Chromosome 3q26 Gain Is an Early Event Driving Coordinated Overexpression of the PRKCI, SOX2, and ECT2 Oncogenes in Lung Squamous Cell Carcinoma

Abstract

Highlights d 3q26 CNG and TP53 mutation associate with progression of carcinoma in situ to LSCC d PRKCI, SOX2, and ECT2 overexpression transforms Trp53 À/À mouse lung basal stem cells d Active PKCi-SOX2 and PKCi-ECT2 signaling is required for LBSC transformation d A PKCi-SOX2 molecular signature suggests unique therapeutic vulnerabilities in LSCC

Protein kinase Cι promotes UBF1–ECT2 binding on ribosomal DNA to drive rRNA synthesis and transformed growth of non-small-cell lung cancer cells

“…Our published studies have demonstrated that PKC phosphorylates other targets within the nucleus to promote the transformed phenotype of cancer cells. Specifically, PKC phosphorylates the oncogenic transcription factors SOX2 and ELF3 in LSCC and LADC cells, respectively, leading to activation of transcriptional activity (52)(53)(54)(55). Indeed, our recent study demonstrated that PKC-mediated SOX2 phosphorylation is required for expression of a SOX2 transcriptional program that drives lineage-restricted transformation of lung basal stem cells, a major cell of origin, into LSCC (55).…”

Oxidative Stress and the Intersection of Oncogenic Signaling and Metabolism in Squamous Cell Carcinomas

“…Targeted gene-sequencing analysis of both physiologically normal skin and normal esophageal epithelium revealed strong positive selection for canonical SCC driver mutations such as NOTCH1 , which exhibits mutation prevalence as high as 20% and 12 to 80% in normal skin and esophagus, respectively [ 119 , 120 ]. Furthermore, copy number gains (CNGs) critically linked with SCC development such as the amplification of chromosome 3q, which contains PIK3CA , TP63 , and SOX2 , were detected within normal esophageal tissue, and 3q26 CNG was recently reported to be an early event in LSCC development cooperating with mutant p53 to drive progression [ 121 ]. Ultimately, the mutational landscape of normal tissue demonstrates not only clonal expansion in the context of normal cells harboring mutations conferring a selective advantage but also more nuance and complexity in factors contributing to cancer initiation and intratumoral heterogeneity.…”

Mapping lung squamous cell carcinoma pathogenesis through in vitro and in vivo models

“…Inactivation of Trp53 (the mouse orthologue of TP53) in bulk mouse tracheal epithelial cells has been shown to enhance organoid formation efficiency 31 . When 3D cultures were initiated with purified basal cells, p53 deficiency increased both organoid number and size and enabled longer-term passaging, indicative of aberrant stem/progenitor cell self-renewal 32 . Depletion of Kelchlike ECH associated protein (KEAP1), a negative regulator of the oxidative stress response, also augmented organoid forming capacity of tracheal epithelial cells 31 .…”

“…Using lentiviral vectors to model amplification of different genes located within the 3q26 chromosomal region, it has been shown that SOX2, ECT2 and PRKCI exert cooperative interactions to induce neoplastic transformation of Trp53-depleted murine basal cells 32 . In organoid cultures, SOX2, ECT2, and PRKCI were found to each have a dominant role in the control of basal cell self-renewal, cell proliferation and epithelial polarity, respectively.…”

“…Simultaneous overexpression of the three genes in p53-deficient basal cells led to increased number and size of organoids and acquisition of disorganised solid morphology. When grafted into mice, these cells gave rise to tumours with features of LUSC 32 . As both SOX2 and ECT2 are phosphorylation targets of PRKCI 33,34 , phosphorylation-resistant mutant forms of each gene were used in organoid cultures to demonstrate that the effects of PRKCI on airway epithelial cell polarity and proliferation are mediated by SOX2 and ECT2, respectively 32 .…”