Conditional Pten inactivation in pituitary results in sex-specific prolactinoma formation.

Pituitary tumors, including prolactinomas, present significant clinical challenges that require a deeper understanding of their molecular roots for improved diagnostics and therapies. Here, we investigate the role of the phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K) pathway in pituitary tumorigenesis using a mouse model. Conditional knockout of Pten in all pituitary cell lineages resulted in prolactinoma formation exclusively in female mice, demonstrating the critical role of PTEN in pituitary homeostasis.

Recurrent adamantinomatous craniopharyngiomas show MAPK pathway activation, clonal evolution and rare TP53-loss-mediated malignant progression.

The two types of craniopharyngioma, adamantinomatous (ACP) and papillary (PCP), are clinically relevant tumours in children and adults. Although the biology of primary craniopharyngioma is starting to be unravelled, little is known about the biology of recurrence. To fill this gap in knowledge, we have analysed through methylation array, RNA sequencing and pERK1/2 immunohistochemistry a cohort of paired primary and recurrent samples (32 samples from 14 cases of ACP and 4 cases of PCP).

Rebound growth of BRAF mutant pediatric glioma cells after MAPKi withdrawal is associated with MAPK reactivation and secretion of microglia-recruiting cytokines.

Introduction: Patients with pediatric low-grade gliomas (pLGGs), the most common primary brain tumors in children, can often benefit from MAPK inhibitor (MAPKi) treatment. However, rapid tumor regrowth, also referred to as rebound growth, may occur once treatment is stopped, constituting a significant clinical challenge.

Methods: Four patient-derived pediatric glioma models were investigated to model rebound growth in vitro based on viable cell counts in response to MAPKi treatment and withdrawal.

Unraveling the complexity of the senescence-associated secretory phenotype in adamantinomatous craniopharyngioma using multimodal machine learning analysis.

Background: Cellular senescence can have positive and negative effects on the body, including aiding in damage repair and facilitating tumor growth. Adamantinomatous craniopharyngioma (ACP), the most common pediatric sellar/suprasellar brain tumor, poses significant treatment challenges. Recent studies suggest that senescent cells in ACP tumors may contribute to tumor growth and invasion by releasing a senesecence-associated secretory phenotype.

Implications of cellular senescence in paediatric pituitary tumours.

The long-standing view of senescent cells as passive and dysfunctional biological remnants has recently shifted into a new paradigm where they are main players in the development of many diseases, including cancer. The senescence programme represents a first line of defence that prevents tumour cell growth but also leads to the secretion of multiple pro-inflammatory and pro-tumourigenic factors that fuel tumour initiation, growth, and progression. Here, we review the main molecular features and biological functions of senescent cells in cancer, including the outcomes of inducing or targeting senescence.

Effects of senescence on the tumour microenvironment and response to therapy.

Cellular senescence is a state of durable cell arrest that has been identified both in vitro and in vivo. It is associated with profound changes in gene expression and a specific secretory profile that includes pro-inflammatory cytokines, growth factors and matrix-remodelling enzymes, referred to as the senescence-associated secretory phenotype (SASP). In cancer, senescence can have anti- or pro-tumour effects.

Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer.

The accumulation of senescent cells in the tumor microenvironment can drive tumorigenesis in a paracrine manner through the senescence-associated secretory phenotype (SASP). Using a new p16-FDR mouse line, we show that macrophages and endothelial cells are the predominant senescent cell types in murine KRAS-driven lung tumors. Through single cell transcriptomics, we identify a population of tumor-associated macrophages that express a unique array of pro-tumorigenic SASP factors and surface proteins and are also present in normal aged lungs.

An expression and function analysis of the CXCR4/SDF-1 signalling axis during pituitary gland development.

The chemokine SDF-1 (CXCL12) and its receptor CXCR4 control several processes during embryonic development such as the regulation of stem cell proliferation, differentiation, and migration. However, the role of this pathway in the formation of the pituitary gland is not understood. We sought to characterise the expression patterns of CXCR4, SDF-1 and CXCR7 at different stages of pituitary gland development.

Contemporary Biological Insights and Clinical Management of Craniopharyngioma.

Craniopharyngiomas (CPs) are clinically aggressive tumors because of their invasive behavior and recalcitrant tendency to recur after therapy. There are 2 types based on their distinct histology and molecular features: the papillary craniopharyngioma (PCP), which is associated with BRAF-V600E mutations and the adamantinomatous craniopharyngioma (ACP), characterized by mutations in CTNNB1 (encoding β-catenin). Patients with craniopharyngioma show symptoms linked to the location of the tumor close to the optic pathways, hypothalamus, and pituitary gland, such as increased intracranial pressure, endocrine deficiencies, and visual defects.

BH3 mimetics targeting BCL-XL impact the senescent compartment of pilocytic astrocytoma.

Background: Pilocytic astrocytoma (PA) is the most common pediatric brain tumor and a mitogen-activated protein kinase (MAPK)-driven disease. Oncogenic MAPK-signaling drives the majority of cells into oncogene-induced senescence (OIS). While OIS induces resistance to antiproliferative therapies, it represents a potential vulnerability exploitable by senolytic agents.

Hypothalamic syndrome.

Hypothalamic syndrome (HS) is a rare disorder caused by disease-related and/or treatment-related injury to the hypothalamus, most commonly associated with rare, non-cancerous parasellar masses, such as craniopharyngiomas, germ cell tumours, gliomas, cysts of Rathke's pouch and Langerhans cell histiocytosis, as well as with genetic neurodevelopmental syndromes, such as Prader-Willi syndrome and septo-optic dysplasia. HS is characterized by intractable weight gain associated with severe morbid obesity, multiple endocrine abnormalities and memory impairment, attention deficit and reduced impulse control as well as increased risk of cardiovascular and metabolic disorders. Currently, there is no cure for this condition but treatments for general obesity are often used in patients with HS, including surgery, medication and counselling.

Adamantinomatous craniopharyngioma as a model to understand paracrine and senescence-induced tumourigenesis.

Cellular senescence is a process that can prevent tumour development in a cell autonomous manner by imposing a stable cell cycle arrest after oncogene activation. Paradoxically, senescence can also promote tumour growth cell non-autonomously by creating a permissive tumour microenvironment that fuels tumour initiation, progression to malignancy and metastasis. In a pituitary tumour known as adamantinomatous craniopharyngioma (ACP), cells that carry oncogenic β-catenin mutations and overactivate the WNT signalling pathway form cell clusters that become senescent and activate a senescence-associated secretory phenotype (SASP).

Cell senescence in neuropathology: A focus on neurodegeneration and tumours.

The study of cell senescence is a burgeoning field. Senescent cells can modify the cellular microenvironment through the secretion of a plethora of biologically active products referred to as the senescence-associated secretory phenotype (SASP). The consequences of these paracrine signals can be either beneficial for tissue homeostasis, if senescent cells are properly cleared and SASP activation is transient, or result in organ dysfunction, when senescent cells accumulate within the tissues and SASP activation is persistent.

Galactose-modified duocarmycin prodrugs as senolytics.

Senescence is a stable growth arrest that impairs the replication of damaged, old or preneoplastic cells, therefore contributing to tissue homeostasis. Senescent cells accumulate during ageing and are associated with cancer, fibrosis and many age-related pathologies. Recent evidence suggests that the selective elimination of senescent cells can be effective on the treatment of many of these senescence-associated diseases.

Biological Behaviour of Craniopharyngiomas.

Jakob Erdheim (1874-1937) first described craniopharyn-giomas (CPs) as "hypophyseal duct tumours" and postulated the existence of two tumour types based on their histological features: (1) an aggressive type showing similarities to adamantinomas (tumours of the jaw) and (2) a more benign form characterised by the presence of papillary structures. More than a century later, these initial observations have been confirmed; based on their distinct genetic, epigenetic, and histological features, the WHO classifies CPs into two types: adamantinomatous CPs (ACPs) and papillary CPs (PCPs). Considerable knowledge has been generated on the biology of CPs in the last 20 years.

Learning from cases: Analysis of two cases of craniopharyngioma from the 19 to the 21 centuries.

This manuscript describes the study of two cases of craniopharyngioma, which have been examined repeatedly over three separate centuries. This includes analysis by Josef Engel in 1839, who sought to uncover the physiological role of the pituitary gland; Jacob Erdheim in 1904, who initially described the disease we now call craniopharyngioma, and recent high resolution MRI and micro-CT imaging and attempted DNA analyses of the tumours. The cases highlight how, rightly or wrongly, our interpretation of data is shaped by the technologies, methodologies and prevailing theories of a given time.

Cardiac glycosides are broad-spectrum senolytics.

Senescence is a cellular stress response that results in the stable arrest of old, damaged or preneoplastic cells. Oncogene-induced senescence is tumor suppressive but can also exacerbate tumorigenesis through the secretion of pro-inflammatory factors from senescent cells. Drugs that selectively kill senescent cells, termed senolytics, have proved beneficial in animal models of many age-associated diseases.

Genetic Deletion of Hesx1 Promotes Exit from the Pluripotent State and Impairs Developmental Diapause.

The role of the homeobox transcriptional repressor HESX1 in embryonic stem cells (ESCs) remains mostly unknown. Here, we show that Hesx1 is expressed in the preimplantation mouse embryo, where it is required during developmental diapause. Absence of Hesx1 leads to reduced expression of epiblast and primitive endoderm determinants and failure of diapaused embryos to resume embryonic development after implantation.

Craniopharyngioma.

Craniopharyngiomas are rare malformational tumours of low histological malignancy arising along the craniopharyngeal duct. The two histological subtypes, adamantinomatous craniopharyngioma (ACP) and papillary craniopharyngioma (PCP), differ in genesis and age distribution. ACPs are diagnosed with a bimodal peak of incidence (5-15 years and 45-60 years), whereas PCPs are restricted to adults mainly in the fifth and sixth decades of life.

Conditional Dicer1 depletion using Chrnb4-Cre leads to cone cell death and impaired photopic vision.

Irreversible photoreceptor cell death is a major cause of blindness in many retinal dystrophies. A better understanding of the molecular mechanisms underlying the progressive loss of photoreceptor cells remains therefore crucial. Abnormal expression of microRNAs (miRNAs) has been linked with the aetiology of a number of retinal dystrophies.

Author Correction: P53 and mTOR signalling determine fitness selection through cell competition during early mouse embryonic development.

The original version of this article contained an error in the spelling of Juan Pedro Martinez-Barbera, which was incorrectly given as Juan Pedro Martinez Barbera. This error has now been corrected in both the PDF and HTML versions of the Article.

Senescence drives non-cell autonomous tumorigenesis in the pituitary gland.

Novel detrimental functions of senescent cells have been recently uncovered in the context of cancer development and progression, which they mainly exert through the secretion of several pro-tumorigenic factors. Here we discuss how cellular senescence and its secretory phenotype can be involved in the widely unexplored phenomenon of paracrine tumorigenesis.