Dataset Information

Generation of fibronectin fragments by pancreatic trypsin: a physiological mechanism hampering PDAC progression.

ABSTRACT: In this study we demonstrate that spheroids isolated from normal pancreas and co-trasplanted with PDAC orthotopically in mouse pancreas , inhibited tumor growth. Fibronectin proteolytic fragments generated by trypsin and released by pancreatic spheroids, were responsible for of the observed effect. Specifically, in vitro analysis revealed that FAK and FGFR1 signalling were turned off in tumor cells inducing tumor cell detachment, indicating a cooperative activity between the two signalling pathways. This mutual relationship was confirmed by the addition of FGF2 that reversed both FGFR1 and FAK defosphorilation and promoted PDAC cell adhesion and proliferation. Mass spectrometry proteomic analysis and the use of mAb allowed the identification of the FN fragments belonging to the Type III domain responsible of PDAC inhibition. Finally, the effect of FAK and FGFR signalling inhibitors was tested in combination both in vivo and in vitro to emulate the effect of normal pancreatic spheroids on PDAC growth.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Pancreas

SUBMITTER: Laura Brunelli

LAB HEAD: Roberta Pastorelli

PROVIDER: PXD035770 | Pride | 2023-10-24

REPOSITORIES: Pride

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Publications

Fibronectin fragments generated by pancreatic trypsin act as endogenous inhibitors of pancreatic tumor growth.

Resovi Andrea A Persichitti Perla P Brunelli Laura L Minoli Lucia L Borsotti Patrizia P Garattini Giulia G Tironi Matteo M Dugnani Erica E Redegalli Miriam M De Simone Giulia G Pastorelli Roberta R Bani Maria Rosa MR Piemonti Lorenzo L Mosher Deane F DF Giavazzi Raffaella R Taraboletti Giulia G Belotti Dorina D

Journal of experimental & clinical cancer research : CR 20230809 1

<h4>Background</h4>The pancreatic microenvironment has a defensive role against cancer but it can acquire tumor-promoting properties triggered by multiple mechanisms including alterations in the equilibrium between proteases and their inhibitors. The identification of proteolytic events, targets and pathways would set the basis for the design of new therapeutic approaches.<h4>Methods and results</h4>Here we demonstrate that spheroids isolated from human and murine healthy pancreas and co-transpl ...[more]

PMID: 37559126

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Project description:Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) dramatically limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that VS-4718 rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME thus rendering tumors more responsive to immunotherapy. We treated KP orthotopic tumor-bearing mice with vehicle and FAK inhibitor (FAKi) for 14 days, then extracted total RNA from tumor tissues.

Dataset Information

Generation of fibronectin fragments by pancreatic trypsin: a physiological mechanism hampering PDAC progression.

Publications

Fibronectin fragments generated by pancreatic trypsin act as endogenous inhibitors of pancreatic tumor growth.

Similar Datasets

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