Autophagy is an intracellular recycling process that promotes proteostasis, stress adaptation and cell survival. The autophagy process provides nutrients and energy through lysosomal degradation of cytoplasmic components engulfed in double membrane-bound vesicles known as autophagosomes. Autophagy occurs at basal rates in virtually all eukaryotic cells to fulfill homeostatic functions such as the recycling of long-lived proteins and damaged organelles. In this way, autophagy acts to safeguard genome integrity and suppress tumorigenesis. Under cellular stress conditions, autophagy is upregulated as an adaptive survival response. Cancer cells may exploit elevated autophagy to survive low nutrient conditions, fuel proliferation, and escape the effects of chemotherapy and other treatments.
RFP-GFP-LC3B reporter in nutrient starved
SKBR3 breast cancer cells.
Consequently, autophagy is under investigation as a target for anticancer therapy in preclinical studies and clinical trials. However, our understanding of the mechanisms by which cells utilize the autophagy pathway to promote both normal development and cancer progression is limited.
To help elucidate these mechanisms, the overall goals of my research program are to identify and characterize regulators of autophagy, investigate the roles of autophagy during normal development and cancer progression, and evaluate the therapeutic potential of autophagy modulation for cancer treatment.
Choutka CB, DeVorkin L, Go N, Hou Y-C , Moradian A, Morin G, and Gorski SM. Hsp83 loss suppresses proteasomal activity resulting in an upregulation of caspase-dependent compensatory autophagy. Autophagy, 2017, accepted.
Bortnik S, Choutka C, Horlings HM, Leung S, Dragowska WH, Bally MB, Gelmon KA, Gorski SM. Identification of breast cancer cell subtypes sensitive to ATG4B inhibition. Oncotarget. .
Lebovitz CB, DeVorkin L, Bosc D, Rothe K, Singh J, Bally M, Jiang X, Young RN, Lum JJ, Gorski SM. Precision autophagy: Will the next wave of selective autophagy markers and specific autophagy inhibitors feed clinical pipelines? Autophagy. 2015 Oct 3;11(10):1949-52.
Lebovitz CB, Robertson G, Goya R, Jones S, Morin RD, Marra MA, Gorski SM. Cross-cancer profiling of molecular alterations within the human autophagy interaction network. Autophagy. 2015 Sep 2;11(9):1668-87.
Chittaranjan S, Xu J, Dullat HK, Wilton J, DeVorkin L, Lebovitz C, Morin GB, Marra MA, Gorski SM. The Drosophila TIPE family member Sigmar interacts with the Ste20-like kinase Misshapen and modulates JNK signaling, cytoskeletal remodeling and autophagy. Biology Open. 2015 Apr 2;4(5):672-84.
Chittaranjan S, Chan S, Yang C, Yang K, Chen V, Moradian A, Firme M, Song J, Go N, Blough M, Chan JA, Cairncross G, Gorski SM, Morin GB, Yip S, Marra MA. Mutations in CIC and IDH1 cooperatively regulate 2-hydroxyglutarate levels and cell clonogenicity. Oncotarget. 2014 Sep 15;5(17):7960-79.
DeVorkin L, Gorski SM. A mitochondrial-associated link between an effector caspase and autophagic flux. Autophagy. 2014 Oct 1;10(10):1866-1867.
Chittaranjan S, Bortnik S, Dragowska V, Xu J, Abeysundra N, Leung A, Erro Go N, DeVorkin L, Weppler S, Gelmon K, Yapp D, Bally M, Gorski SM. Autophagy inhibition augments the anticancer effects of epirubicin treatment in anthracycline-sensitive and resistant triple negative breast cancer. Clinical Cancer Research. 2014 Jun 15;20(12):3159-73.
Rothe K, Lin H, Lin KB, Leung A, Wang HM, Malekesmaeili M, Brinkman RR, Forrest DL, Gorski SM, Jiang X. Identification of the core autophagy protein ATG4B as a potential biomarker and therapeutic target in CML stem/progenitor cells. Blood. 2014 Jun 5;123(23):3622-34.
DeVorkin L, Go NE, Hou YC, Moradian A, Morin GB, Gorski SM. The Drosophila effector caspase Dcp-1 regulates mitochondrial dynamics and autophagic flux via SesB. Journal of Cell Biology. 2014 May 26;205(4):477-492.
Jardon MA, Rothe K, Bortnik S, Vezenkov L, Jiang X, Young RN, Lum JJ, Gorski SM. Autophagy: From structure to metabolism to therapeutic regulation. Autophagy. 2013 Dec;9(12):2180-2.
Dragowska WH, Weppler SA, Wang JC, Wong LY, Kapanen AI, Rawji JS, Warburton C, Qadir MA, Donohue E, Roberge M, Gorski SM, Gelmon KA, Bally MB. Induction of autophagy is an early response to gefitinib and a potential therapeutic target in breast cancer. PLoS One. 2013 Oct 11;8(10):e76503.
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013 Jul 4;499(7456):43-9.
Lebovitz CB, Bortnik SB and Gorski SM. Here there be dragons: Charting autophagy-related alterations in human tumors. Clinical Cancer Research, 2012 Mar 1;18(5): 1214-26.
Jardon MA, Sattha B, Braasch K, Leung AO, Côté HC, Butler M, Gorski SM, Piret JM. Inhibition of glutamine-dependent autophagy increases t-PA production in CHO Cell fed-batch processes. Biotechnol Bioeng. 2012 May;109(5):1228-38.
Chittaranjan S, McConechy M, Hou YC, Freeman JD, DeVorkin L and Gorski SM. Steroid hormone control of cell death and cell survival: molecular insights using RNAi. Plos Genetics. 2009, 5(2) e/000379.
Hou YC, Hannigan AM, Gorski SM. An executioner caspase regulates autophagy. Autophagy. 2009, May;5(4):530-3.
Hou YC, Chittaranjan S, Gonzalez S, McCall K and Gorski SM. Effector caspase Dcp-1 and IAP protein Bruce regulate starvation-induced autophagy during Drosophila melanogaster oogenesis. The Journal of Cell Biology. 2008, Sept. 22;182(6):1127-39.
Qadir M, Kwok B, Dragowska WH, To KH, Le D, Bally MB, and Gorski SM. Macroautophagy inhibition sensitizes tamoxifen-resistant breast cancer cells and enhances mitochondrial depolarization. Breast Cancer Research and Treatment. 2008 Dec;112(3):389-403.
DeVorkin L, Choutka C, Gorski SM. "The interplay between autophagy and apoptosis" Chapter XXIV in Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, and Infection, Volume 3. Editor E. Hayat, Elsevier Publishing. 2014.
Phan L and Gorski SM. "Tamoxifen and Autophagy: to cease and resist" Chapter III in Tamoxifen Concepts and Cancer: New Paradigms, Nova Science Publishers, Inc. 2013.
Armstrong LJ and Gorski SM. "Breast Cancer and Autophagy" Chapter II in Breast Cancer: Causes, Diagnosis and Treatment, Nova Science Publishers, Inc. 2010.
Sharon Gorski's Complete Publications List including selected links to full text articles.