Endothelial Smad6 and Smad7 harmonize blood vessel development and tumor progression

Functional maturation of an organotypic blood vessel system and maintenance of vascular quiescence throughout life are features of health and longevity. During vascular development and angiogenesis, endothelial cells (EC) are responsive to stimuli and proliferate but once blood vessels mature, they transition into an actively maintained quiescent state characterized by diminished signaling response and proliferative activity. Moreover, EC quiescence is not a one-way street of cell fate but a transient state and it is still not deciphered what molecular programs are critical for its acquisition and long-term maintenance. To investigate the mechanisms by which EC acquire and actively maintain their quiescent resting state, Schlereth et al. performed genome-wide epigenetic and transcriptomic screens of continuous lung EC in newborn and adult mice. Here, TGFβ signaling, and the inhibitors Smad6 and Smad7, were most prominently regulated. The TGFβ superfamily is imperative for facilitating vascular development and endothelial cell fate but its role in maturation and adult homeostasis is only recently emerging. Notably, the unique integration of TGFβ and BMP- mediated signaling by the intracellular inhibitors Smad6 and Smad7 over vascular development, maturation and quiescence is less well established. By deleting endothelial Smad6 and Smad7 at different developmental stages up until adult homeostasis, I show that embryonic deletion in Smad6IECKO mice led to widespread hemorrhages and lethality with moderate penetrance by E18.5. Postnatal deletion of endothelial Smad6 did not affect retinal angiogenesis but led to increased pathological neovascularization during oxygen-induced retinopathy (OIR). In contrast, Smad7IECKO mice after embryonic deletion were viable and postnatal loss of endothelial Smad7 impaired retinal angiogenesis. Combined embryonic deletion of endothelial Smad6 and Smad7 led to lethality with high penetrance before E13.5 and postnatal deletion phenocopied impaired retinal angiogenesis in Smad7IECKO mice. By challenging adult Smad6- and Smad7IECKO mice with two tumor models (LLC and B16F10) I found endothelial Smad6 and Smad7 to differentially affect tumor size and survival. Loss of endothelial Smad6 led to increased tumor size and higher survival during metastasis. Loss of endothelial Smad7 led to decreased tumor size and lower survival in metastasis. Interestingly, loss of endothelial Smad6 and Smad7 negated the effects from single deletion. Taken together, I found that Smad6 and Smad7 differentially regulate physiological and pathological angiogenesis but only have a nuanced or perhaps dispensable role in vascular quiescence. Preliminary data also suggests endothelial Smad6 and Smad7 may discreetly regulate primary tumor growth and metastatic dissemination

T cell senescence and CAR-T cell exhaustion in hematological malignancies

Abstract T cell senescence has been recognized to play an immunosuppressive role in the aging population and cancer patients. Strategies dedicated to preventing or reversing replicative and premature T cell senescence are required to increase the lifespan of human beings and to reduce the morbidity from cancer. In addition, overcoming the T cell terminal differentiation or senescence from lymphoma and leukemia patients is a promising approach to enhance the effectiveness of adoptive cellular immunotherapy (ACT). Chimeric antigen receptor T (CAR-T) cell and T cell receptor-engineered T (TCR-T) cell therapy highly rely on functionally active T cells. However, the mechanisms which drive T cell senescence remain unclear and controversial. In this review, we describe recent progress for restoration of T cell homeostasis from age-related senescence as well as recovery of T cell activation in hematological malignancies

Patched 1 expression in Merkel cell carcinoma

The relevance of Hedgehog signaling in Merkel cell carcinoma has only been addressed by a few studies with conflicting results. Thus, we aimed to establish the expression of Hedgehog signaling molecules in Merkel cell carcinoma to characterize causes of aberrant expression and to correlate these findings with the clinical course of the patients. Immunohistochemistry was performed for Sonic, Indian, Patched 1 (PTCH1) and Smoothened on patients' tumor tissue. Respective mRNA expression was analyzed in 10 Merkel cell carcinoma cell lines using quantitative real-time polymerase chain reaction. PTCH1 sequencing and DNA methylation microarray analyses were carried out on tumor tissues as well as cell lines. PTCH1 immunoreactivity in Merkel cell carcinoma was similar to that of basal cell carcinomas, which both significantly differed from PTCH1 immunoreactivity in healthy skin. Most PTCH1 mutations found were synonymous or without known functional impact. However, on average, the promoter regions of both PTCH1 were hypomethylated independently from PTCH1 gene expression or Merkel cell polyomavirus status. PTCH1 and GLI1/2/3 genes were differently expressed in different cell lines; notably, there was a significant correlation between GLI2 and PTCH1 mRNA expression. Similar to PTCH1 protein expression in patient tissues, PTCH1 gene expression in Merkel cell carcinoma cell lines is highly variable, but due to the similar methylation pattern across Merkel cell carcinoma cell lines, effects other than methylation seem to be the reason for the differential expression and PTCH1 appears to be upregulated by GLI as a classical Hedgehog target gene