Tissue specificity of oncogenic BRAF targeted to lung and thyroid through a shared lineage factor

Schoultz, Elin; Liang, Shawn; Carlsson, Therese; Filges, Stefan; Ståhlberg, Anders; Fagman, Henrik; Wiel, Clotilde; Sayin, Volkan I.; Nilsson, Mikael

doi:10.1016/j.isci.2023.107071

Cited by 2 publications

(2 citation statements)

References 52 publications

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“…As for PTCs, in our model, the expression of thyroid transcription factors Pax8 and Nkx2-1 was also globally maintained. However, a partial decrease of Nkx2.1 levels was observed at 7 days, which corroborates recent findings suggesting that thyroid cells transiently downregulated NKX2.1 in early tumor stages 60 . Conversely, Galectin 3 (Lgals3) expression, which has been suggested as a marker for thyroid malignancies and, more specifically, for PTC 61 , was significantly increased at 48 h and 7 days of 4OHT treatment (Fig.…”

Section: Resultssupporting

confidence: 91%

Dual targeting of MAPK and PI3K pathways unlocks redifferentiation ofBraf-mutated thyroid cancer organoids

Lasolle

Schiavo

Tourneur

et al. 2023

Preprint

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Thyroid cancer is the most common endocrine malignancy and several genetic events have been described to promote the development of thyroid carcinogenesis. Besides the effects of specific mutations on thyroid cancer development, the molecular mechanisms controlling tumorigenesis, tumor behavior, and drug resistance are still largely unknown. Cancer organoids have been proposed as a powerful tool to study aspects related to tumor development and progression and appear promising to test individual response to therapies. Here, using mESC-derived thyroid organoids, we developed a BrafV637E-inducible model able of recapitulating the features of papillary thyroid cancer in vitro. Overexpression of BrafV637E rapidly leads to MAPK activation, cell dedifferentiation, and disruption of follicular organization. BrafV637E-expressing organoids show a transcriptomic signature for p53, focal adhesion, ECM-receptor interactions, EMT, and inflammatory signaling pathways. Finally, PTC-like thyroid organoids were used for drug screening assays. The combination of MAPK and PI3K inhibitors reversed Braf oncogene-promoted cell dedifferentiation while restoring thyroid follicle organization and function in vitro. Our results demonstrate that pluripotent stem cells-derived thyroid cancer organoids can mimic tumor development and features while providing an efficient tool for testing novel targeted therapies.

show abstract

Section: Resultssupporting

confidence: 91%

Dual targeting of MAPK and PI3K pathways unlocks redifferentiation ofBraf-mutated thyroid cancer organoids

Lasolle

Schiavo

Tourneur

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…As for PTCs, in our model, the expression of thyroid transcription factors Pax8 and Nkx2-1 was also globally maintained. However, a partial decrease of Nkx2.1 levels was observed at 7 days, which corroborates recent findings suggesting that thyroid cells transiently downregulated NKX2.1 in early tumor stages [ 59 ]. Conversely, Galectin 3 (Lgals3) expression, which has been suggested as a marker for thyroid malignancies and, more specifically, for PTC [ 60 ], was significantly increased at 48 h and 7 days of 4OHT treatment (Fig.…”

Section: Resultssupporting

confidence: 91%

Dual targeting of MAPK and PI3K pathways unlocks redifferentiation of Braf-mutated thyroid cancer organoids

Lasolle,

Schiavo,

Tourneur

et al. 2023

Oncogene

View full text Add to dashboard Cite

Thyroid cancer is the most common endocrine malignancy and several genetic events have been described to promote the development of thyroid carcinogenesis. Besides the effects of specific mutations on thyroid cancer development, the molecular mechanisms controlling tumorigenesis, tumor behavior, and drug resistance are still largely unknown. Cancer organoids have been proposed as a powerful tool to study aspects related to tumor development and progression and appear promising to test individual responses to therapies. Here, using mESC-derived thyroid organoids, we developed a BrafV637E-inducible model able to recapitulate the features of papillary thyroid cancer in vitro. Overexpression of the murine BrafV637E mutation, equivalent to BrafV600E in humans, rapidly triggers to MAPK activation, cell dedifferentiation, and disruption of follicular organization. BrafV637E-expressing organoids show a transcriptomic signature for p53, focal adhesion, ECM-receptor interactions, EMT, and inflammatory signaling pathways. Finally, PTC-like thyroid organoids were used for drug screening assays. The combination of MAPK and PI3K inhibitors reversed BrafV637E oncogene-promoted cell dedifferentiation while restoring thyroid follicle organization and function in vitro. Our results demonstrate that pluripotent stem cells-derived thyroid cancer organoids can mimic tumor development and features while providing an efficient tool for testing novel targeted therapies.

show abstract

Tissue specificity of oncogenic BRAF targeted to lung and thyroid through a shared lineage factor

Cited by 2 publications

References 52 publications

Dual targeting of MAPK and PI3K pathways unlocks redifferentiation ofBraf-mutated thyroid cancer organoids

Dual targeting of MAPK and PI3K pathways unlocks redifferentiation ofBraf-mutated thyroid cancer organoids

Dual targeting of MAPK and PI3K pathways unlocks redifferentiation of Braf-mutated thyroid cancer organoids

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