CRTC1/MAML2 directs a PGC-1α-IGF-1 circuit that confers vulnerability to PPARγ inhibition

• Published in: Cell reports (Cambridge) Vol. 34; no. 8; p. 108768
• Main Authors: Musicant, Adele M., Parag-Sharma, Kshitij, Gong, Weida, Sengupta, Monideepa, Chatterjee, Arindam, Henry, Erin C., Tsai, Yi-Hsuan, Hayward, Michele C., Sheth, Siddharth, Betancourt, Renee, Hackman, Trevor G., Padilla, Ricardo J., Parker, Joel S., Giudice, Jimena, Flaveny, Colin A., Hayes, David N., Amelio, Antonio L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.02.2021; Elsevier
• Subjects: Animals; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Autocrine Communication; cancer; Carcinoma, Mucoepidermoid - drug therapy; Carcinoma, Mucoepidermoid - genetics; Carcinoma, Mucoepidermoid - metabolism; Carcinoma, Mucoepidermoid - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; chromosomal translocation; CRTC1-MAML2; Female; Gene Expression Regulation, Neoplastic; Gene Fusion; Humans; IGF-1 inhibitor; Insulin-Like Growth Factor I - genetics; Insulin-Like Growth Factor I - metabolism; Male; Mice; Mice, Nude; Middle Aged; Molecular Targeted Therapy; oncogene; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - genetics; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; PPAR gamma - antagonists & inhibitors; PPAR gamma - genetics; PPAR gamma - metabolism; PPARGC1A, IGF-1; Protein Isoforms; Receptor, IGF Type 1 - antagonists & inhibitors; Receptor, IGF Type 1 - metabolism; Salivary Gland Neoplasms - drug therapy; Salivary Gland Neoplasms - genetics; Salivary Gland Neoplasms - metabolism; Salivary Gland Neoplasms - pathology; Signal Transduction; Trans-Activators - genetics; Trans-Activators - metabolism; Transcription Factors - genetics; Transcription Factors - metabolism; transcriptional co-activator; Tumor Burden - drug effects; Xenograft Model Antitumor Assays; PPARGC1A, IGF-1; IGF-1 inhibitor; gene fusion; cancer; oncogene; transcriptional co-activator; CRTC1-MAML2; chromosomal translocation
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.108768

Mucoepidermoid carcinoma (MEC) is a life-threatening salivary gland cancer that is driven primarily by a transcriptional coactivator fusion composed of cyclic AMP-regulated transcriptional coactivator 1 (CRTC1) and mastermind-like 2 (MAML2). The mechanisms by which the chimeric CRTC1/MAML2 (C1/M2) oncoprotein rewires gene expression programs that promote tumorigenesis remain poorly understood. Here, we show that C1/M2 induces transcriptional activation of the non-canonical peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) splice variant PGC-1α4, which regulates peroxisome proliferator-activated receptor gamma (PPARγ)-mediated insulin-like growth factor 1 (IGF-1) expression. This mitogenic transcriptional circuitry is consistent across cell lines and primary tumors. C1/M2-positive tumors exhibit IGF-1 pathway activation, and small-molecule drug screens reveal that tumor cells harboring the fusion gene are selectively sensitive to IGF-1 receptor (IGF-1R) inhibition. Furthermore, this dependence on autocrine regulation of IGF-1 transcription renders MEC cells susceptible to PPARγ inhibition with inverse agonists. These results yield insights into the aberrant coregulatory functions of C1/M2 and identify a specific vulnerability that can be exploited for precision therapy. [Display omitted] •CRTC1-MAML2-fusion-positive salivary mucoepidermoid carcinomas (MECs) express IGF-1•CRTC1-MAML2 coordinates IGF-1 expression via aberrant PGC-1α4 splice variant expression•PGC-1α4 regulates IGF-1 in a PPARγ-dependent manner in CRTC1-MAML2-positive MECs•IGF-1R and PPARγ inhibitors reduce growth and survival of CRTC1-MAML2-positive MECs Musicant et al. demonstrate that the CRTC1-MAML2 gene fusion aberrantly regulates expression of the minor splice variant PGC-1α4, which in turn coactivates PPARγ to induce IGF-1 expression. This synthetic signal circuit establishes pro-growth and pro-survival signaling in mucoepidermoid carcinomas, sensitizing tumors to drugs that disable IGF-1 signaling by targeting PPARγ.