The Water to Land Transition Submerged: Multifunctional Design of Pectoral Fins for Use in Swimming and in Association with Underwater Substrate.

Fins of fishes provide many examples of structures that are beautifully designed to power and control movement in water; however, some species also use their fins for substrate-associated behaviors where interactions with solid surfaces are key. Here, we examine how the pectoral fins of ray-finned fish with these multifunctional behavioral demands, in water and on solid surfaces, are structured and function. We subdivide fins used in swimming and substrate contact into two general morphological categories, regionalized vs. generalized fins. Regionalized fins have ventral rays that are free from connecting membrane or in which that membrane is reduced. Dorsally they maintain a more typical membranous fin. While all pectoral fins vary somewhat in their morphology from leading to trailing edge, generalized fins do not have the substantial membrane loss between rays that is seen in regionalized fins and the distal edge anatomy changes gradually along its margin. We add a new case study in regionalized fins with the dwarf hawkfish (Cirrhitichthys falco). Hawkfishes are most often found perching and moving on structures in their environments. During perching, the free ventral rays are in contact with the substrate and splayed. We found that unlike other fish with regionalized pectoral fins, hawkfish maintain use of the dorsal membranous region of its pectoral fin for rhythmic swimming. We found that typically hawkfish bend their ventral free rays under, toward the medial hemitrichs or hold them straight during substrate-associated postures. This appears also to be the case for the ventral free rays of other species with regionalized fins. Generalized fin use for substrate contact was reviewed in round gobies (Neogobius melanostomus). In addition, although their lobe fins are not representative of ray-finned fish anatomy, we explored fin contact on submerged substrates in the Senegal bichir (Polypterus senegalus), which has a generalized distal fin (no free fin rays or distinct membrane regions). Both groups use their pectoral fins for swimming. During substrate-based postures, unlike hawkfish, their distal rays generally bend outward toward the lateral hemitrichs and a large swath of the fin membrane can contact the surface. The alternative demands on multifunctional fins suggest specialization of the mechanosensory system. We review mechanosensation related to fin movement and surface contact. These alternative regionalized and generalized strategies for serving aquatic and substrate-based functions underwater provide opportunities to further investigate specializations, including sensory structures and systems, that accompany the evolution of substrate-based behaviors in vertebrates.

Cancer cell-intrinsic expression of MHC II in lung cancer cell lines is actively restricted by MEK/ERK signaling and epigenetic mechanisms.

BACKGROUND: Programmed death 1/programmed death ligand 1 (PD-1/PD-L1) targeted immunotherapy affords clinical benefit in ~20% of unselected patients with lung cancer. The factor(s) that determine whether a tumor responds or fails to respond to immunotherapy remains an active area of investigation. We have previously defined divergent responsiveness of two KRAS-mutant cell lines to PD-1/PD-L1 blockade using an orthotopic, immunocompetent mouse model. Responsiveness to PD-1/PD-L1 checkpoint blockade correlates with an interferon gamma (IFNγ)-inducible gene signature and major histocompatibility complex class II (MHC II) expression by cancer cells. In the current study, we aim to identify therapeutic targets that can be manipulated in order to enhance cancer-cell-specific MHC II expression. METHODS: Responsiveness to IFNγ and induction of MHC II expression was assessed after various treatment conditions in mouse and human non-small cell lung cancer (NSCLC) cell lines using mass cytometric and flow cytometric analysis. RESULTS: Single-cell analysis using mass and flow cytometry demonstrated that IFNγ consistently induced PD-L1 and MHC class I (MHC I) across multiple murine and human NSCLC cell lines. In contrast, MHC II showed highly variable induction following IFNγ treatment both between lines and within lines. In mouse models of NSCLC, MHC II induction was inversely correlated with basal levels of phosphorylated extracellular signal-regulated kinase (ERK) 1/2, suggesting potential mitogen-activated protein (MAP) kinase-dependent antagonism of MHC II expression. To test this, cell lines were subjected to varying levels of stimulation with IFNγ, and assessed for MHC II expression in the presence or absence of mitogen-activated protein kinase kinase (MEK) inhibitors. IFNγ treatment in the presence of MEK inhibitors significantly enhanced MHC II induction across multiple lung cancer lines, with minimal impact on expression of either PD-L1 or MHC I. Inhibition of histone deacetylases (HDACs) also enhanced MHC II expression to a more modest extent. Combined MEK and HDAC inhibition led to greater MHC II expression than either treatment alone. CONCLUSIONS: These studies emphasize the active inhibitory role that epigenetic and ERK signaling cascades have in restricting cancer cell-intrinsic MHC II expression in NSCLC, and suggest that combinatorial blockade of these pathways may engender new responsiveness to checkpoint therapies.