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Prognostic significance of integrin subunit alpha 2 (ITGA2) and role of mechanical cues in resistance to gemcitabine in pancreatic ductal adenocarcinoma (PDAC)

ABSTRACT: Prognostic significance of integrin subunit alpha 2 (ITGA2) and role of mechanical cues in resistance to gemcitabine in pancreatic ductal adenocarcinoma (PDAC)

PROVIDER: PRJNA854619 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19908652.fastq.gz	Fastqsanger.gz
	SRR19908653.fastq.gz	Fastqsanger.gz

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Project description:IntroductionPDAC is an extremely aggressive tumor with a poor prognosis and remarkable therapeutic resistance. The dense extracellular matrix (ECM) which characterizes PDAC progression is considered a fundamental determinant of chemoresistance, with major contributions from mechanical factors. This study combined biomechanical and pharmacological approaches to evaluate the role of the cell-adhesion molecule ITGA2, a key regulator of ECM, in PDAC resistance to gemcitabine.MethodsThe prognostic value of ITGA2 was analysed in publicly available databases and tissue-microarrays of two cohorts of radically resected and metastatic patients treated with gemcitabine. PANC-1 and its gemcitabine-resistant clone (PANC-1R) were analysed by RNA-sequencing and label-free proteomics. The role of ITGA2 in migration, proliferation, and apoptosis was investigated using hydrogel-coated wells, siRNA-mediated knockdown and overexpression, while collagen-embedded spheroids assessed invasion and ECM remodeling.ResultsHigh ITGA2 expression correlated with shorter progression-free and overall survival, supporting its impact on prognosis and the lack of efficacy of gemcitabine treatment. These findings were corroborated by transcriptomic and proteomic analyses showing that ITGA2 was upregulated in the PANC-1R clone. The aggressive behavior of these cells was significantly reduced by ITGA2 silencing both in vitro and in vivo, while PANC-1 cells growing under conditions resembling PDAC stiffness acquired resistance to gemcitabine, associated to increased ITGA2 expression. Collagen-embedded spheroids of PANC-1R showed a significant matrix remodeling and spreading potential via increased expression of CXCR4 and MMP2. Additionally, overexpression of ITGA2 in MiaPaCa-2 cells triggered gemcitabine resistance and increased proliferation, both in vitro and in vivo, associated to upregulation of phospho-AKT.ConclusionsITGA2 emerged as a new prognostic factor, highlighting the relevance of stroma mechanical properties as potential therapeutic targets to counteract gemcitabine resistance in PDAC.

Dataset Information

Prognostic significance of integrin subunit alpha 2 (ITGA2) and role of mechanical cues in resistance to gemcitabine in pancreatic ductal adenocarcinoma (PDAC)

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