Imbach, K. J. | 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↗

bioRxiv2023

Radical fringe facilitates NOTCH1 and JAG1 cis interactions to sustain Hematopoietic stem cell fate

Hematopoietic stem cells (HSCs) develop within a short time window from the hemogenic endothelium in the aorta- gonads-and mesonephros (AGM) region during embryonic development. The first HSCs reside within Intra-aortic hematopoietic clusters (IAHC) along with hematopoietic progenitors (HPC). The signalling mechanisms that divert HSCs from HPCs are unknown. Notch signaling is essential for arterial specification, IAHC formation and HSC activity, but current studies on how Notch drives these different fates are inconsistent. To determine the role of Notch in the specification of hemogenic endothelium, HSC and/or HPCs, we extensively analyzed Notch dynamics in the period of HSC generation. We defined the expression pattern of Notch signalling molecules at the gene and protein level and established a molecular mechanism that reconcile previous studies demonstrating the loss of HSC activity in NOTCH1, JAG1 and RBPJ null mutants, the enhanced HSC generation by blocking specific Notch activities or the abrogation of emerging HSCs by high Notch activation. We now demonstrate that Notch activity is highest in a subset of Gfi1+ hemogenic endothelial cells and is gradually lost with HSC maturation. We uncover that the HSC phenotype is maintained through loss of Notch activity due to increasing levels of NOTCH1 and JAG1 interactions on the surface of the same cell (cis) that renders the NOTCH1 receptor from being activated. Forcing activation of the NOTCH1 receptor in IAHC cells activates a hematopoietic differentiation program and supports a cis-inhibitory function for JAG1 and NOTCH1. Furthermore, we demonstrate that this cis-inhibitory interaction is enabled by RADICAL FRINGE (RFNG), a glycosyltransferase that enhances the affinity of NOTCH1 to JAG1 in cis. Finally, our results indicate that NOTCH1-JAG1 cis-inhibition is necessary for preserving the HSC phenotype in the hematopoietic clusters of the aorta.

developmental biology↗