Autophagy in the Pathogenesis of Disease

Interest in the topic of tumour metabolism has waxed and waned over the past century of cancer research. The early observations of Warburg and his contemporaries established that there are fundamental differences in the central metabolic pathways operating in malignant tissue. However, the initial hypotheses that were based on these observations proved inadequate to explain tumorigenesis, and the oncogene revolution pushed tumour metabolism to the margins of cancer research. In recent years, interest has been renewed as it has become clear that many of the signalling pathways that are affected by genetic mutations and the tumour microenvironment have a profound effect on core metabolism, making this topic once again one of the most intense areas of research in cancer biology.

/pdf/regulation-of-cancer-cell-metabolism-1dhy51t2fl.pdf

Regulation of cancer cell metabolism

https://www.cell.com/molecular-cell/pdf/S1097-2765(08)00169-X.pdf

AMPK phosphorylation of raptor mediates a metabolic checkpoint.

From the Departments of Thoracic/Head and Neck Medical Oncology (R.S.H., J.V.H., S.M.L.), Cancer Biology (R.S.H., J.V.H.), and Clinical Cancer Prevention (S.M.L.), University of Texas M.D. Anderson Cancer Center, Houston. Address reprint requests to Dr. Lippman at the Department of Thoracic/Head and Neck Medical Oncology, Unit 432, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, or at slippman@ mdanderson.org.

Molecular origins of cancer: Lung cancer

In the past decade, studies of the human tumour suppressor LKB1 have uncovered a novel signalling pathway that links cell metabolism to growth control and cell polarity. LKB1 encodes a serine-threonine kinase that directly phosphorylates and activates AMPK, a central metabolic sensor. AMPK regulates lipid, cholesterol and glucose metabolism in specialized metabolic tissues, such as liver, muscle and adipose tissue. This function has made AMPK a key therapeutic target in patients with diabetes. The connection of AMPK with several tumour suppressors suggests that therapeutic manipulation of this pathway using established diabetes drugs warrants further investigation in patients with cancer.

The LKB1-AMPK pathway: metabolism and growth control in tumour suppression.

Germline mutation in serine/threonine kinase 11 (STK11, also called LKB1) results in Peutz-Jeghers syndrome, characterized by intestinal hamartomas and increased incidence of epithelial cancers. Although uncommon in most sporadic cancers, inactivating somatic mutations of LKB1 have been reported in primary human lung adenocarcinomas and derivative cell lines. Here we used a somatically activatable mutant Kras-driven model of mouse lung cancer to compare the role of Lkb1 to other tumour suppressors in lung cancer. Although Kras mutation cooperated with loss of p53 or Ink4a/Arf (also known as Cdkn2a) in this system, the strongest cooperation was seen with homozygous inactivation of Lkb1. Lkb1-deficient tumours demonstrated shorter latency, an expanded histological spectrum (adeno-, squamous and large-cell carcinoma) and more frequent metastasis compared to tumours lacking p53 or Ink4a/Arf. Pulmonary tumorigenesis was also accelerated by hemizygous inactivation of Lkb1. Consistent with these findings, inactivation of LKB1 was found in 34% and 19% of 144 analysed human lung adenocarcinomas and squamous cell carcinomas, respectively. Expression profiling in human lung cancer cell lines and mouse lung tumours identified a variety of metastasis-promoting genes, such as NEDD9, VEGFC and CD24, as targets of LKB1 repression in lung cancer. These studies establish LKB1 as a critical barrier to pulmonary tumorigenesis, controlling initiation, differentiation and metastasis.

http://cancer.med.unc.edu/nhayes/publications/Article%20PDFs/2007-08%20Nature.pdf

LKB1 modulates lung cancer differentiation and metastasis

The excitatory neurotransmitter glutamate shapes learning and memory, but the underlying epigenetic mechanism of glutamate regulation in neuron remains poorly understood. Here, we showed that lysine demethylase KDM6B was expressed in excitatory neurons and declined in hippocampus with age. Conditional knockout of KDM6B in excitatory neurons reduced spine density, synaptic vesicle number and synaptic activity, and impaired learning and memory without obvious effect on brain morphology in mice. Mechanistically, KDM6B upregulated vesicular glutamate transporter 1 and 2 (VGLUT1/2) in neurons through demethylating H3K27me3 at their promoters. Tau interacted and recruited KDM6B to the promoters of Slc17a7 and Slc17a6, leading to a decrease in local H3K27me3 levels and induction of VGLUT1/2 expression in neurons, which could be prevented by loss of Tau. Ectopic expression of KDM6B, VGLUT1, or VGLUT2 restored spine density and synaptic activity in KDM6B-deficient cortical neurons. Collectively, these findings unravel a fundamental mechanism underlying epigenetic regulation of synaptic plasticity and cognition. 

KDM6B cooperates with Tau and regulates synaptic plasticity and cognition via inducing VGLUT1/2

Despite of several decades of efforts, lung cancer remains one of most deadly diseases, with a 5-year survival rate approximately 15% worldwide. In China, the situation is even worse. Although there is no official data released yet, the 5-year survival rate is estimated to be around 10%. In past 30 years, there was a dramatic increase of lung cancer related death about 465% in mainland China. Annually, about 400000 people die of lung cancer and the number is still climbing. At the same time, the number of new lung cancer cases also increase rapidly. The high mortality of lung cancer is mainly ascribed to two factors: the lack of effective ways to identify early diagnostic biomarkers and to treat metastatic cancer. Lung cancer can be pathologically divided into small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), among which NSCLC accounts for about 80% of all cases. In this review, we will focus on the recent efforts and progress in finding biomarkers in NSCLC. Since biomarkers are derived from both invasive and noninvasive ways, we divide them into these two categories and review them separately. We hope the discovery of biomarkers will eventually change the current clinical practice in NSCLC patients and improve their quality of life.

Lei Bao

Papers

LKB1 modulates lung cancer differentiation and metastasis

KDM6B cooperates with Tau and regulates synaptic plasticity and cognition via inducing VGLUT1/2

Finding biomarkers for non-small cell lung cancer diagnosis and prognosis