Advanced treatment for basal cell carcinomas

Basal cell carcinomas (BCCs) are very common epithelial cancers that depend on the Hedgehog pathway for tumor growth. Traditional therapies such as surgical excision are effective for most patients with sporadic BCC; however, better treatment options are needed for cosmetically sensitive or advanced and metastatic BCC. The first approved Hedgehog antagonist targeting the membrane receptor Smoothened, vismodegib, shows remarkable effectiveness on both syndromic and nonsyndromic BCCs. However, drug-resistant tumors frequently develop, illustrating the need for the development of next generation Hedgehog antagonists targeting pathway components downstream from Smoothened.

Atwood, S.X., Whitson, R.J., Oro, A.E. Advanced treatment for basal cell carcinomas. Cold Spring Harb Perspect Med. 4(7):a013581. Link PDF

Atwood, S.X. and Oro, A.E. "Atypical" regulation of Hedgehog-dependent cancer. Cancer Cell. 25(2):133-4. Link

Tang, Y., Gholamin, S., Schubert, S., Willardson, M.I., Lee, A., Bandopadhayay, P., Bergthold, G., Masoud, S., Nguyen, B., Vue, N., Balansay, B., Yu, F., Oh, S., Chen, S., Woo, P., Chen, S., Ponnuswami, A., Monje, M., Atwood, S.X., Whitson, R.J., Mitra, S., Cheshier, S.H., Qi, J., Beroukhim, R., Tang, J.Y., Wechsler-Reya, R., Oro, A.E., Link, B.A., Bradner, J.E., Cho, Y-J. Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition. Nat Med. 20(7):732-40. Link

Chang, A.L.S., Atzmon, G., Bergman, A., Brugmann, S., Atwood, S.X., Chang, H.Y., Barzilai, N. Identification of genes promoting skin youthfulness by genome-wide association study. J Invest Dermatol. 134(3):651-7. Link PDF

Woo, W.M., Whitson, R.J., Atwood, S.X., Oro, A.E. Spatial and temporal Hedgehog response drives hair follicle morphogenesis. Wiley. Forthcoming.


Gli activation by atypical protein kinase C iota/lambda regulates the growth of basal cell carcinomas

Growth of basal cell carcinomas (BCCs) requires high levels of hedgehog (HH) signalling through the transcription factor GLI1. Although inhibitors of membrane protein smoothened (SMO) effectively suppress HH signalling, early tumour resistance illustrates the need for additional downstream targets for therapy. Here we identify atypical protein kinase C iota/lambda (aPKC) as a novel GLI regulator in mammals. aPKC and its polarity signalling partners co-localize at the centrosome and form a complex with missing-in-metastasis (MIM), a scaffolding protein that potentiates HH signalling. Genetic or pharmacological loss of aPKC function blocks HH signalling and proliferation of BCC cells. Prkci is a HH target gene that forms a positive feedback loop with GLI and exists at increased levels in BCCs. Genome-wide transcriptional profiling shows that aPKC and SMO control the expression of similar genes in tumour cells. aPKC functions downstream of SMO to phosphorylate and activate GLI1, resulting in maximal DNA binding and transcriptional activation. Activated aPKC is upregulated in SMO-inhibitor-resistant tumours and targeting aPKC suppresses signalling and growth of resistant BCC cell lines. These results demonstrate that aPKC is critical for HH-dependent processes and implicates aPKC as a new, tumour-selective therapeutic target for the treatment of SMO-inhibitor- resistant cancers.

Atwood, S.X., Li, M., Lee, A., Tang, J.Y., Oro, A.E. Gli activation by atypical protein kinase C iota/lambda regulates the growth of basal cell carcinomas. Nature. 494(7438):484-8. Link PDF

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Woo, W.M.**, Atwood, S.X.**, Zhen, H.H., Oro, A.E. Rapid genetic analysis of epithelial-mesenchymal signaling during hair regeneration. J Vis Exp. (72):e4344. Link PDF

Atwood, S.X.**, Whitson, R.J.**, Oro, A.E. "Patch"ing up our tumor signaling knowledge. J Invest Dermatol. 133(5):1131-3. Link PDF

Chang, A.L.S., Atwood, S.X., Tartar, D.M., Oro, A.E. Surgical excision after neoadjuvant therapy with vismodegib for a locally advanced basal cell carcinoma and resistant basal cell carcinomas in Gorlin syndrome. JAMA Dermatol. 149(5):639-41. Link PDF


Hedgehog pathway inhibition and the race against tumor evolution

One of the emerging themes in cancer biology is the dependence of cancer subtypes on certain signaling pathways for continued tumor growth. For example, mutations that activate the Hedgehog (Hh) signaling pathway drive growth of a variety of cancers including basal cell carcinomas (BCCs) and medulloblastomas, along with pancreatic, prostate, and small cell lung cancer that account for up to 25% of all human cancer deaths. BCCs are the most prevalent cancer in the world, and nearly half of all US citizens are likely to develop this cancer before retirement. Twenty years of extensive research identifying Hh pathway components and their functional roles recently culminated in the newly FDA approved Hh pathway antagonist vismodegib for the treatment of locally advanced or metastatic BCCs. Although vismodegib and other Smo inhibitors appear effective, treatment-driven tumor evolution has resulted in the outgrowth of tumor cell variants resistant to the drug. This rapid tumor evolution during treatment highlights the continued need to understand how tumors circumvent pathway blockade and identify new therapeutic targets for treating Hh-dependent cancers.

Atwood, S.X., Chang, A.L.S., Oro, A.E. Hedgehog pathway inhibition and the race against tumor evolution. J Cell Biol. 199(2):193-7. Link PDF

Graybill, C., Wee, B., Atwood, S.X., Prehoda, K.E. Partitioning-defective protein 6 (Par-6) activates atypical protein kinase C (aPKC) by pseudosubstrate displacement. J Biol Chem. 287(25):21003-11. Link PDF


Bershteyn, M., Atwood, S.X., Woo, W.M., Li, M., Oro, A.E. MIM and Cortactin antagonism regulates ciliogenesis and Hedgehog signaling. Dev Cell. 19(2):270-83. Link PDF

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-- Preview by: Kozminski, K.G. & Schafer, D.A. Multiplexing MIM. Dev Cell. 19(2):189-90. Link


aPKC phosphorylates Miranda to polarize fate determinants during neuroblast asymmetric cell division

Asymmetric cell divisions generate daughter cells with distinct fates by polarizing fate determinants into separate cortical domains. Atypical protein kinase C (aPKC) is an evolutionarily conserved regulator of cell polarity. In Drosophila neuroblasts, apically restricted aPKC is required for segregation of neuronal differentiation factors such as Numb and Miranda to the basal cortical domain. Whereas Numb is polarized by direct aPKC phosphorylation, Miranda asymmetry is thought to occur via a complicated cascade of repressive interactions (aPKC –| Lgl –| myosin II –| Miranda). Here we provide biochemical, cellular, and genetic data showing that aPKC directly phosphorylates Miranda to exclude it from the cortex and that Lgl antagonizes this activity. Miranda is phosphorylated by aPKC at several sites in its cortical localization domain and phosphorylation is necessary and sufficient for cortical displacement, suggesting that the repressive-cascade model is incorrect. In investigating key results that led to this model, we found that Y-27632, a Rho kinase inhibitor used to implicate myosin II, efficiently inhibits aPKC. Lgl3A, a nonphosphorylatable Lgl variant used to implicate Lgl in this process, inhibits the formation of apical aPKC crescents in neuroblasts. Furthermore, Lgl directly inhibits aPKC kinase activity.

Atwood, S.X. & Prehoda, K.E. aPKC phosphorylates Miranda to polarize fate determinants during neuroblast asymmetric cell division. Curr Biol. 19(9):723-9. Link PDF


Atwood, S.X., Chabu, C., Penkert, R.R., Doe, C.Q., Prehoda, K.E. Cdc42 acts downstream of Bazooka to regulate neuroblast polarity through Par-6-aPKC. J Cell Sci. 120(Pt 18):3200-6. Link PDF

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