here we exploit a syngeneic hypermutated high-grade glioma model with dichotomous response to combined PD-1 and CTLA-4 inhibition to unravel determinants of tumor-infiltrating T-cells driving response. Tumor-infiltrating T-cells from ICI-responsive and non-responsive tumors were analyzed by single-cell RNA and T-cell receptor sequencing and tumor-reactive T-cell receptor clonotypes were functionally validated to characterize their transcriptional phenotypes. We verify our findings in IDH1 wildtype glioblastoma patients treated with neoadjuvant pembrolizumab. Results: ICI response was associated with intratumoral clonal expansion of tumor-reactive cytotoxic T-cells and increased infiltration of CXCR6+ CD4+ tissue resident memory T-cells (Trm). CD4 stem-like memory T-cells in responding tumors demonstrated elevated interferon responses, following trajectories toward clonally expanded Trm, versus trajectories toward exhaustion in non-responsive tumors. In responsive tumors, CD4+ Trm interacted with infiltrating CXCR3+ tumor-reactive and clonally expanded, yet transcriptionally versatile cytotoxic T-cells. Probing the post neoadjuvant ICI high-grade glioma patient tissue dataset, we confirmed increased CXCR6 expression in CD4+ T cells and the association of CD4+ Trm with prolonged overall survival. Conclusion: These findings identify CD4 tissue-resident memory T-cells as determinants of ICI response in IDH1 wildtype high-grade glioma and warrant their further investigation to improve immunotherapy outcomes.

cancer biology↗

bioRxiv2026

Low-dose doxorubicin drives caveolin-1 depended re-epithelialization of breast cancer cells as a mechanism of cancer plasticity

Breast cancer progression is driven by dynamic changes in epithelial plasticity, membrane organization, and intracellular signaling, yet the effects of sustained low-dose chemotherapy on these processes remain poorly understood. Here, we investigated the impact of prolonged low-dose doxorubicin on membrane remodeling, epithelial phenotype, membrane-associated Ras lipid-anchor localization, and autophagy in mesenchymal-like MDA-MB-231 breast cancer cells. Low-dose doxorubicin significantly increased Caveolin-1 expression and enhanced E-cadherin protein levels, accompanied by a transition toward a more compact epithelial-like morphology with increased cell-cell contacts. Live-cell imaging demonstrated a significant reduction in the membrane-to-cytoplasm fluorescence ratio of the lipid-anchored GFP-tH probe, indicating redistribution from the plasma membrane to the cytoplasm following treatment. Analysis of autophagy-related proteins revealed decreased LC3-I together with increased LC3-II, ATG5, and p62 expression, consistent with autophagosome accumulation and impaired autophagic flux. Collectively, our findings demonstrate that low-dose doxorubicin promotes extensive remodeling of plasma membrane organization, epithelial plasticity, membrane-associated lipid-anchor localization, and autophagy. This integrated response reveals previously unrecognized links between membrane architecture, Ras membrane association, and autophagy during phenotypic reprogramming of breast cancer cells, providing mechanistic insight into cellular adaptations elicited by sub-cytotoxic doxorubicin exposure.

cancer biology↗