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Ganci, M.

Publications and source records attributed to Ganci, M..

2 recordsLinked to original sources
bioRxiv2025

The Pdgfd-Pdgfrb axis orchestrates tumor-nerve crosstalk in pancreatic cancer

Nerves are an integral component of the tumor microenvironment, contributing to cancer progression, metastasis, morbidity, and mortality. In pancreatic ductal adenocarcinoma (PDAC), worse clinical outcomes are associated with perineural invasion (PNI), a process by which cancer cells surround and invade nerves. Here, we employed whole-transcriptome and single-cell spatial transcriptomics to identify candidate tumor-nerve interactions that promote PNI. We discovered that Pdgfd signaling promotes key features of nerve invasion. Mechanistically, Pdgfd stimulated cancer cell invasiveness, neurite outgrowth, and direct physical engagement with glia. Pharmacological blockade of this axis reduced each of these processes in vitro as well as PNI in vivo. Thus, Pdgfd-Pdgfrb signaling mediates PNI by coordinating multifaceted cancer-neuron-glia interactions and represents a promising therapeutic strategy aimed at disrupting harmful cancer-nerve crosstalk.

cancer biology↗
bioRxiv2025

Distinct malignant cell states and myeloid glutamate signaling associated with aggressive pancreatic neuroendocrine tumors

Pancreatic neuroendocrine tumors (PNET) are rare malignancies of the endocrine pancreas with diverse clinical outcomes. While some PNETs are indolent, others are aggressive and metastasize quickly. However, clinically-relevant molecular stratification for PNET to predict outcomes and guide therapeutic decision-making is limited. Thus, there is an urgent need to understand the molecular heterogeneity of PNETs to refine prognostication and discover novel therapeutic vulnerabilities. We performed single-nucleus RNA sequencing on resected primary and metastatic PNETs (n = 20), including two PNETs with neoadjuvant treatment. We inferred gene expression programs (GEPs) of malignant and non-malignant cells and investigated associations with clinical outcomes. Next, we inferred interactions in the tumor microenvironment (TME) and performed transwell assays for functional validation. Finally, we explored genomic and transcriptomic evolution in a unique case study of an untreated primary PNET with two asynchronous hepatic metastases. A malignant GEP enriched for neural/synaptic signaling genes was associated with worse overall survival, broad chromosomal loss of heterozygosity, and alternative lengthening of telomeres. Another malignant GEP enriched for VEGF signaling increased throughout metastatic progression in our case study. We found that macrophage-derived glutamate drives polarization towards an immunosuppressive phenotype and activates the MAPK/ERK pathway in malignant cells to increase migratory capacity. This study provides a detailed single-nucleus transcriptomic classification of malignant, stromal, and immune cell types and states in PNETs, their interactions in the TME, and associations with clinical outcomes. The refined molecular taxonomy of PNET may guide the development of more efficacious biomarkers and therapeutic strategies.

cancer biology↗