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Biology subjects

Doan, L. T.

Publications and source records attributed to Doan, L. T..

2 recordsLinked to original sources
bioRxiv2020

MTOR promotes basal cell carcinoma growth through atypical PKC

Advanced basal cell carcinomas (BCCs) are driven by the Hedgehog (HH) pathway and often possess inherent resistance to SMO inhibitors. Identifying and targeting pathways that bypass SMO could provide alternative treatments. Here, we use a combination of RNA-sequencing analysis of advanced BCC tumor-normal pairs and immunostaining of human and mouse BCC samples to identify an MTOR signature in BCC. Pharmacological inhibition of MTOR activity in BCC cells significantly reduces cell proliferation without affecting HH signaling. Similarly, treatment of Ptch1fl/fl; Gli1-CreERT2 mice with everolimus reduces tumor growth and aPKC activity, suggesting that MTOR promotes tumor growth by activating aPKC and demonstrating that suppressing MTOR could be a promising target for BCC patients.

cancer biology↗
bioRxiv2020

aPKC drives cilia-independent Hedgehog signaling to maintain basal cell carcinoma growth

Primary cilia loss is a common feature of advanced cancers. While primary cilia are necessary to initiate Hedgehog (HH)-driven cancers, how HH pathway activity is maintained in advanced cancers devoid of primary cilia is unclear. Here, we find that HH-driven basal cell carcinoma (BCC) accumulates mutations in Alstrom and Usher syndrome genes. Loss of Alstrom and Usher syndrome gene expression, which are common underlying causes of deafness and blindness, suppresses primary ciliogenesis and HH signaling but enhances expression of atypical protein kinase C iota/lambda (aPKC), a GLI1 kinase necessary for advanced BCC growth. We show that aPKC expression is inversely correlated with primary ciliogenesis and that superficial BCCs display less primary cilia and higher aPKC expression, with the opposite trend in nodular BCC subtypes. Surprisingly, a constitutively active isoform of aPKC but not full-length protein drives HH pathway activity. Overexpression of the constitutively active aPKC variant can maintain HH pathway activity and tumor growth in the absence of primary cilia. Our results suggest tumors enhance isoform-specific expression of aPKC to prevent mutation-induced cessation of tumor growth.

cancer biology↗