Biology subjects

Tomasini, R.

Publications and source records attributed to Tomasini, R..

5 recordsLinked to original sources

bioRxiv2026

The methionine cycle sustains the mesenchymal phenotype of tumor cells and drives PDA progression

Mesenchymal traits are associated with poor prognosis in Pancreatic Ductal Adenocarcinoma (PDA), but direct targeting of mesenchymal tumor cells remains a challenge. Metabolic profiling of tumor cells isolated from murine PDA and liver metastases (LM) revealed that LM rely more on the methionine cycle than does primary PDA. This metabolic shift was specifically associated with increased activation of the methionine cycle in mesenchymal tumor cells compared to differentiated tumor cells. We show that the targeting of the key enzyme of the methionine cycle S-adenosylhomocysteine hydrolase (SAHH) in mesenchymal cells lowers the levels of homocysteine (Hcy) and glutathione, resulting in reduced antioxidant capacity, deregulated intracellular calcium homeostasis, and ultimately loss of mesenchymal markers. Together, these events decrease cell proliferation and invasion, blunting the tumorigenic and metastatic potential of SAHH-deficient cells, eventually impeding tumor growth and progression of the metastatic disease. Clinically, the high expression of SAHH in patients with mesenchymal PDA is correlated with poor survival, positioning SAHH as a potential therapeutic target to impede the pro-metastatic, mesenchymal phenotype of PDA.

cancer biology↗

bioRxiv2026

Co-translational O-glycosylation driven by GALNTs spatial reprogramming fosters pancreatic cancer growth

Signal-driven relocation of GalNAc-transferases (GALNTs) from the Golgi to the ER, termed GALA, promotes tumour growth, but its effects on glycosylation are unclear. Unlike N-glycosylation, which is co-translational, O-glycosylation initiates post-translationally in the Golgi. Here we show that GALA subverts this arrangement in pancreatic ductal adenocarcinomas (PDAC) and in murine pancreatic tumours, where it stimulates growth. Quantitative glycoproteomics on a cellular model reveals a substantial expansion of the O-glycoproteome, consisting in thousands of sites across hundreds of proteins, ER-resident proteins, cell-surface receptors, secreted factors, and extracellular matrix components. Profiling of murine tumours and patient-derived xenografts confirms widespread activation and cross-species conservation of glycosylation patterns. Structural analysis reveals that GALA-specific residues have solvent accessibility as low as N-glycosylation sites, and below Golgi O-glycosylation or phosphorylation sites, indicating that ER O-glycosylation occurs co-translationally. By inverting the normal temporal sequence of folding and glycosylation, cancer cells generate alternative glycoforms that foster tumour growth.

cancer biology↗

bioRxiv2025

The extracellular matrix drives guanylate production and protects pancreatic cancer cells from oxaliplatin-induced DNA damage.

The excessive production of extracellular matrix (ECM) and the metabolic adaptations in pancreatic ductal adenocarcinoma (PDAC) contribute individually to enhanced chemoresistance, dramatic tumor progression and dismal patient survival. However, ECM-driven metabolic alterations that promote chemoresistance in PDAC are so far unexplored. Here, we use in-vitro-generated ECM bio-scaffolds that recapitulate cell-ECM interactions and induce broad metabolic alterations in PDAC cells. High-throughput integration of multi-omics datasets coupled with metabolic tracing showed that the ECM enhances the generation of guanylates in PDAC cells, the accumulation of which alleviates oxaliplatin-induced DNA damage, and boosts PDAC cell proliferation. These events are guided by the guanosine monophosphate (GMP)-producing enzymes Impdh and Gmps, the expression of which correlated with that of matrisomal and DNA repair genes in PDAC patient samples. We propose that targeting ECM-driven metabolic processes, like the enhanced Impdh activity, may be an effective therapeutic approach for PDAC patients that bypasses the negative side effects of direct targeting of the ECM itself.

cancer biology↗

bioRxiv2020

DECONbench: a benchmarking platform dedicated to deconvolution methods for tumor heterogeneity quantification

MotivationQuantification of tumor heterogeneity is essential to better understand cancer progressionand to adapt therapeutic treatments to patient specificities. ResultsWe present DECONbench, a web-based application to benchmark computational methods dedicated to quantify of cell-type heterogeneity in cancer. DECONbench includes benchmark datasets, computational methods and performance evaluation. It allows submission of new methods. Availability and implementationDECONbench is hosted on the open source codalab competition platform. It is freely available at: https://competitions.codalab.org/competitions/23660. Supplementary informationAdditional information is available online and on our website: https://cancer-heterogeneity.github.io/deconbench.html.

bioinformatics↗

bioRxiv2020

Sympathetic axonal sprouting induces changes in macrophage populations and protects against pancreatic cancer

Recent evidence has highlighted the presence of neuronal nerve processes in the tumor microenvironment. However, the origin of intra-tumoral nerves remains poorly known, in part because of technical difficulties in tracing nerve fibers via regular histological preparations. Here, we employed three-dimensional (3D) imaging of cleared tissues for a comprehensive analysis of sympathetic innervation in pancreatic ductal adenocarcinoma (PDAC). The results support two independent, but coexisting, mechanisms: passive engulfment of pre-existing nerves within tumors and active, localized sprouting of nerve terminals into non-neoplastic lesions and tumor periphery. Nerve ablation revealed an inverse correlation between sympathetic innervation and tumor growth and spread. Furthermore, sympathectomy increased CD163+ macrophage levels, which contributed to worse outcomes. Altogether, our findings revealed protective properties of the sympathetic nervous system in PDAC immunity and progression that could pave the way for new treatments.

cancer biology↗