Pancreatic Lkb1 Deletion Leads to Acinar Polarity Defects and Cystic Neoplasms

Abstract

LKB1 is a key regulator of energy homeostasis through the activation of AMP-activated protein kinase (AMPK) and is functionally linked to vascular development, cell polarity, and tumor suppression. In humans, germ line LKB1 loss-of-function mutations cause Peutz-Jeghers syndrome (PJS), which is characterized by a predisposition to gastrointestinal neoplasms marked by a high risk of pancreatic cancer. To explore the developmental and physiological functions of Lkb1 in vivo, we examined the impact of conditional Lkb1 deletion in the pancreatic epithelium of the mouse. The Lkb1-deficient pancreas, although grossly normal at birth, demonstrates a defective acinar cell polarity, an abnormal cytoskeletal organization, a loss of tight junctions, and an inactivation of the AMPK/MARK/SAD family kinases. Rapid and progressive postnatal acinar cell degeneration and acinar-to-ductal metaplasia occur, culminating in marked pancreatic insufficiency and the development of pancreatic serous cystadenomas, a tumor type associated with PJS. Lkb1 deficiency also impacts the pancreas endocrine compartment, characterized by smaller and scattered islets and transient alterations in glucose control. These genetic studies provide in vivo evidence of a key role for LKB1 in the establishment of epithelial cell polarity that is vital for pancreatic acinar cell function and viability and for the suppression of neoplasia.LKB1 encodes an evolutionarily conserved serine/threonine kinase that is involved in the regulation of cellular responses to energy stress and in the establishment of cell polarity (1,3,23). In response to an increase in the AMP/ATP ratio, LKB1 phosphorylates and activates AMP-activated protein kinase (AMPK), a key negative regulator of mTOR. Activation of the LKB1-AMPK axis results in a decrease in ATP-consuming processes and an increase in ATP production via inactivated mTOR, diminished fatty acid and glucose metabolism, and enhanced glucose transport. LKB1 also activates other members of the AMPK-related kinase subfamily including the microtubule affinity-regulating kinases 1 to 4 (MARK1, -2, -3 and -4) and the SAD/Brsk kinases (SAD-A and SAD-B) that induce cell polarity (30). Notably, LKB1 is required for the establishment of cell polarity in Drosophila melanogaster and Caenorhabditis elegans, as well as in cultured mammalian epithelial cells (2, 31, 48). Along similar lines, LKB1 and the SAD kinase define a pathway required for the polarization of neurons (6,43). Recent studies have demonstrated that AMPK regulates tight junction assembly and cell polarity in mammalian cells and in Drosophila in a manner linked to the response to energy stress (28, 51, 52). Mouse knockouts of MARK2 show metabolic defects (19). Collectively, these data support the view that energy sensing and cell polarity may be broadly integrated under the control of LKB1-AMPK signaling.In humans, germ line loss-of-function mutations of LKB1 are associated with Peutz-Jeghers syndrome (PJS), a disease characterized by benign gastrointestinal polyps (ham...

Tumor suppressor function of Liver kinase B1 (Lkb1) is linked to regulation of epithelial integrity

“…Discussion Par-4/Lkb1, like other Par proteins, centrally controls establishment of the apicobasal polarity and epithelial integrity in invertebrates. In mammals, Lkb1 is necessary for formation of proper epithelial architecture and cell orientation (18,23), and it is sufficient to program apical identity in cultured cells (17). Nonetheless, it has remained unclear how loss of the Lkb1 polarity function, which affects individual cells, translates into defects in epithelial tissue integrity and how these defects might be linked to tumor progression.…”

“…In Drosophila oocytes, Lkb1/ Par-4 participates in the formation of anterior-posterior axis and apicobasal polarity (15), whereas loss of Lkb1/Par-4 or its downstream target AMPK-α in follicle cells leads to polarity defects and increased proliferation, especially under energetic stress (16). In mammals, forced Lkb1 activity is sufficient to induce polarization of single intestinal epithelial cells (17), and in murine pancreatic acini, loss of Lkb1 leads to cell polarity defects in conjunction with formation of cystic neoplasms (18). Germline mutations in Lkb1 gene are causal to hereditary Peutz-Jeghers syndrome, characterized by gastrointestinal polyps and predisposition to several types of cancer, including pancreatic, ovarian, and breast cancer (19).…”

Pancreatic cancer modeling using retrograde viral vector delivery and in vivo CRISPR/Cas9-mediated somatic genome editing

“…7B). Given the frequent down-regulation and genomic loss of LKB1/STK11 in human PDAC (Morton et al 2010;Waddell et al 2015), the predisposition of Peutz-Jeghers syndrome patients to develop pancreatic tumors (Su et al 1999), and the impact of Lkb1 inactivation in other pancreatic tumor models (Hezel et al 2008;Morton et al 2010;Lo et al 2012), we chose Lkb1 as an initial target for CRISPR/Cas9-mediated somatic alteration in the adult pancreas. To assess the impact of Lkb1 loss on pancreatic cancer initiation and growth, we generated and screened Lenti-sgRNA/Cre vectors targeting Lkb1 (Supplemental Fig.…”

Deletion of Lkb1 in Renal Tubular Epithelial Cells Leads to CKD by Altering Metabolism

“…Some effects of LKB1 are independent of AMPK and they are mediated via microtubule affinity-regulating kinase, synapses of the amphid defective kinase, and salt-inducible kinase. [18][19][20] Kidney fibrosis is the histologic manifestation of CKD. Kidney fibrosis is characterized by accumulation of matrix and inflammatory cells.…”