Biology subjects

Tarcan, Z.

Publications and source records attributed to Tarcan, Z..

3 recordsLinked to original sources

bioRxiv2026

Neoantigen-reactive CD8+ T cell engagement marks exceptional survivors of pancreatic cancer

Pancreatic cancer (PC) is largely refractory to immune checkpoint blockade (ICB), although homologous recombination-deficient (HRD) tumors may derive benefit. In the POLAR trial of maintenance pembrolizumab plus olaparib after platinum-based chemotherapy for metastatic PC, responses remained heterogeneous. To define determinants of productive antitumor immunity, we integrated longitudinal blood TCR sequencing with tumor single-cell and spatial profiling. Durable benefit was associated with rare tumor-infiltrating, peripherally expanding (TIE) CD8+ T cell clonotypes, a subset of which were functionally neoantigen-reactive. TIE patients showed markedly prolonged survival beyond established genomic and immune biomarkers. Conversely, resistance was associated with spatial T cell exclusion, myCAF-rich stromal remodeling, basal-like/KRAS-associated malignant-cell programs, and expansion of CTLA4 regulatory T cells linked to local immunosuppressive remodeling. These findings define a clonotype-resolved framework for immune monitoring and identify complementary stromal, tumor-intrinsic, and regulatory immune barriers that may guide rational combination immunotherapy in PC.

cancer biology↗

bioRxiv2026

Invasion status stratifies the composition of the human pancreatic cancer perineural niche

The peripheral nervous system innervates the pancreatic ductal adenocarcinoma (PDAC) microenvironment, and perineural invasion (PNI), the invasion of cancer cells in and around nerves, correlates with metastatic burden and poor outcomes. Though PDAC innervation is near universal and the majority of PDAC patients harbor PNI, the cellular and molecular composition of the heterocellular perineural niche is largely unknown, obscuring functional significance. Here we provide a deeply phenotyped spatial and single-cell atlas of the human PDAC perineural niche, enabling a high-resolution comparison of invaded versus non-invaded nerve neighborhoods. This atlas leverages a novel vision-centric artificial intelligence model for imaging-based spatial transcriptomics, coupled with pathology-guided single-nucleus RNA-seq. These analyses revealed that invaded nerve neighborhoods harbor cancer cells of the classical subtype, together with myofibroblastic cancer-associated fibroblasts (CAFs) and lipid-associated macrophages. Non-invaded nerve neighborhoods, in contrast, harbor inflammatory CAFs and infiltration of B and T lymphocytes. These findings raise the possibility that PNI and not innervation itself is immune-suppressive in this setting, motivating functional studies. Statement of SignificanceHuman PDAC is innervated and almost invariably harbors PNI, but the composition and functions of perineural niches remain unclear. Here we provide a spatial and single-cell atlas of the human PDAC perineural niche, defining cancer and stromal cell states in the context of PNI and nominating this process as potentially immune-suppressive.

cancer biology↗

bioRxiv2021

The p97 cofactor Ubxn7 facilitates replisome disassembly during S-phase

Complex cellular processes are driven by the regulated assembly and disassembly of large multi-protein complexes. In eukaryotic DNA replication, whilst we are beginning to understand the molecular mechanism for assembly of the replication machinery (replisome), we still know relatively little about the regulation of its disassembly at replication termination. Over recent years, the first elements of this process have emerged, revealing that the replicative helicase, at the heart of the replisome, is polyubiquitylated prior to unloading and that this unloading requires p97 segregase activity. Two different E3 ubiquitin ligases are now known to ubiquitylate the helicase under different conditions: Cul2Lrr1 and TRAIP. Here we have found two p97 cofactors, Ubxn7 and Faf1, which can interact with p97 during replisome disassembly in S-phase. Only Ubxn7 however facilitates efficient replisome disassembly through its interaction with both Cul2Lrr1 and p97. Our data therefore characterise Ubxn7 as the first substrate-specific p97 cofactor regulating replisome disassembly in vertebrates.

biochemistry↗