Biology subjects

Passeron, T.

Publications and source records attributed to Passeron, T..

4 recordsLinked to original sources

bioRxiv2026

Arginine synthesis pathway and ASS1 play a critical role in mRNA translation reprogramming and ICI resistance in cutaneous melanoma

Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment, but their efficacy has now reached a plateau. ICIs are the first class of treatment targeting the crosstalk between immune and tumor cells, making it crucial to understand the complex interactions within the tumor microenvironment (TME) to enhance therapeutic responses. The elevated consumption of resources by cancer cells, coupled with limited vascularization, often results in a TME that is deficient in nutrients, leading to competition for resources between cancer and stromal cells. Consequently, targeting tumor metabolism has emerged as a promising strategy to improve the efficacy of ICIs. Through metabolomic analysis, we have identified metabolic alterations in melanoma cells that are resistant to ICIs, specifically an increase in arginine synthesis and upregulation of ASS1, the rate-limiting enzyme in this pathway. By using gain and loss of function models, as well as a pharmacological inhibitor specific for ASS1, we demonstrated that modulations in the expression or activity of ASS1 is associated with translational reprogramming, characterized by an inhibition of the cap-dependent mRNA translation mediated through mTORC1/4EBP1 axis. We also demonstrated that targeting ASS1 in vivo, resensitize tumors initially resistant to ICI. Taken together, our results highlight the interaction between modulations of arginine synthesis pathway, mRNA translation reprogramming, antitumor immunity, and restauration of sensitivity to anti-PD-1. Our work also demonstrates the therapeutic potential of targeting arginine synthesis pathway, and especially ASS1, to offer new treatments to patients suffering from cutaneous melanoma resistant to ICIs.

cancer biology↗

bioRxiv2025

MELK controls tumor metabolism to promote resistance to melanoma therapy

Melanoma is the most aggressive form of skin cancer, and despite major advances in targeted and immune therapies, durable responses remain limited due to the emergence of resistance mechanisms. Metabolic reprogramming has emerged as a key driver of therapy resistance, allowing tumor cells to adapt to environmental and therapeutic pressures. Here, we identify the maternal embryonic leucine zipper kinase (MELK) as a critical mediator of resistance in melanoma. We demonstrate that MELK stimulates intracellular accumulation of amino acids, leading to activation of mTORC1 signaling and enhanced mitochondrial metabolism and biogenesis. This metabolic shift promotes resistance to immune checkpoint blockade. Importantly, preclinical MELK inhibition sensitizes resistant melanoma cells to immunotherapy, revealing a potential combinatorial strategy to overcome resistance. Our findings establish MELK as a central regulator of metabolic adaptation and therapeutic resistance in melanoma, highlighting its potential as a promising therapeutic target.

cancer biology↗

bioRxiv2021

Invasive dedifferentiated melanoma cells inhibit JAK1-STAT3-driven actomyosin contractility of human fibroblastic reticular cells of the lymph node

Fibroblastic reticular cells (FRC) are immunologically specialized fibroblasts controlling the size and microarchitecture of the lymph node (LN), partly through their contractile properties. Swelling is a hallmark of tumor-draining LN in lymphophilic cancers such as cutaneous melanoma, a very aggressive and heterogeneous tumor with high risk of early metastasis. Melanoma cells can dynamically switch between melanocytic proliferative and dedifferentiated mesenchymal-like invasive phenotypes, which are characterized by distinct transcriptional signatures. Melanoma secreted cues, such as extracellular vesicles, growth factors or proinflammatory cytokines, promote LN stroma remodeling and metastatic spreading. But how FRC integrate these pro-metastatic signals and modulate their contractile functions remains poorly characterized. Here, we show that factors secreted by dedifferentiated melanoma cells, but not by melanocytic cells, strongly inhibit FRC actomyosin-dependent contractile forces by decreasing the activity of the RHOA-ROCK pathway and the mechano-responsive transcriptional co-activator YAP, leading to a decrease in F-actin stress fibers and cell elongation. Transcriptional profiling and biochemical analyses indicate that FRC actomyosin cytoskeleton relaxation is driven by inhibition of JAK1 and its downstream transcription factor STAT3, and is associated with increased FRC proliferation and activation. Interestingly, dedifferentiated melanoma cells reduce FRC contractility in vitro independently of extracellular vesicle secretion. These data show that FRC are specifically modulated by proteins secreted by invasive dedifferentiated melanoma cells and suggest that melanoma-derived cues could modulate the biomechanical properties of distant LN before metastatic invasion. They also highlight that JAK1-STAT3 and YAP signaling pathways contribute to the maintenance of the spontaneous contractility of resting human FRC.

cancer biology↗

bioRxiv2019

Targeting DDR1 and DDR2 overcomes matrix-mediated melanoma cell adaptation to BRAF-targeted therapy

Resistance to BRAF and MEK inhibitors in BRAFV600E mutant melanomas remains a major obstacle that limits patient benefit. Microenvironment components including the extracellular matrix (ECM) can support tumor cell adaptation and tolerance to targeted therapies, however the underlying mechanisms remain poorly understood. Here, we investigated the process of matrix-mediated drug resistance (MM-DR) in response to BRAF inhibition in melanoma. We demonstrate that physical and structural cues from fibroblast-derived ECM abrogate anti-proliferative responses to BRAF/MEK inhibition. MM-DR is mediated by the drug-induced clustering of DDR1 and DDR2, two tyrosine kinase collagen receptors. Genetic depletion and pharmacological inhibition of DDR1 and DDR2 overcome ECM-mediated resistance to BRAF inhibition. In melanoma xenografts, targeting DDRs by Imatinib enhances BRAF inhibitor efficacy, counteracts drug-induced collagen remodeling and delays tumor relapse. Mechanistically, DDR-mediated MM-DR fosters a targetable pro-survival NIK/IKK/NF-{kappa}B2 pathway. Our study reveals a novel role of collagen-rich matrix and DDRs in tumor cell adaptation and therapy resistance, thus providing important insights into environment-mediated drug resistance and a pre-clinical rationale for targeting DDR1/2 signaling in combination with BRAF-targeted therapy in melanoma.

cancer biology↗