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Articles by Patrick Mehlen
Mechanistic insights into NET1–UNC5B complex formation and Its targeted disruption by NP137 fab and NET1 peptide competitors
Abstract Netrin‑1, a secreted protein initially characterized for its role in axon guidance, has emerged as a critical mediator of cancer progression. Preclinical studies with the anti‑netrin‑1 antibody NP137, which blocks the netrin‑1–UNC5B interaction, have demonstrated reactivation of tumor suppressor functions and sensitization of cancer cells to chemotherapy.
Netrin1 blockade alleviates resistance to chemotherapy in pancreatic cancer
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Abstract Netrin1, a developmental cue, is a master regulator of tumour epithelial-to-mesenchymal transition (EMT)1, a mechanism that is known to drive resistance to chemotherapy2. A netrin1 antibody (NP137)3 has been shown to inhibit tumour EMT in preclinical1 and clinical4 settings. In animal models of pancreatic cancer, netrin1 and its receptor neogenin have been shown to promote tumour progression5, EMT5 and metastasis6.
By Gaël S. Roth, Pascal Artru, Olivier Bouché Verified, Nicolas Williet, Julien Ghelfi, Anthony Turpin, Astrid Lièvre, Jean-Frédéric Blanc, Camille Evrard, Jean-Baptiste Bachet, Pauline Parent, Marc Manceau, Matthieu Roustit, Anna Borowik, Aurélie Durand, Edouard Girard, Mircea Chirica, Nicolas Rama, Hector Hernandez-Vargas, Jean-Yves Scoazec, Jérôme Cros, Sébastien Hazard, Benjamin Ducarouge, Thomas Decaens, Agnès Bernet, Patrick Mehlen, Victoire Granger, Christelle d’Engremont, Nicolas Braissand, Eugénie Modolo, Elise Georges
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Nature
Verified
Pancreatic cancer: an antibody proves itself in an early clinical trial
In many cancers, some tumour cells resist treatment by activating what is referred to as “epithelial-to-mesenchymal transition,” by which they quickly change shape and behaviour, thereby avoiding standard treatments.
Neural function of Netrin-1 in precancerous lesions of the pancreas - Nature Communications
Abstract The nervous system undergoes dynamic structural remodeling to infiltrate cancerous tumors, contributing to their growth and progression. Emerging evidence indicates that neuroplasticity initiates early, with nerve terminals detecting and responding to tissue changes even during precancerous stages. Notably, dense sympathetic axon sprouting has been observed around pancreatic intraepithelial neoplasia (PanIN), a common precursor lesion to pancreatic cancer.
Sonic hedgehog medulloblastomas are dependent on Netrin-1 for survival - Nature Communications
Abstract Netrin-1 signaling is an essential prototypical neuronal guidance mechanism during embryonic development that also regulates tumor cell survival in a variety of adult cancer entities. In line with these data, a monoclonal netrin-1 blocking antibody (anti-netrin-1 mAb/NP137) has been preclinically developed and netrin-1 blockade has recently been investigated in phase 1 and 2 clinical trials in several adult cancers.
Comprehensive molecular portrait reveals genetic diversity and distinct molecular subtypes of small intestinal neuroendocrine tumors - Nature Communications
Abstract Small intestinal neuroendocrine tumors (siNETs) are rare bowel tumors arising from malignant enteroendocrine cells, which normally regulate digestion throughout the intestine. Though infrequent, their incidence is rising through better diagnosis, fostering research into their origin and treatment. To date, siNETs are considered to be a single entity and are clinically treated as such.
Netrin-1 blockade inhibits tumor associated Myeloid-derived suppressor cells, cancer stemness and alleviates resistance to chemotherapy and immune checkpoint inhibitor | Cell Death & Differentiation
Abstract Drug resistance and cancer relapse represent significant therapeutic challenges after chemotherapy or immunotherapy, and a major limiting factor for long-term cancer survival. Netrin-1 was initially identified as a neuronal navigation cue but has more recently emerged as an interesting target for cancer therapy, which is currently clinically investigated. We show here that netrin-1 is an independent prognostic marker for clinical progression of breast and ovary cancers.
Adamtsl3 mediates DCC signaling to selectively promote GABAergic synapse function
Highlights • Adamtsl3 is widely expressed at hippocampal synapses • Adamtsl3 is a ligand for DCC during synaptogenesis and in the mature brain • Presynaptic and postsynaptic Adamtsl3 contribute toward GABAergic synapse maintenance via DCC • Autocrine Adamtsl3-DCC signaling mediates plasticity adaptations at GABAergic postsynapse Summary The molecular code that controls synapse formation and maintenance in vivo has remained quite sparse.
Pharmacological targeting of netrin-1 inhibits EMT in cancer - Nature
Author notes These authors contributed equally: Justine Lengrand, Ievgenia Pastushenko, Sebastiaan Vanuytven Authors and Affiliations Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB), Brussels, Belgium Justine Lengrand, Ievgenia Pastushenko, Yura Song, Rahul M.
Synergistic Activity of Floor-Plate- and Ventricular-Zone-Derived Netrin-1 in Spinal Cord Commissural Axon Guidance
Highlights • Both floor-plate- and VZ-derived netrin-1 guide spinal cord commissural axons • Commissural axons go astray to the midline in the absence of floor plate netrin-1 • Commissural axon fasciculation is modified in the absence of VZ netrin-1 • Midline crossing mechanisms differ between the spinal cord and hindbrain Summary In vertebrates, commissural axons extend ventrally toward the floor plate in the spinal cord and hindbrain.
Notch Signaling in the Tumor Microenvironment
The Notch signaling pathway regulates many aspects of cancer biology. Most attention has been given to its role in the transformed cell. However, it is now clear that cancer progression and metastasis depend on the bidirectional interactions between cancer cells and their environment, forming the tumor microenvironment (TME). These interactions are mediated and constantly evolve through paracrine and juxtacrine signaling.
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