Mansukhani Lab - Microbiology
Associate Professor, Department of Microbiology
Medical Science Building , Room 252, 251C
550 First Avenue, New York, NY 10016
Office: (212) 263-5906
Fax: (212) 263-8276
Lab: (212) 263-5331
stem cells, mesenchymal stem cells, fibroblast growth factors, tyrosine kinase receptors, cell lineage fate, osteosarcoma, cancer stem cells, Wnt and hippo signaling, mouse genetics, conditional knockout, bone, fat
MS in Biological Sciences at Northern Illinois University, Dekalb, IL.
NYU School of Medicine
Associate Professor, 2011
Dept Microbiology, Graduate Admissions, Sackler Graduate Program
Regulation of adult stem cell lineage fate
Tissue and organs are maintained by a small population of adult stem cells that self renew and give rise to more lineage restricted cell types. We study the early signals that determine cell fate to undergo quiescence, proliferation, or lineage differentiation. Mesenchymal stem cells (MSCs) are found in many tissues and can form the precursor cells (osteo and adipo progenitors) that give rise to bone and fat cells. Under the influence of signals such as FGFs, BMPs, and Wnts, these multipotent cells commit to become progenitors of osteoblasts, adipocytes, chondrocytes and myocytes that form bone, fat, cartilage and muscle respectively. The decision to enter the osteoblastic or adipocytic programs is reciprocally regulated.
We found that the pluripotency transcription factor, Sox2, is required for maintaining the progenitors of the osteoblast lineage. More recently we identified Sox2 target genes and have uncovered a direct connection between Sox2 and YAP, another potent growth regulator that is restrained by the Hippo pathway. Along with YAP, Sox2 influences the reciprocal commitment to the adipocyte and osteogenic fates by blocking osteogenic differentiation while favoring adipogenesis. Sox2 transcriptionally targets YAP to regulate this process. These findings point to a new role for Sox2 and YAP in determining early osteo-adipo lineage fate in MSCs.
Using a combination of genomics, in vitro and in vivo studies, we investigate the early regulatory mechanisms that govern stem cells of the osteoblast and adipocytic lineages. Our goal is to identity the network of genes and miRNAs directly regulated by Sox2 to determine how it maintains self-renewal and regulates cell fate in the osteo-adipocytic lineage.
Sox2 and YAP are regulators of the osteo-adipo lineage fate switch in MSCs. Sox2 induces YAP to maintain MSC self renewal. Sox2 and YAP inhibit osteogenesis by cooperating to block wnt signaling. With adipogenic stimuli, Sox2 promotes adipogenesis which is sensitive to the level of YAP.
Understanding the circuitry that regulate the fate switches in the osteo-adipo lineage will aid in the development of stem cell-based therapies for skeletal repair and regeneration, as well as discover new mechanisms that may have implications for adipose-linked metabolic syndrome conditions like obesity and diabetes.
Cancer stem cells
Alongside normal MSCs, we study cancer cells that arise from this lineage. Osteosarcomas are undifferentiated bone tumors that arise from MSCs or osteoprogenitor cells that no longer heed the signals to differentiate. We have found that in osteosarcomas, Sox2 and YAP are overexpressed leading to inhibition of the Wnt and hippo signaling pathways to maintain the undifferentiated and tumorigenic state. Our studies are directed at understanding the dysregulated targets that contribute to these tumors and developing novel therapeutic strategies. We are examining differentiation-based therapies for these types of cancers. Re-enabling Wnt or hippo tumor suppressive pathways in these mesenchymal-derived cancers is also a potential therapeutic strategy.
|Oil Red O positive fat cells containing lipids (adipocytes)||Alkaline phosphatase positive bone cells (osteoblasts)|
"Sox2 represses the hippo pathway leading to unrestrained YAP"
PPARγ agonists promote differentiation of cancer stem cells by restraining YAP transcriptional activity.
Basu-Roy U, Han E, Rattanakorn K, Gadi A, Verma N, Maurizi G, Gunaratne PH, Coarfa C, Kennedy OD, Garabedian MJ, Basilico C, Mansukhani A.
Oncotarget. 2016 Aug 12. doi: 10.18632/oncotarget.11273. [Epub ahead of print]
miR-509-3p is clinically significant and strongly attenuates cellular migration and multi-cellular spheroids in ovarian cancer.
Pan Y, Robertson G, Pedersen L, Lim E, Hernandez-Herrera A, Rowat AC, Patil SL, Chan CK, Wen Y, Zhang X, Basu-Roy U, Mansukhani A, Chu A, Sipahimalani P, Bowlby R, Brooks D, Thiessen N, Coarfa C, Ma Y, Moore RA, Schein JE, Mungall AJ, Liu J, Pecot CV, Sood AK, Jones SJ, Marra MA, Gunaratne PH.
Oncotarget. 2016 Mar 27. doi: 10.18632/oncotarget.8412. [Epub ahead of print]
Two FGF Receptor Kinase Molecules Act in Concert to Recruit and Transphosphorylate Phospholipase Cγ.
Huang Z, Marsiglia WM, Basu Roy U, Rahimi N, Ilghari D, Wang H, Chen H, Gai W, Blais S, Neubert TA, Mansukhani A, Traaseth NJ, Li X, Mohammadi M.
Mol Cell. 2016 Jan 7;61(1):98-110. doi: 10.1016/j.molcel.2015.11.010. Epub 2015 Dec 10. Erratum in: Mol Cell. 2016 Jan 21;61(2):324.
Sox2 antagonizes the Hippo pathway to maintain stemness in cancer cells.
Upal Basu-Roy, Sumru Bayin, Kirk Rattanakorn, Eugenia Han, Dimitris Placantonakis, Alka Mansukhani and Claudio Basilico
Nature Comm (2015) Apr 2;6:6411. doi: 10.1038/ncomms7411.
Alternatively activated macrophages derived from monocytes and tissue macrophages are phenotypically and functionally distinct
Gundra UM, Girgis NM, Ruckerl D, Jenkins S, Ward LN, Kurtz ZD, Wiens KE, Tang MS, Basu-Roy U, Mansukhani A, Allen JE, Loke P.
Blood. (2014) May 15;123(20).
SOX2 Regulates YAP1 to Maintain Stemness and Determine Cell Fate in the Osteo-Adipo Lineage
Eunjeong Seo, Upal Basu-Roy, Preethi H. Gunaratne, Cristian Coarfa, Dae-sik Lim, Claudio Basilico and Alka Mansukhani
Cell Reports, 2013 Jun 27;3(6):2075-87.
Perspectives on cancer stem cells in osteosarcoma.
Basu-Roy U, Basilico C, Mansukhani A.
Cancer Lett. 2013 Sep 10;338(1):158-67.
Molecular studies on the roles of Runx2 and Twist1 in regulating FGF signaling.
Lu Y, Li Y, Cavender AC, Wang S, Mansukhani A, D'Souza RN.
Dev Dyn. 2012 Nov;241(11):1708-15.
Distinct functions of Sox2 control self-renewal and differentiation in the osteoblast lineage.
Seo, E., Basu-Roy U, Zavadil J, Basilico C, Mansukhani A (2011)
Mol Cell Biol. Nov;31(22):4593-608. Supplementary data. PMID:21930787.
Sox2 maintains tumor initiating cells in osteosarcoma.
Basu-Roy U, Seo E, Ramanathapuram L, Rapp TB, Perry J, Orkin, S, Mansukhani A and Basilico C (2011)
Oncogene. 2012 May 3;31(18):2270-82. doi: 10.1038/onc.2011.405. Epub 2011 Sep 19.
The transcription factor Sox2 is required for osteoblast self-renewal.
Basu-Roy U, Ambrosetti, A, Favaro R, Nicolis, SK, Mansukhani A and Basilico C (2010)
Cell Death and Differentiation. Aug;17(8):1345-53. Epub 2010 May 21.
Early onset of craniosynostosis in an Apert mouse model reveals critical features of this pathology.
Holmes G, Rothschild G, Roy UB, Deng CX, Mansukhani A, Basilico C (2009)
Dev. Biol. Apr 15;328(2):273-84. Epub 2009 Jan 29.
Fibroblast growth factor signaling uses multiple mechanisms to inhibit Wnt-induced transcription in osteoblasts.
Ambrosetti D, Holmes G, Mansukhani A, Basilico C (2008)
Mol Cell Biol. Aug;28(15):4759-71.
Osteoblast proliferation or differentiation is regulated by relative strengths of opposing signaling pathways.
Raucci A; Bellosta P; Grassi R; Basilico C; Mansukhani A (2008)
Journal of Cellular Physiology. May;215(2):442-51.
Enhanced Paracrine FGF10 Expression Promotes Formation of Multifocal Prostate Adenocarcinoma and an Increase in Epithelial Androgen Receptor.
Memarzadeh S, Xin L, Mulholland DJ, Mansukhani A, Wu H, Teitell MA, Witte ON (2007)
Cancer cell. Dec; 12: 572 (#J0132178)