Biology subjects

Di-Tommaso, S.

Publications and source records attributed to Di-Tommaso, S..

3 recordsLinked to original sources

bioRxiv2025

Cancer cells transfer invasive properties through microRNAs contained in collagen-tracks

Invasion is a prerequisite for metastasis formation. During tumor development, the extracellular matrix (ECM) is remodeled in part through overexpression of type I collagen, increasing tumor microenvironment stiffness, and facilitating cancer dissemination. During breast cancer cell migration, we observed membrane debris left behind, attached to the collagen fibrils, along the migration path. We named these structures collagen-tracks. These collagen-tracks can be deposited in 3D matrices in vitro and in vivo and their formation is stimulated by the interaction between the ECM and matrix receptors, such as the discoidin-domain receptor (DDR1). However, they are different from structures already known to be involved in cell-cell communication such as exosomes and migrasomes, due to their specific nucleic acid and protein contents. When deposited by highly invasive breast cancer cells, internalized collagen-tracks reprogram non-invasive cells into highly pro-metastatic ones by inducing a partial epithelial-mesenchymal transition (EMT). This cell reprogramming is dependent on specific miRNAs present in the collagen-tracks, that are necessary to promote ECM degradation, increase cell motility and invasiveness. Collagen-tracks thus represent a new form of cell-cell communication important for driving tumor invasion that could be targeted to prevent metastasis.

cell biology↗

bioRxiv2025

Proteomic profiling of advanced hepatocellular carcinoma identifies predictive signatures of response to treatments

PurposeHepatocellular carcinoma (HCC) is the most common form of liver cancer with a bad prognosis in case of advanced HCC, only eligible for palliative systemic therapies. After a decade of exclusive sorafenib monotherapy, with a response rate of <10%, the advent of immunotherapies represents a revolution in HCC. The combination of atezolizumab/bevacizumab is recommended as the first-line systemic treatment, with a response rate around 30%. However, there are currently no predictive factors for response to these treatment options. Experimental DesignWe profiled, by high-resolution mass spectrometry-based proteomics combined with machine learning analysis, a selected cohort of fixed biopsies of advanced HCC. We grouped subjects according to their objective response to treatments, corresponded to a tumor regression vs tumor progression at 4 months after treatment. ResultsWe generated a proteome database of 50 selected HCC samples. We compared the relative protein abundance between tumoral and non-tumoral liver tissues from advanced HCC patients treated. The clear distinction of these two groups for each treatment is based on deregulation for 141 protein or 87 for atezolizumab/bevacizumab and sorafenib treatment, respectively. These specific proteomic signatures were sufficient to predict the response to treatment, and revealed biological pathways involved in treatments resistance. Particularly, we validated a shift in tumor cell metabolism with an immunosuppressive environment involved in the resistance to atezolizumab/bevacizumab combination. ConclusionsWe performed an in-depth analysis of quantitative proteomic data from HCC biopsies to predict the treatment response to advanced HCC giving the ability to optimize patient management.

cancer biology↗

bioRxiv2019

Counteracting resistance to targeted therapy in melanoma by inhibiting discoidin domain receptors

Anti-BRAF plus anti-MEK are used as first-line treatment of patients with metastatic melanomas harboring BRAF V600E mutation. The main issue with targeted therapy is acquired cellular resistance. In 70% of acquired resistance, melanoma cells switch their phenotype and become more aggressive and invasive. The molecular signature of this phenotype is MITF low, AXL high associated with actin cytoskeleton reorganization. After this switch, resistant cells present an anarchic cell proliferation due to MAP kinase pathway hyper-activation. We demonstrate that resistant cell lines presenting phenotype switching overexpress DDR1 and DDR2. We show that DDR2 inhibition induces a decrease in AXL and reduces actin stress fiber formation. Once this phenotype switching is acquired, we report that both DDRs promotes tumor cell proliferation, but only DDR2 can over-activate the MAP kinase pathway in resistant invasive cells in vitro and in vivo. Therefore, DDRs inhibition could be a promising strategy for countering this resistance mechanism. SignificanceOur results show that DDR2 is a relevant target in melanoma resistance. DDR2 is required at the beginning of resistance for melanoma cell phenotype switching to occur. After phenotype switching, DDRs promote tumor cell proliferation of resistant invasive melanoma cells, but only DDR2 is able to over-activate the MAP kinase pathway. We put forward dasatinib (a DDR inhibitor) as a potential second-line treatment after targeted dual therapy for resistant patients overexpressing DDRs.

cancer biology↗