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Alka Mansukhani

Adjunct Associate Professor, Department of Microbiology

Keywords
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, cancer, microbiology, stem cell biology
Summary

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 MSCs and stem cells of the osteoblast (bone) lineage. In identifying Sox2 target genes, we 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 early factors like Sox2 to determine how self-renewal and cell fate is regulated in the osteo-adipocytic lineage.

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 stem cells (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.

Phone

212-263-5906

Academic office

550 First Avenue

New York, NY 10016

Lab Website
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Adjunct Associate Professor, Department of Microbiology

Fellowship, NYU School of Medicine, Tyrosine Kinase Receptors and Cell Transformation

Tran, Mai Hoang; Seo, Eunjeong; Min, Soohong; Nguyen, Quynh-Anh T; Choi, Juyong; Lee, Uk-Jin; Hong, Soon-Sun; Kang, Hyuk; Mansukhani, Alka; Jou, Ilo; Lee, Sang Yoon

Journal of cellular & molecular medicine. 2018 Sep; 22(9):4117-4129

Maurizi, Giulia; Verma, Narendra; Gadi, Abhilash; Mansukhani, Alka; Basilico, Claudio

Oncogene. 2018 Aug; 37(33):4626-4632

Verma, Narendra Kumar; Gadi, Abhilash; Maurizi, Giulia; Roy, Upal Basu; Mansukhani, Alka; Basilico, Claudio

Stem cells. 2017 12; 35(12):2340-2350

Liao, Sally; Ruiz, Yuleisy; Gulzar, Hira; Yelskaya, Zarina; Ait Taouit, Lyes; Houssou, Murielle; Jaikaran, Trisha; Schvarts, Yuriy; Kozlitina, Kristina; Basu-Roy, Upal; Mansukhani, Alka; Mahajan, Shahana S

PLoS one. 2017 Jun; 12(2):e0171256

Basu-Roy, Upal; Han, Eugenia; Rattanakorn, Kirk; Gadi, Abhilash; Verma, Narendra; Maurizi, Giulia; Gunaratne, Preethi H; Coarfa, Cristian; Kennedy, Oran D; Garabedian, Michael J; Basilico, Claudio; Mansukhani, Alka

Oncotarget. 2016 Sep 20; 7(38):60954-60970

Pan, Yinghong; Robertson, Gordon; Pedersen, Lykke; Lim, Emilia; Hernandez-Herrera, Anadulce; Rowat, Amy C; Patil, Sagar L; Chan, Clara K; Wen, Yunfei; Zhang, Xinna; Basu-Roy, Upal; Mansukhani, Alka; Chu, Andy; Sipahimalani, Payal; Bowlby, Reanne; Brooks, Denise; Thiessen, Nina; Coarfa, Cristian; Ma, Yussanne; Moore, Richard A; Schein, Jacquie E; Mungall, Andrew J; Liu, Jinsong; Pecot, Chad V; Sood, Anil K; Jones, Steven J M; Marra, Marco A; Gunaratne, Preethi H

Oncotarget. 2016 May 03; 7(18):25930-48

Huang, Zhifeng; Marsiglia, William M; Basu Roy, Upal; Rahimi, Nader; Ilghari, Dariush; Wang, Huiyan; Chen, Huaibin; Gai, Weiming; Blais, Steven; Neubert, Thomas A; Mansukhani, Alka; Traaseth, Nathaniel J; Li, Xiaokun; Mohammadi, Moosa

Molecular cell. 2016 Jan 07; 61(1):98-110

Basu-Roy, Upal; Bayin, N Sumru; Rattanakorn, Kirk; Han, Eugenia; Placantonakis, Dimitris G; Mansukhani, Alka; Basilico, Claudio

Nature communications. 2015 Apr 02; 6:6411