LKB1 conundrum: LKB1 in thyroid cancer

LKB1 conundrum: LKB1 in thyroid cancer LKB1 is a known tumor suppressor. first identified in Peutz Jeghers Syndrome, characterized by general hamartomatous polyposis leading to the formation of multiple tumors at several sites in the body. Loss or inactivation of LKB1 has been shown in lung cancer and other organ systems confirming its role as a tumor suppressor. LKB1 is known to act as a tumor suppressor through various different mechanisms. One of the important mechanisms being activation of downstream tumor suppressor, AMPK. AMPK in turn inhibits mTOR which is important for regulation of metabolic pathways in tumor cells. However, recent evidence suggests that AMPK might not be a tumor suppressor but promote tumor growth under certain contexts. There are reports suggesting both AMPK and mTOR to be active in tumors without compromising the action of one another. This is turn also applies to the protein upstream of AMPK, i.e. LKB1. Therefore both LKB1-AMPK have now been termed as context-dependent tumor suppressor/promoter. In thyroid cancers, there is hardly any evidence to suggest inactivation of LKB1. To further corroborate the evidence, the LKB1 downstream protein AMPK is also shown to be upregulated in papillary thyroid cancers. Despite all of this evidence, the role of LKB1 in thyroid tumors has so far not being explored properly. In this regard, two recent articles are worth mentioning. The first one was from a group at Upenn describing two LKB1 mutations in thyroid cancer. Of the two mutations described, one was a splice site mutation and another one was missense mutation in C-terminal non-catalytic site of LKB1. It remains to be further explored as to how common are these mutations in thyroid cancer and more importantly their functional relevance to the thyroid cancer. Another recent article described the transcriptional profile of PTCs and FTCs. The authors proposed various new drivers of tumor growth in thyroid cancers, one of which was LKB1 mutant (STK11R86fs). Again, just like the previous article, the functional significance of the mutant remains to be explored. Despite the new evidence, it seems to corroborate the fact that LKB1 mutations do not constitute a major part in growth and progression of thyroid tumors. But, to err on the side of caution, it is possible that as cost of sequencing keeps going down, more research groups would focus on characterizing the tumor suppressor profile of thyroid cancers and may throw up interesting results for LKB1. But to continue with my hypothesis of role of LKB1 as a tumor promoter in thyroid cancers, it is possible that differentiated thyroid cancers have robust expression of LKB1 and maybe its activation as well. LKB1 is also known to activate and stabilize p53. p53 loss leads to the formation of undifferentiated thyroid cancer (anaplastic thyroid cancers). It remains to be explored whether loss of LKB1 from differentiated thyroid cancers is the trigger for the development of anaplastic thyroid cancers.
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