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Mechanisms of Follicular Thyroid Cancer Development and Progression in the Context of Dysregulated PKA

Pringle, Daphne R

Abstract Details

, Doctor of Philosophy, Ohio State University, Molecular, Cellular and Developmental Biology.
Thyroid cancer is the most commone endocrine malignancy in the population and incidence rates continue to rise. The two most common types of thyroid cancer, papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC) are generally treatable with good prognoses. However, in a small subset of patients, progression to invasive and distantly metastatic disease occurs. Once progression occurs, treatment options are limited and many patients ultimately die of metastatic disease. Study of the genetics of sporadic human PTCs and FTCs has found that the Ras/Raf/Mek/Erk signaling pathway is a key reglator of PTC growth, and mouse models harboring mutations in this pathway in the thyroid generally develop PTC in good analogy to the human disease. While some mutations have been identiifed in sporadic FTC, a central pathway has not been identified, and mouse models of many of the mutations found in humans fail to produce FTC when modeled in the mouse. In addition to studying the genetics of patients with sporadic FTC in order to identify important signaling pathways and druggable targets, another source of information about the genetic etiology of this disease is the study of inherited syndromes with FTC in the clinical spectra of disease. The work described here describes two new mouse models of FTC with genetic alterations that mimic those in both inherited and sporadic FTC cases. These mouse models point to dysregulation of Protein Kinase A (PKA) as a key signaling node in FTC and that the PKA pathway can synergize with the PI3K/Akt pathway, also implicated in sporadic and inherited FTC, to foment disease progression. Thus, these models, in agreement with previous data, further support the hypothesis that at least two genetic alterations are necessary for FTC to progress to aggressive and distantly metastatic disease. This work also identifies strong activation of PKA in a set of sporadic human FTC, confirming the relevance of these mouse models to human disease. Further study of these mouse models, human thyroid cancer cell lines, and human thyroid cancer samples point to PKA signaling leading to downstream acivation of mTOR, which has been proposed previously. This activation of mTOR appears to be regulated by a modification of mTOR by an unknown downstream effector of PKA, suggesting that the synergy between PI3K/Akt and PKA signaling could be explained by their convergence on activation of the mTOR pathway. The data presented here not only describe two novel mouse models of FTC which represent excellent models for pre-clinical drug testing, but also provide clues into how dysregulated PKA signaling can initiate thyroid cancer progression and interact with other oncogenic pathways to give rise to aggressive FTC. The finding that PKA and PI3K/Akt signaling can synergize and lead to overactivation of mTOR could lead to the development and testing of combination therapies against these pathways for patients with currently treatment refractory disease.
Lawrence Kirschner (Advisor)
Sissy Jhiang (Committee Member)
Krista La Perle (Committee Member)

Recommended Citations

Citations

  • Pringle, D. R. (n.d.). Mechanisms of Follicular Thyroid Cancer Development and Progression in the Context of Dysregulated PKA [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1373732842

    APA Style (7th edition)

  • Pringle, Daphne. Mechanisms of Follicular Thyroid Cancer Development and Progression in the Context of Dysregulated PKA. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1373732842.

    MLA Style (8th edition)

  • Pringle, Daphne. "Mechanisms of Follicular Thyroid Cancer Development and Progression in the Context of Dysregulated PKA." Doctoral dissertation, Ohio State University. Accessed MARCH 28, 2024. http://rave.ohiolink.edu/etdc/view?acc_num=osu1373732842

    Chicago Manual of Style (17th edition)