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Thyroid Center Research Overview
Research in the Pediatric Thyroid Cancer Translational Research Lab is focused on determining the genetic and molecular features driving tumorigenesis in pediatric patients, with the goal of improving therapeutic options and long-term survivorship. Researchers are particularly interested in determining why pediatric thyroid tumors behave differently than those of adults, and using this information to personalize care of pediatric and young adult patients. Working in close collaboration with the Pediatric Thyroid Center team, researchers in the Pediatric Thyroid Cancer Translational Research Laboratory seek to better understand the unique challenges of pediatric patients with thyroid cancer.
Areas of Research
Many thyroid tumors are enriched with fibroblasts that deposit collagen in the tumor microenvironment. We have shown that collagen from fibroblasts can stimulate migration of tumor cells and trigger tumor cell proliferation. We hypothesize that collagen deposits within the tumor contribute to tumor growth and spread. In collaboration with biomedical engineers, we are investigating how collagen and the physical properties within the tumor microenvironment change cell behavior, gene expression and tumor progression.
Tumors are complex ecosystems comprised of many different cell types, including tumor cells, blood vessels, immune cells and other stromal cells. Working with mouse models of thyroid cancer, we have shown that different subtypes of thyroid cancer recruit different cells to the tumor microenvironment. We are now seeking to determine how these different cell types communicate within the tumor microenvironment and how this changes between adult and pediatric patients. Although many pediatric and adult thyroid cancer patients are driven by the same mutations, the tumors behave very differently based on the age of the patient. We are working with novel mouse models to explore how this crosstalk changes with aging.
Thyroid cancer is the most common endocrine malignancy and incidences are rising. Thyroid cancers of follicular cell origin stand out among solid tumors because many of the tumor-initiating genetic events are known. Activating mutations of effectors of the MAPK signaling pathway are associated with both follicular and papillary thyroid cancer, and occur throughout the spectrum of thyroid diseases from benign adenomas through therapeutically refractive poorly-differentiated disease. Despite sharing activation of the MAPK pathway, activation via different effectors in the pathway results in distinct and unique pathological outcomes, including metastasis to distinct distant sites. We do not understand how activation of a single pathway via different mutations within the signaling cascade results in different pathological outcomes and recruitment of different tumor microenvironments. This paradigm is seen not only in thyroid cancer, but in other malignancies. We utilize novel mouse models of thyroid cancer to model follicular and papillary thyroid cancers to study how activation of the oncogene Hras versus Braf affects tumor development and modifies the tumor microenvironment. We hypothesize that mode of activation contributes to stromal recruitment and extracellular matrix (ECM) modification, thus contributing to the pathobiology of tumor formation and progression. These studies will provide a better understanding of the mechanisms by which different oncogenic events that activate the same pathway predisposes the development of distinct pathological outcomes.
Franco AT, Labourier E, Adlordeppey KK, Surrey LF, Mostoufi-Moab S, Isaac A, Adzick NS, Kazahaya K, Kumar G, Bauer AJ. miRNA expression can classify pediatric thyroid lesions and increases the diagnostic yield of mutation testing. Pediatric Blood Cancer. 2020 Jun;67(6): e28276. PMID: 32196952
Jana A, Nookaew I, Singh J, Behkam B, Franco AT, Nain AS. Crosshatch nanofiber networks of tunable interfiber spacing induce plasticity in cell migration and cytoskeletal response. FASEB J. 2019 Oct;33(10):10618-10632. PMID: 31225977
Hinson AM, Massoll NA, Jolly LA, Stack BC, Bodenner D, Franco AT. Structural alterations in tumor-draining lymph nodes before papillary thyroid carcinoma metastasis. Head & Neck. 2017 Aug;39(8):1639-1646. PMID: 28467685
Jolly LA, Massoll N, Franco AT. Immune suppression mediated by myeloid and lymphoid derived immune cells in the tumor microenvironment facilitates progression of thyroid cancers criven by HrasG12V and Pten Loss. J Clin Cell Immunol. 2016 Oct;7(5):451. PMID: 27942419.
Jolly LA, Novitskiy SV, Owens P, Massoll N, Cheng N, Fang W, Moses HA, Franco AT. Fibroblast-mediated collagen remodeling within the tumor microenvironment facilitates progression of thyroid cancers driven by BrafV600E and Pten loss. Cancer Res. 2016 Apr 1;76(7):1804-13. PMID: 26818109
Franco AT, Malaguarnera R, Refetoff S, Liao X, Lundsmith E, Kimura S, Pritchard C, Marais R, Davies T, Weinstein LS, Chen M, Rosen N, Ghossein R, Knauf JA, and Fagin JA. Thyrotrophin receptor signaling-dependence of braf-induced thyroid tumor initiation in mice. Proc Natl Acad Sci USA. 2011 Jan 25;108(4):1615-20. PMID: 21220306