Dr. Subhamoy Dasgupta joined the faculty of Cell Stress Biology at the Roswell Park Comprehensive Cancer Center in July 2017 as an Assistant Member and Assistant Professor of Oncology. Subho earned his BS in Chemistry and Microbiology from Bangalore University, a MS in Biochemistry from Banaras Hindu University, India and a PhD in Biomedical Sciences from UNT Health Science Center at Fort Worth, Texas. As a graduate student he characterized the functional role of a novel oncogene named C17orf37/MIEN1 in prostate and breast cancer invasion-metastasis (Oncogene, 2009) under the mentorship of Dr. JK Vishwanatha. His doctoral thesis revealed how isoprenylation of MIEN1 protein can regulate its translocation to the plasma membrane and activate signaling events leading to increased invasive phenotype (JBC, 2011; Mol Can, 2015).
Dr. Dasgupta performed postdoctoral fellowship in the laboratory of Dr. Bert W. O'Malley at Baylor College of Medicine at Houston, where he demonstrated that transcriptional coregulator steroid receptor coactivator 2 (SRC-2/NCOA2) regulates metabolic reprogramming to accentuate prostate cancer metastasis (JCI, 2015). As a Susan G. Komen Postdoctoral fellow, he uncovered a novel interplay between a glycolytic enzyme and oncogenic coactivator SRC-3/AIB1 leading to increased proliferation and metastasis of breast tumors.
His laboratory is interested in understanding the role of metabolic adaptations in breast and prostate cancer progression, and elucidating mechanisms that promote therapy resistant aggressive metastatic disease. Dr. Dasgupta’s laboratory is funded by grants from National Cancer Institute (NCI) and Department of Defense (DoD).
Metabolic reprogramming is an essential hallmark of tumor progression and metastasis. Cancer cells use altered metabolic pathways to sustain rapid growth and to overcome enormous stress encountered in tumor microenvironment. Tumor cells constantly alter their metabolic state in response to oncogenic stimuli, nutrient availability, and interaction with immune cells however the precise regulation that precedes the metabolic alteration is poorly understood. We believe information about a tumor cell's metabolic state is integrated into the regulation of transcription, and understanding these regulatory checkpoints will certainly allow us to intervene tumor progression and metastasis. Our lab uses state-of-art facilities such as metabolomics, proteomics, and genomics along with molecular biology techniques to investigate the crosstalk between metabolic signaling and transcriptional networks. Multiple animal model systems including genetically engineered mouse models (GEMMs), patient-derived xenograft (PDX), and syngeneic tumor models are used to investigate metabolic adaptations that promote tumor progression and metastasis. Current ongoing projects funded by National Cancer Institute (NCI) and Department of Defense (DoD) are as follows:
Metabolic adaptations driving castration resistant prostate cancer
Prostate cancer is the second most common epithelial cancer and one of the leading causes of cancer related death for men. Patients with organ-confined prostate cancer are treated with androgen deprivation therapy (ADT); however, once the tumor cells disseminate from the primary site an aggressive metastatic prostate cancer termed as castration-resistant prostate cancer (CRPC) develops, which is resistant to ADT (lethal variant). Unlike other solid tumors, prostate tumors predominantly do not exhibit the classical ‘glycolytic switch’ or the ‘Warburg effect’, and instead these tumors demonstrate an aberrant increase in de novo lipogenesis. Recent study from our laboratory identified ‘glutamine metabolism’ is significantly enhanced in metastatic tumors facilitating aberrant increase in de novo lipogenesis. Currently, we are investigating the tumor intrinsic mechanisms that support increased ‘glutaminolysis’ in CRPC by understanding the role of mitochondrial enzymes in the process.
Oncogenic drivers of bone metastatic prostate cancer
About 80% of patients with advanced-stage prostate cancer exhibit bone metastases. This leads to skeletal complications such as ineffective haematopoiesis, pain, skeletal related events (SREs) and eventual death. There is a great need to prevent SREs since these events are associated with decreased quality of life, increased pain and worsened survival, and currently available therapies are ineffective. To discover new drugs to effectively cure bone metastasis, there is an urgent need to identify and validate novel targets. We have found that androgen receptor (AR) binding partner named steroid receptor coactivator-2 (SRC-2/NCOA2) plays a key role in the survival of metastatic CRPC promoting successful distant organ metastasis. Using a bone-metastatic mouse model we are now investigating the importance of this pathway and defining the molecular players that are essential for prostate-to-bone metastasis.
Mechanisms of breast tumor recurrence and metastasis
Breast cancer is the second most common cancer in women but recent advancements have significantly improved overall percent survival five years after diagnosis. However, in many women cancer returns, sometimes even after a decade often as aggressive variant resistant to conventional therapies. This tumor recurrence often shows up in different sites such bones, lung, liver, or brain and primarily responsible for breast cancer related deaths. So there is an urgent need to understand the mechanisms of breast tumor recurrence and metastasis so that new therapeutic targets can be identified. From an un-biased genetic screen we uncovered a novel interplay between the glycolytic enzyme and a transcriptional coregulator regulating expression of anabolic genes involved in DNA synthesis. Current studies in the laboratory are exploring in detail the functional role of this pathway in therapy resistant tumors, mechanisms pertaining to their activation in metastatic tumors, role in immune suppression, and selective pharmacological interventions that may be effective to overcome resistance to conventional therapies.
- Dasgupta S, Putluri N, Long W, Kaushik AK, Zhang B, Bhowmik SK, Wang J, Stashi E, Brennan CA, Ittmann MM, Mitsiades N, Chinnaiyan AM, Sreekumar A, O’Malley BW. Coactivator SRC-2-dependent metabolic reprogramming mediates prostate cancer survival and metastasis. Journal of Clinical Investigation. 2015 Mar 2;125(3):1174-88. PMID:25664849 PMCID: PMC4362260. [Featured Publication and Highlighted as Scientific Showstopper: http://www.jci.org/posts/259]
- Zhu B, Stashi E, Gates LA, Dasgupta S, Gonzales N, Dean A, York B and O’Malley BW. Coactivator-Dependent Oscillation of Chromatin Accessibility Dictates Circadian Gene Amplitude through REV-ERB Loading. Molecular Cell. 2015 Dec 3;60(5):769-83. PMID:26611104 PMCID:PMC4671835
- Dasgupta S, Lonard DM, and O’Malley BW. Nuclear Receptor Coactivators: Master Regulators of Human Health and Disease. Annual Reviews of Medicine.2014;65:279-92. PMID: 24111892 PMCID: PMC4327818
- Dasgupta S, Cushman I, Kpetemey M, Casey PJ, and Vishwanatha JK. (2011) Prenylated C17ORF37 induces filopodia formation to promote cell migration and metastasis. Journal of Biological Chemistry 22;286(29):25935-46. PMID:21628459
- Dasgupta S, Wasson LM, Rauniyar N, Prokai L, Borejdo J, and Vishwanatha JK. (2009). Novel gene C17orf37 in 17q12 amplicon promotes migration and invasion of prostate cancer cells. Oncogene 28:2860-2872. PMID: 19503095 PMCID: PMC2726905