Fortian, A. | bioRxiv Science

bioRxiv2026

Convergent stromal and immune remodeling defines spatial tumor dynamics in PARP inhibitor-resistant high-grade serous ovarian cancer

Acquired resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) remains a major barrier to durable clinical benefit in patients with high-grade serous ovarian cancer (HGSOC), yet the profiles of tumors at resistance remain poorly understood. We profiled longitudinal HGSOC patient tumors spanning diagnosis, post-neoadjuvant therapy, and progression on PARPi with complementary spatial transcriptomics platforms, integrating single-cell-resolution Xenium analysis in paired longitudinal cases with cohort-level Visium profiling. PARPi failure was associated with spatial remodeling of the tumor microenvironment, marked by hypoxia-associated malignant transcriptional programs, increased stromal compartmentalization, and exclusion of effector immune cells. Together, these findings indicate that PARPi resistance in HGSOC is accompanied by reproducible spatial niche remodeling, underscoring the tumor microenvironment as a key contextual determinant of therapeutic failure.

cancer biology↗

bioRxiv2022

Charting the Spatial Landscape of Cancer Hallmarks

Tumors are complex ecosystems with dozens of interacting cell types. The concept of Cancer Hallmarks distills this complexity into a set of underlying principles that govern tumor growth. Here, we exploit this abstraction to explore the physical distribution of Cancer Hallmarks across 63 primary untreated tumors from 10 cancer types using spatial transcriptomics. We show that Hallmark activity is spatially organized-with 7 out of 13 Hallmarks consistently more active in cancer cells than within the non-cancerous tumor microenvironment (TME). The opposite is true for the remaining six Hallmarks. Additionally, we discovered that genomic distance between tumor subclones correlates with differences in Cancer Hallmark activity, even leading to clone-Hallmark specialization in some cases. Finally, we demonstrate interdependent relationships between Cancer Hallmarks at the junctions of TME and cancer compartments. In conclusion, including the spatial dimension, particularly through the lens of Cancer Hallmarks, can improve our understanding of tumor ecology. SignificanceWe explored Cancer Hallmarks in 63 primary untreated tumors from 10 cancer types using spatial transcriptomics. This study unveiled spatial patterns in Hallmark activity, with some being more active in cancer cells and others in the non-cancerous tumor environment. Genomic distance impacted Hallmark activity, and we identified interdependencies at the TME-cancer junctions, improving our understanding of tumor ecology.

cancer biology↗