We are an interdisciplinary group of basic scientists and clinical researchers with intersecting interests in model systems of cancer, and basic and translational cancer research with a focus on oral, head and neck tumors. The goal of our group is to define the molecular basis for how adaptive response mechanisms are exploited by cancers to drive disease progression. These adaptive signaling networks directly influence tumor development and progression by enabling cancer cells to cope with both tumor cell-intrinsic and cell-extrinsic insults and develop acquired resistance to therapeutic interventions. This is due in part to dynamic transcriptional rewiring induced by oncogenes in response to cues that promote cell survival and malignant transformation. To achieve these ambitious goals, we have focused on the development of preclinical models and technologies to detect, measure, and manipulate cell signaling pathways both in vitro at the cellular level, and in vivo at the organismal level. We apply an interdisciplinary approach that integrates a combination of bioinformatics, genetically engineered cell line and animal models, pharmacologic and molecular genetic analyses, and synthetic biology approaches to investigate how spatial and temporal control of cell signaling impacts the expression of adaptive response genes involved in various aspects of tumor development and progression. By working at the interface of oral oncology, chemical and molecular biology, and targeted therapeutics, we hope to bring ‘unconventional’, yet efficacious treatments for these cancers into the clinic.
- Head and Neck Cancer Biology
Head and neck squamous cell carcinomas (HNSCCs) are the 6th most common cancer worldwide with an estimated 65,000 new cases in the United States alone annually. Unfortunately, patients afflicted with HNSCCs still face high mortality rates in spite of decades of research due in part to acquired resistance to therapeutic interventions. Such adaptations to therapy are linked to dynamic transcriptional ‘re-wiring’ induced by oncogenes in response to signaling cues that promote cell survival and malignant transformation. The CRTCs are cell signaling integrators that regulate adaptive response genes via association with CREB and evidence for an oncogenic role of deregulated CRTC function is supported by its involvement in a t(11;19) chromosomal translocation that constitutes the key driver genetic alteration in over 50% of salivary mucoepidermoid carcinomas. Risk factors for other HNSCCs include: (1) tobacco and alcohol use and (2) infection with Human Papilloma Virus (HPV), but the role that CRTCs may play in these other oral, head and neck cancers remains poorly defined. Thus, a major focus in my lab is directed towards generation, validation, and implementation of novel pre-clinical models for investigating the functional contribution of CRTCs to the pathobiology of these cancers.
Sato K, Parag-Sharma K, Terajima M, Musicant AM, Murphy RM, Ramsey MR, Hibi H, Yamauchi M, Amelio AL. Lysyl hydroxylase 2-induced collagen cross-link switching promotes metastasis in head and neck squamous cell carcinomas. Neoplasia. 2021;23(6):594-606. doi:10.1016/j.neo.2021.05.014.
Musicant AM, Parag-Sharma K, Gong W, Sengupta M, Chatterjee A, Henry EC, Tsai YH, Hayward MC, Sheth S, Betancourt R, Hackman TG, Padilla RJ, Parker JS, Giudice J, Flaveny CA, Hayes DN, Amelio AL. CRTC1/MAML2 directs a PGC-1α-IGF-1 circuit that confers vulnerability to PPARγ inhibition. Cell Reports. 2021 Feb 23;34(8):108768. doi: 10.1016/j.celrep.2021.108768. PMID: 33626346; PMCID: PMC7955229.
Carper, M. B., Troutman, S., Wagner, B. L., Byrd, K. M., Selitsky, S. R., Parag-Sharma, K., Henry, E. C., Li, W., Parker, J. S., Montgomery, S. A., Cleveland, J. L., Williams, S. E., Kissil, J. L., Hayes, D. N., Amelio, A. L. (2019). An Immunocompetent Mouse Model of HPV16(+) Head and Neck Squamous Cell Carcinoma. Cell Reports. 2019 Nov 5;29(6):1660-1674.e7. doi: 10.1016/j.celrep.2019.10.005. PMID: 31693903
- Biologic Light Tools For Probing Biology
Tumorigenesis is a complex, multi-factorial process that involves dynamic regulation of cell-cell interactions and deregulation of tumor cell-intrinsic as well as tumor-cell extrinsic signaling and gene expression. However, the mechanisms governing these processes in vivo are unclear. The number of cell types involved, the timing and location of their interactions, the molecular cues exchanged, and the long-term fates of the cells remain poorly characterized in most cases. Thus, part of my lab is directed at designing and engineering custom bioluminescence resonance energy transfer (BRET)-based tools (“LumiFluors”) to visualize various aspects of tumorigenesis in real time and within physiologically relevant contexts. These tools are being deployed to develop tractable models of cancer that enable early detection to gather longitudinal information on targets within adaptive response pathways that may serve as useful biomarkers or therapeutic targets. Moreover, the enhanced light output and spectral tuning afforded by these BRET-based biologic light tools in being evaluated for its utility in regulating photosensitive proteins and small molecules.
Parag-Sharma K, O'Banion CP, Henry EC, Musicant AM, Cleveland JL, Lawrence DS, Amelio AL. Engineered BRET-Based Biologic Light Sources Enable Spatio-Temporal Control Over Diverse Optogenetic Systems. ACS Synth Biol. 2020 Jan 17;9(1):1-9. doi: 10.1021/acssynbio.9b00277. Epub 2019 Dec 17. PMID: 31834783
Wang L, Lee DJ, Han H, Zhao L, Tsukamoto H, Kim YI, Musicant AM, Parag-Sharma K, Hu X, Tseng HC, Chi JT, Wang Z, Amelio AL, Ko CC. Application of bioluminescence resonance energy transfer-based cell tracking approach in bone tissue engineering. J Tissue Eng. 2021 Feb 16;12:2041731421995465. doi: 10.1177/2041731421995465. PMID: 33643604; PMCID: PMC7894599.
Tang Y, Parag-Sharma K, Amelio AL, Cao Y. A Bioluminescence Resonance Energy Transfer-Based Approach for Determining Antibody-Receptor Occupancy In Vivo. iScience. 2019;15:439-51. doi: 10.1016/j.isci.2019.05.003. PubMed PMID: 31121469.
- Adaptive Cellular Response Mechanisms
Cells experience a constant barrage of signals that must be interpreted and integrated. Multicellular organisms have further evolved an elaborate network of intracellular signal transduction cascades to process and transduce these inputs into diverse outputs affecting gene expression, cell proliferation, differentiation, and apoptosis. To a large extent, these adaptive response-signaling networks are sequentially activated to maintain homeostasis and prepare cells to respond to subsequent signaling and/or new stimuli. These adaptations are crucial for cells and tissues to dynamically endure unexpected and changing environmental pressures. However, this biological phenomenon creates an unfortunate liability since oncogenic mutations that arise in cancer cells evolve to co-opt these adaptive regulatory networks. One such network involves the master transcription factor CREB which is centrally located downstream of key developmental and growth signaling pathways and is therefore capable of influencing a broad spectrum of cellular activities in both normal and cancer cells, such as cell survival, growth and differentiation. But this regulation also depends heavily on a recently discovered family of transcriptional co-regulatory molecules, the cAMP Regulated Transcription Coactivators (CRTCs). Thus, we are investigating how controlling CRTC subcellular localization impacts adaptive response genes that regulate tumorigenesis. Understanding the molecular basis for CRTCs in these processes could offer opportunities to develop novel clinically actionable therapeutic approaches for many cancers.
Tasoulas, J., L. Rodón, F.J. Kaye, M. Montminy, and A.L. Amelio, Adaptive Transcriptional Responses by CRTC Coactivators in Cancer. Trends Cancer. 2019. p. 111-127. PubMed PMID: 30755304.
Amelio AL, Caputi M, Conkright MD. Bipartite functions of the CREB co-activators selectively direct alternative splicing or transcriptional activation. EMBO J. 2009;28(18):2733-47. doi: 10.1038/emboj.2009.216. PubMed PMID: 19644446; PMCID: PMC2750025.
Amelio AL, Miraglia LJ, Conkright JJ, Mercer BA, Batalov S, Cavett V, Orth AP, Busby J, Hogenesch JB, Conkright MD. A coactivator trap identifies NONO (p54nrb) as a component of the cAMP-signaling pathway. Proc Natl Acad Sci U SA. 2007;104(51):20314-9. doi: 10.1073/pnas.0707999105.