Mechanical compressive forces increase PI3K output signaling in breast and pancreatic cancer cells.

Mechanical stresses, including compression, arise during cancer progression. In solid cancer, especially breast and pancreatic cancers, the rapid tumor growth and the environment remodeling explain their high intensity of compressive forces. However, the sensitivity of compressed cells to targeted therapies remains poorly known.

A microfluidic mechano-chemostat for tissues and organisms reveals that confined growth is accompanied with increased macromolecular crowding.

Conventional culture conditions are oftentimes insufficient to study tissues, organisms, or 3D multicellular assemblies. They lack both dynamic chemical and mechanical control over the microenvironment. While specific microfluidic devices have been developed to address chemical control, they often do not allow the control of compressive forces emerging when cells proliferate in a confined environment.

Transducing compressive forces into cellular outputs in cancer and beyond.

In living organisms, cells sense mechanical forces (shearing, tensile, and compressive) and respond to those physical cues through a process called mechanotransduction. This process includes the simultaneous activation of biochemical signaling pathways. Recent studies mostly on human cells revealed that compressive forces selectively modulate a wide range of cell behavior, both in compressed and in neighboring less compressed cells.

The nuclear receptors SF1 and COUP-TFII cooperate on the Insl3 promoter in Leydig cells.

In Brief: The insulin-like 3 (INSL3) hormone produced by Leydig cells is essential for proper male sex differentiation, but the regulation of Insl3 expression remains poorly understood. This study describes a new physical and functional cooperation between the nuclear receptors SF1 and COUP-TFII in Insl3 expression.

Abstract: INSL3, a hormone abundantly produced by Leydig cells, is essential for testis descent during fetal life and bone metabolism in adults.

PI3K functions as a hub in mechanotransduction.

Mammalian cells integrate different types of stimuli that govern their fate. These stimuli encompass biochemical as well as biomechanical cues (shear, tensile, and compressive stresses) that are usually studied separately. The phosphatidylinositol 3-kinase (PI3K) enzymes, producing signaling phosphoinositides at plasma and intracellular membranes, are key in intracellular signaling and vesicular trafficking pathways.

A Mouse Model of Cholangiocarcinoma Uncovers a Role for Tensin-4 in Tumor Progression.

Background And Aims: Earlier diagnosis and treatment of intrahepatic cholangiocarcinoma (iCCA) are necessary to improve therapy, yet limited information is available about initiation and evolution of iCCA precursor lesions. Therefore, there is a need to identify mechanisms driving formation of precancerous lesions and their progression toward invasive tumors using experimental models that faithfully recapitulate human tumorigenesis.

Approach And Results: To this end, we generated a mouse model which combines cholangiocyte-specific expression of Kras with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet-induced inflammation to mimic iCCA development in patients with cholangitis.

Dynamics and predicted drug response of a gene network linking dedifferentiation with beta-catenin dysfunction in hepatocellular carcinoma.

Background & Aims: Alterations of individual genes variably affect the development of hepatocellular carcinoma (HCC). Thus, we aimed to characterize the function of tumor-promoting genes in the context of gene regulatory networks (GRNs).

Methods: Using data from The Cancer Genome Atlas, from the LIRI-JP (Liver Cancer - RIKEN, JP project), and from our transcriptomic, transfection and mouse transgenic experiments, we identify a GRN which functionally links LIN28B-dependent dedifferentiation with dysfunction of β-catenin (CTNNB1).

MEF2 and NR2F2 cooperate to regulate Akr1c14 gene expression in mouse MA-10 Leydig cells.

Leydig cells are essential for male reproductive development and health throughout life. Production of androgens [testosterone, dihydrotestosterone (DHT)] as well as intermediate steroids [progesterone, dihydroprogesterone (DHP)] is tightly regulated. In the mouse, the 3α-hydroxysteroid dehydrogenase enzyme (3α-HSD, AKR1C14) catalyses the interconversion of DHP and DHT into less potent steroids.

The Transcription Factor MEF2 Is a Novel Regulator of Gsta Gene Class in Mouse MA-10 Leydig Cells.

Testosterone is essential for spermatogenesis and the development of male sexual characteristics. However, steroidogenesis produces a significant amount of reactive oxygen species (ROS), which can disrupt testosterone production. The myocyte enhancer factor 2 (MEF2) is an important regulator of organogenesis and cell differentiation in various tissues.

Novel Targets for the Transcription Factors MEF2 in MA-10 Leydig Cells.

Testosterone production by Leydig cells is a tightly regulated process requiring synchronized expression of several steroidogenic genes by numerous transcription factors. Myocyte enhancer factor 2 (MEF2) are transcription factors recently identified in somatic cells of the male gonad. In other tissues, MEF2 factors are essential regulators of organogenesis and cell differentiation.

MEF2 Cooperates With Forskolin/cAMP and GATA4 to Regulate Star Gene Expression in Mouse MA-10 Leydig Cells.

In Leydig cells, steroidogenic acute regulatory protein (STAR) participates in cholesterol shuttling from the outer to the inner mitochondrial membrane, the rate-limiting step in steroidogenesis. Steroid hormone biosynthesis and steroidogenic gene expression are regulated by LH, which activates various signaling pathways and transcription factors, including cAMP/Ca(2+)/CAMK (Ca(2+)/calmodulin-dependent kinase)-myocyte enhancer factor 2 (MEF2). The 4 MEF2 transcription factors are essential regulators of cell differentiation and organogenesis in numerous tissues.

The INSL3 gene is a direct target for the orphan nuclear receptor, COUP-TFII, in Leydig cells.

Insulin-like 3 (INSL3), a hormone produced by Leydig cells, regulates testicular descent during foetal life and bone metabolism in adults. Despite its importance, little is known about the molecular mechanisms controlling INSL3 expression. Reduced Insl3 mRNA levels were reported in the testis of mice deficient for chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII), an orphan nuclear receptor known to play critical roles in cell differentiation and lineage determination in several tissues.