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Lkb1 regulates organogenesis and early oncogenesis along AMPK-dependent and -independent pathways

Bryan Lo1, Geraldine Strasser, Meredith Sagolla

  • 1Genentech, South San Francisco, CA 94080, USA.

The Journal of Cell Biology
|December 26, 2012
PubMed

Insights

Loss of the LKB1 tumor suppressor drives early cancer development in the pancreas, independent of AMPK signaling. This study reveals LKB1

Area of Science:

  • Molecular Biology
  • Developmental Biology
  • Cancer Research

Background:

  • Liver kinase B1 (LKB1), also known as STK11/Par-4, is a crucial tumor suppressor regulating cellular energy, proliferation, and polarity.
  • The precise mechanisms by which LKB1 functions remain incompletely understood, particularly its role in developmental processes and cancer initiation.

Purpose of the Study:

  • To investigate the role of LKB1 kinase activity in epithelial morphogenesis and its potential involvement in early carcinogenesis.
  • To elucidate the signaling pathways downstream of LKB1, including adenosine monophosphate-activated kinase (AMPK), in different embryonic tissues.

Main Methods:

  • Generation of mice with a conditional LKB1 kinase-inactivating mutation.
  • Ex vivo culture of embryonic tissues (pancreas and lung) following LKB1 inhibition.
  • Genetic manipulation, including expression of mutant K-Ras and p16/p19 deletion, and chemical genetics (AMPK activation).

Main Results:

  • Acute loss of LKB1 kinase activity disrupted epithelial morphogenesis in embryonic tissues without affecting cell polarity.
  • Pancreatic LKB1 inhibition led to rapid cyst development, resembling precancerous lesions, independent of AMPK signaling.
  • Lung LKB1 inhibition caused cell-autonomous branching defects, which were rescued by AMPK activation.

Conclusions:

  • Loss of LKB1 kinase activity is sufficient to initiate early steps of carcinogenesis in the pancreas ex vivo.
  • LKB1's role in developmental processes and cancer initiation is context-dependent, with distinct pathways involved in pancreatic versus lung development.
  • The combination of embryonic tissue culture, genetic, and chemical genetics provides a powerful platform for studying developmental programs and cancer initiation.

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