Michail Sideris, Consultant Gynaecologist and Gynaecological Oncology Surgeon at The London Clinic, shared on LinkedIn:
“Are all STICs the same? Our new paper suggests they are not.
Serous tubal intraepithelial carcinoma (STIC) is considered the main precursor of high-grade serous carcinoma (HGSC), the most lethal gynaecological cancer.
Yet in practice we still tend to treat STIC as a single entity.
We used trajectory inference (pseudotime) on spatial transcriptomic data from fallopian tube epithelium. This let us reconstruct the transcriptional journey from normal-appearing epithelium to invasive cancer. We asked four questions:
- Are all STICs equally advanced precursors? No. STICs sit at different points along a continuous path towards HGSC. Lesions that look alike under the microscope can be at very different stages transcriptionally, and there is marked variation between patients.
- STICi vs STICc: how do they differ? Isolated STICs (STICi) span early to later states and often show loss of ciliary organisation and less advanced phenotypes. STICs found alongside a cancer (STICc) carry clearly more advanced malignant signatures .
- Which molecular pathways drive progression? The advanced end of the trajectory is marked by cell-cycle activation, epithelial-to-mesenchymal transition (EMT), interferon signalling and DNA-repair programmes.
- Would PARPi work in STICs? Signatures associated with PARP-inhibitor resistance are already present in precursor lesions, to varying degrees, and they persist into invasive disease. If this is confirmed functionally, we should not assume PARPi-based prevention will work uniformly. Stratified approaches deserve investigation.
Why this matters:
For women at high genetic risk, a STIC diagnosis raises difficult questions about follow-up, surveillance and future prevention trials. Histology alone may not tell us how far a lesion has travelled.
Trajectory-informed biomarkers could help us stratify risk and design smarter early-interception strategies.
Grateful to have worked and been guided on this by Eleni Maniati, Frances Balkwill and Ranjit Manchanda.
Special thanks to Tanjina Kader, Professor Sandro Santagata and Professor Ronny Drapkin for their input and enormous effort to build the first atlas on STICs.”
Title: Reconstruction of epithelial transcriptional trajectories reveals heterogeneous progression and early therapy-resistance programs in high-grade serous carcinoma precursors
Authors: Michail Sideris, Eleni Maniati, Tanjina Kader, Sandro Santagata, Ronny Drapkin, Frances Balkwill, Ranjit Manchanda
To which Ranjit Manchanda, Council Member at ESGO – European Society of Gynaecological Oncology, added:
“Great to see our paper out. It has some important messages.
Well done Michail Sideris, Eleni Maniati.
Thanks to all co-authors and stakeholders.”
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