Response to "Is the Reg3α (HIP/PAP) Protein Really an Obesogenic Factor?"

Peer Reviewe

Bénéfice à l’évaluation moléculaire en routine pour les cancers bronchiques métastatiques

International audienceBACKGROUND: EGFR tyrosine kinase inhibitors and crizotinib are nowadays the optimal treatment for metastatic lung cancer with activation of EGFR mutations and ALK rearrangement. In addition, several targeted agents are in development for lung cancer with other oncodrivers. In France, since 2011, six oncodrivers are routinely tested in patients with stage IV. The aim of this study was to assess whether systematic detection of oncodrivers and matched targeted therapy improve overall survival in patients with advanced lung adenocarcinoma.METHODS: This study included all consecutive patients treated in our department for advanced lung adenocarcinoma from January 2012 to December 2013. We studied the impact in survival according to the presence of the driver and the targeted therapy.RESULTS: Among the 261 patients included, oncodrivers alterations were found in 43.5% of patients: EML4-ALK fusion genes (2.1%), EGFR (10.3%), KRAS (27.7%), BRAF (2.5%), HER2 (0.8%), and PI3KCA (0.8%) mutations. Twenty-nine percent of patients (n=32) with oncodrivers received matched targeted therapy. Patient treated by targeted agent appropriate to an oncogenic driver had a median survival of 21.1 months (95% CI: 14.7-27.5). The patients (n=79) who did not receive targeted therapy had a median survival of 6.6 months (95% CI: 4.3-8.9). The patients (n=150) without identified driver had a median survival of 9.7 months (95% CI: 6.7-11.7); P<0.001.CONCLUSION: An actionable oncodriver was routinely detected in nearly half of patients with advanced lung adenocarcinoma. This systematic detection may influence treatment outcomes, notably with matched targeted therapy.Introduction: En France, six altérations moléculaires sont évaluées dans les cancers bronchiques non à petites cellules non épidermoïde. Quel est l’impact global sur la survie des malades ayant un adénocarcinome d’emblée métastatique ?Patients et méthodes: Étude rétrospective monocentrique ayant inclus tous les patients présentant un adénocarcinome pulmonaire d’emblée métastatique sur une période de 2ans. Les caractéristiques cliniques, biologiques, thérapeutiques et le devenir ont été collectés.Résultats:Au total, 261 patients ont été inclus ; une altération moléculaire était trouvée chez 43,5 % des patients : réarrangement EML4-ALK (2,1 %), mutations d’EGFR (10,3 %), KRAS (27,7 %), BRAF (2,5 %), HER2 (0,8 %), et PI3KCA (0,8 %). Parmi les patients avec une altération moléculaire, les patients ayant reçu un traitement bioguidé présentaient (n =32) une médiane de survie globale de 21,1 mois (IC95 % : 14,7–27,5) alors que les patients n’ayant pas reçu de traitement bioguidé (n =79) avaient une médiane de survie globale de 6,6 mois (IC95 % : 4,3–8,9) ; les patients sans altération moléculaire identifiée (n =150) avaient une médiane de survie globale de 9,7 mois (IC95 % : 6,7–11,7 ; p <0,001).Conclusions:Le screening moléculaire systématique proposé par l’Inca conduit à la découverte d’une altération chez environ un malade sur deux présentant un adénocarcinome bronchique métastatique et influence significativement la survie en cas de traitement bioguidé disponible, justifiant les efforts de recherche dans ce domaine

Stromal SLIT2 impacts on pancreatic cancer-associated neural remodeling

International audiencePancreatic ductal adenocarcinoma (PDA) is a critical health issue in the field of cancer, with few therapeutic options. Evidence supports an implication of the intratumoral microenvironment (stroma) on PDA progression. However, its contribution to the role of neuroplastic changes within the pathophysiology and clinical course of PDA, through tumor recurrence and neuropathic pain, remains unknown, neglecting a putative, therapeutic window. Here, we report that the intratumoral microenvironment is a mediator of PDA-associated neural remodeling (PANR), and we highlight factors such as 'SLIT2' (an axon guidance molecule), which is expressed by cancer-associated fibroblasts (CAFs), that impact on neuroplastic changes in human PDA. We showed that 'CAF-secreted SLIT2' increases neurite outgrowth from dorsal root ganglia neurons as well as from Schwann cell migration/ proliferation by modulating N-cadherin/β-catenin signaling. Importantly, SLIT2/ROBO signaling inhibition disrupts this stromal/ neural connection. Finally, we revealed that SLIT2 expression and CAFs are correlated with neural remodeling within human and mouse PDA. All together, our data demonstrate the implication of CAFs, through the secretion of axon guidance molecule, in PANR. Furthermore, it provides rationale to investigate the disruption of the stromal/neural compartment connection with SLIT2/ROBO inhibitors for the treatment of pancreatic cancer recurrence and pain. Even after significant efforts from the scientific community in the past decade, pancreatic ductal adenocarcinoma (PDA) remains one of the most lethal cancers with worrying predictions. 1 Median survival stagnates around 5 months, together with a 5-year survival at 5%. For 5–20% of patients treated surgically, the 5-year survival reaches 20%, with a median survival of 16 months. Metastasis onset and high prevalence of local tumor recurrence after potential curative resection influence patient's survival. A recent study revealed that the overall survival of patients with tumor recurrence was 9.3, versus 26.3 months for patients without early relapse. 2,

The Genome of \u3ci\u3eLaccaria bicolor\u3c/i\u3e Provides Insights into Mycorrhizal Symbiosis

Mycorrhizal symbioses—the union of roots and soil fungi—are universal in terrestrial ecosystems and may have been fundamental to land colonization by plants. Boreal, temperate and montane forests all depend on ectomycorrhizae. Identification of the primary factors that regulate symbiotic development and metabolic activity will therefore open the door to understanding the role of ectomycorrhizae in plant development and physiology, allowing the full ecological significance of this symbiosis to be explored. Here we report the genome sequence of the ectomycorrhizal basidiomycete Laccaria bicolor (Fig. 1) and highlight gene sets involved in rhizosphere colonization and symbiosis. This 65-megabase genome assembly contains ~20,000 predicted protein-encoding genes and a very large number of transposons and repeated sequences. We detected unexpected genomic features, most notably a battery of effector-type small secreted proteins (SSPs) with unknown function, several of which are only expressed in symbiotic tissues. The most highly expressed SSP accumulates in the proliferating hyphae colonizing the host root. The ectomycorrhizae-specific SSPs probably have a decisive role in the establishment of the symbiosis. The unexpected observation that the genome of L. bicolor lacks carbohydrate-active enzymes involved in degradation of plant cell walls, but maintains the ability to degrade non-plant cell wall polysaccharides, reveals the dual saprotrophic and biotrophic lifestyle of the mycorrhizal fungus that enables it to grow within both soil and living plant roots. The predicted gene inventory of the L. bicolor genome, therefore, points to previously unknown mechanisms of symbiosis operating in biotrophic mycorrhizal fungi. The availability of this genome provides an unparalleled opportunity to develop a deeper understanding of the processes by which symbionts interact with plants within their ecosystem to perform vital functions in the carbon and nitrogen cycles that are fundamental to sustainable plant productivity

Homotypic cell cannibalism, a cell-death process regulated by the nuclear protein 1, opposes to metastasis in pancreatic cancer.

International audiencePancreatic adenocarcinoma (PDAC) is an extremely deadly disease for which all treatments available have failed to improve life expectancy significantly. This may be explained by the high metastatic potential of PDAC cells, which results from their dedifferentiation towards a mesenchymal phenotype. Some PDAC present cell-in-cell structures whose origin and significance are currently unknown. We show here that cell-in-cells form after homotypic cell cannibalism (HoCC). We found PDAC patients whose tumours display HoCC develop less metastasis than those without. In vitro, HoCC was promoted by inactivation of the nuclear protein 1 (Nupr1), and was enhanced by treatment with transforming growth factor β. HoCC ends with death of PDAC cells, consistent with a metastasis suppressor role for this phenomenon. Hence, our data indicates a protective role for HoCC in PDAC and identifies Nupr1 as a molecular regulator of this process