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Les patients (pts) atteints d’un mélanome réséqué de stade IIB/C présentent un risque élevé de récidive, similaire à celui des pts atteints d’un mélanome réséqué de stade IIIB. L’essai CM 76K (NCT04099251) a démontré une réduction significative du risque de récidive ou de décès avec le nivolumab (NIVO) par rapport au placebo (PBO) chez les pts atteints d’un mélanome de stade IIB/C et ayant eu une résection complète. Les données actualisées avec un suivi de 3 ans sont présentées ici.

NIVO en adjuvant a significativement prolongé la survie sans récidive (SSR) versus PBO dans le mélanome de stade IIB/C dans l’essai randomisé de phase III Checkmate 76K (HR : 0,42 ; IC95 % [0,30–0,59]). Pour la première fois, une sélection de BMs et leur association avec la SSR ont été analysées dans le mélanome de stade précoce traité avec un agent anti-PD-1.

Metastatic competence is contingent upon the aberrant activation of a latent embryonic program, known as the epithelial–mesenchymal transition (EMT), which bestows stem cell properties as well as migratory and invasive capabilities upon differentiated tumor cells. We recently identified the transcription factor FOXC2 as a downstream effector of multiple EMT programs, independent of the EMT-inducing stimulus, and as a key player linking EMT, stem cell traits and metastatic competence in breast cancer. As such, FOXC2 could serve as a potential therapeutic target to attenuate metastasis. However, as FOXC2 is a transcription factor, it is difficult to target by conventional means such as small-molecule inhibitors. Herein, we identify the serine/threonine-specific kinase p38 as a druggable upstream regulator of FOXC2 stability and function that elicits phosphorylation of FOXC2 at serine 367 (S367). Using an orthotopic syngeneic mouse tumor model, we make the striking observation that inhibition of p38-FOXC2 signaling selectively attenuates metastasis without impacting primary tumor growth. In this model, circulating tumor cell numbers are significantly reduced in mice treated with the p38 inhibitor SB203580, relative to vehicle-treated counterparts. Accordingly, genetic or pharmacological inhibition of p38 decreases FOXC2 protein levels, reverts the EMT phenotype and compromises stem cell attributes in vitro. We also identify the EMT-regulator ZEB1—known to directly repress E-cadherin/CDH1—as a downstream target of FOXC2, critically dependent on its activation by p38. Consistent with the notion that activation of the p38-FOXC2 signaling axis represents a critical juncture in the acquisition of metastatic competence, the phosphomimetic FOXC2(S367E) mutant is refractory to p38 inhibition both in vitro and in vivo, whereas the non-phosphorylatable FOXC2(S367A) mutant fails to elicit EMT and upregulate ZEB1. Collectively, our data demonstrate that FOXC2 regulates EMT, stem cell traits, ZEB1 expression and metastasis in a p38-dependent manner, and attest to the potential utility of p38 inhibitors as antimetastatic agents.

Advanced prostate adenocarcinomas enriched in stem-cell features, as well as variant androgen receptor (AR)-negative neuroendocrine (NE)/small-cell prostate cancers are difficult to treat, and account for up to 30% of prostate cancer-related deaths every year. While existing therapies for prostate cancer such as androgen deprivation therapy (ADT), destroy the bulk of the AR-positive cells within the tumor, eradicating this population eventually leads to castration-resistance, owing to the continued survival of AR-/lostem-like cells. In this study, we identified a critical nexus between p38MAPK signaling, and the transcription factor Forkhead Box Protein C2 (FOXC2) known to promote cancer stem-cells and metastasis. We demonstrate that prostate cancer cells that are insensitive to ADT, as well as high-grade/NE prostate tumors, are characterized by elevated FOXC2, and that targeting FOXC2 using a well-tolerated p38 inhibitor restores epithelial attributes and ADT-sensitivity, and reduces the shedding of circulating tumor cells in vivo with significant shrinkage in the tumor mass. This study thus specifies a tangible mechanism to target the AR-/lopopulation of prostate cancer cells with stem-cell properties.

1. Recent conceptualizations of the neural systems used during navigation have classified two types of sensory information used by animals: landmark cues and internally based (idiothetic; e.g., vestibular, kinesthetic) sensory cues. Previous studies have identified neurons in the postsubiculum and the anterior thalamic nuclei that discharge as a function of the animal's head direction in the horizontal plane. The present study was designed to determine how animals use head direction (HD) cells for spatial orientation and the types of sensory cues involved. 2. HD cell activity was monitored in the postsubiculum and anterior thalamic nucleus of rats in a dual-chamber apparatus in an experiment that consisted of two phases. In the first phase, HD cell activity was monitored as an animal moved from a familiar environment to a novel environment. It was hypothesized that if HD cells were capable of using idiothetic sensory information, then the direction of maximal discharge should remain relatively unchanged as the animal moved into an environment where it was unfamiliar with the landmark cues. In the second phase, HD cells were monitored under conditions in which a conflict situation was introduced between the established landmark cues and the animal's internally generated sensory cues. 3. HD cells were initially recorded in a cylinder containing a single orientation cue (familiar environment). A door was then opened, and the rat entered a U-shaped passageway leading to a rectangular chamber containing a different prominent cue (novel environment). For most HD cells, the preferred direction remained relatively constant between the cylinder and passageway/rectangle, although many cells showed a small (6-30 degrees) shift in their preferred direction in the novel environment. This directional shift was maintained across different episodes in the passageway/rectangle. 4. Before the next session, the orientation cue in the cylinder was rotated 90 degrees, and the animal returned to the cylinder. The cell's preferred direction usually shifted between 45 and 90 degrees in the same direction. 5. The rat was then permitted to walk back through the passageway into the now-familiar rectangle. Immediately upon entering the passageway, the preferred direction returned to its original (prerotation) orientation and remained at this value while the rat was in the rectangle. When the rat was allowed to walk back into the cylinder, one of three outcomes occurred: 1) the cell's preferred direction shifted, such that it remained linked to the cylinder's rotated cue card; 2) the cell's preferred direction remained unchanged from its orientation in the rectangle; or 3) the cell's preferred direction shifted to a new value that lay between the preferred directions for the rotated cylinder condition and rectangle. 6. There was little change in the HD cell's background firing rate, peak firing rate, or directional firing range for both the novel and cue-conflict situations. 7. Simultaneous recordings from multiple cells in different sessions showed that the preferred directions remained "in register" with one another. Thus, when one HD cell shifted its preferred direction a specific amount, the other HD cell also shifted its preferred direction the same amount. 8. Results across different series within the same animal showed that the amount the preferred direction shifted in the first Novel series was about the same amount as the shifts observed in subsequent Novel series. In contrast, as the animal experienced more Conflict series, HD cells tended to use the cylinder's cue card less as an orientation cue when the animal returned to the rotated cylinder condition from the rectangle. 9. These results suggest that HD cells in the postsubiculum and anterior thalamic nuclei receive information from both landmark and idiothetic sensory cues, and when both types of cues are available, HD cells preferentially use the landmark cues as long as they are perceived

Abstract:  Head direction (HD) and place cells were recorded in rats that had previously exhibited significant acquisition deficits on a radial arm maze task following disorientation treatment. In this study we determined whether this behavioral impairment was associated with a lack of landmark stimulus control over the preferred orientations of HD and place cells. Neurons were recorded as animals retrieved food pellets in a cylindrical apparatus containing a single cue card. Some of these HD cells were also recorded while animals explored an eight-arm radial maze in a similar cue-controlled environment. The stimulus control of the landmarks in each environment was assessed by rotating the landmark and examining the subsequent preferred orientations of HD and place cells. Animals underwent disorientation treatment before and after each recording session. Despite this disorientation, rotation of the cue card in the cylindrical apparatus resulted in a corresponding shift in the preferred orientations of HD and place cells in 13 of 15 and 7 of 7 recording sessions, respectively. On the radial arm maze, rotation of the landmark cue was associated with a corresponding shift in the HD cell’s preferred orientation in 7 of 9 sessions. These results suggest that a visual landmark’s stimulus control may not require a learned association between that landmark and an animal’s stable experience in an environment. Furthermore, instability in the HD cell system is unlikely to account for the impaired performance of the disoriented animals in the radial arm maze. Rather, these impairments may be due to the animal’s inability to utilize stable representations of the environment provided by HD and place cells.