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Welcome to the Lala lab! We are a research laboratory within the Department of Anatomy & Cell Biology at The University of Western Ontario in London, Ontario, Canada. We are located in the newly designed research wing of the department on the fourth floor of the Medical Sciences Building Rooms 433A, B (laboratory), 430, 434, 436 (offices). In addition, we share major equipment such as imaging and confocal microscopes, and fluorescence activated cell sorter. Research in this lab deals with the biology of the human placenta as an invasive structure, the human placenta as a model for tumor progression, and biology of breast cancer progression and metastasis. These projects complement one another in concepts as well as methodology.

Principal Investigator: Dr. P. K. Lala, MD, PhD.

Dr. Lala's photo

Professor-Emeritus (active) and Past Chair
Professor, Department of Oncology
Ph.D. University of Calcutta
M.D. University of Calcutta
M.B.B.S. University of Calcutta
D.Sc. (Honoris Causa) University of Western Ontario
Office: M436 Medical Sciences Building
Phone:
519-661-3015
Fax:
519-661-3936
Email:
pklala@uwo.ca

Research Interests:

Research in our laboratory investigates cellular and molecular mechanisms at the fetal-maternal interface responsible for human placental development in health and disease, and those responsible for invasion and metastasis in breast cancer with a goal to prevent certain fetal-maternal maladies, and to develop new modes of breast cancer therapy.

Biology of the fetal-maternal interface:

The human placenta, an essential organ for fetal survival, is a highly invasive pseudo-tumor-like structure in which certain placental cells known as the extravillous trophoblast (EVT) invade the uterus and its arteries to derive adequate nutrients for the fetus. Poor EVT cell invasion of uterine arteries results in inadequate flow of maternal blood to the placenta, which in turn, can cause poor fetal growth and also a serious pregnancy-associated disorder in the mother called preeclampsia. On the other hand, uncontrolled EVT cell invasion is a feature of trophoblastic tumors. Thus EVT cell invasiveness must be exquisitely regulated in situ to maintain a healthy utero-placental homeostasis. Our research has identified many molecules produced at the fetal-maternal interface which regulate EVT cell growth, migration and invasiveness in a positive or a negative manner, as well as the signaling mechanisms responsible for such regulation. Certain molecular/genetic alterations causing trophoblast hyper-invasiveness (in trophoblastic pre-cancer or cancer) or hypo-invasiveness (e.g. in preeclampsia) have also been identified. Current research focuses on the molecular mechanisms in EVT cell differentiation from trophoblast stem cells, mechanisms underlying the actions of two uterine decidua-derived invasion-controlling molecules TGF-β and decorin, and their alterations in the pathogenesis of preeclampsia.  

Mechanisms in COX-2 mediated breast cancer progression:

Our past research on the mechanisms of cancer growth and spread had led to new protocols for treating certain human cancers such as melanomas and kidney cancers with success. Present research focuses on human breast cancer. It revolves around our discoveries that aberrant expression of Cyclo-oxygenase (COX)-2 (an enzyme responsible for high Prostaglandin E2 production) by cancer cells and host cells, promotes breast cancer progression and metastasis by multiple cellular events: (a) an inactivation of cancer-fighting immune cells, (b) a stimulation of cancer cell migration and invasiveness, (c) a stimulation of tumor-associated angiogenesis (formation of new blood vessels to feed the tumor),  (d) a stimulation lymphangiogenesis (formation of new lymphatics, that support lymphatic metastasis) and (e) induction and sustenance of “ stem-like cells (SLC)”, a minor tumor cell subset responsible for tumor perpetuation and relapse after  traditional therapies. Molecular mechanisms and signaling pathways underlying all these events are under study to identify appropriate molecular targets for breast cancer therapy; in particular, for eradicating SLCs. Prostaglandin E receptor EP4 has been identified as a novel common therapeutic target for all these events, so that EP4 antagonists have been successful in abrogating them in our preclinical breast cancer models. We have also identified certain micro-RNAs as potential SLC-linked biomarkers for breast cancer.


Selected Publications:

  1. Xu, G., Chakraborty, C. andLala, P. K. Reconstitution of Smad3 restores TGF-b response of tissue inhibitor of metalloprotease-1 upregulation in human choriocarcinoma cells. Biochem Biophys Res Commun. 300, 383-390, 2003.

  2. Liu, J., Chakraborty, C., Barbin Y.P., Dixon S.J. and Lala P.K. Non catalytic domain of uPA stimulates human extravillous trophoblast migration by utilising phospholipase C, P-I-3 kinase and MAP kinase, Exp. Cell Res. 286, 138-151, 2003.

  3. Chakraborty, C., Barbin Y.P., Dixon, S.J., Chakraborty, S., Chidiac P. and Lala, P.K. Endothelin-1 promotes migration, elevation of [Ca++]i and phosphorylation of MAP kinase in a human extravillous trophoblast cell line. Mol. Cell Endcrinol. 201, 63-73, 2003.

  4. Lala, P.K. and Chakraborty C. Factors regulating trophoblast migration and invasiveness: Possible derangements contributing to preeclampsia and fetal injury (current topic). Placenta, 24 (6) 575-587, 2003, 2003.

  5. Jadeski, L.C., Chakraborty C., and Lala, P. K. Nitric Oxide-mediated promotion of mammary tumor cell migration requires seqented activation of Nitric Oxide synthase, guanylate cyclase and MAP Kinase. Int. J. Cancer. 106, 496-504. 2003.

  6. Timoshenko, A.V., Xu, G., Chakrabarti, S., Lala, P.K., and Chakraborty, C. Role of postaglandin E2 receptors in migration of murine and human breast cancer cells. Exp Cell Res. 289(2), 265-74, 2003.

  7. Timoshenko, A. V., Lala, P. K., Chakraborty, C. PGE2-mediated up-regulation of iNOS in murine breast cancer cells through the activation of EP4 receptors. Int. J. Cancer, 108, 384-389, 2004.

  8. Munir, S, Xu, G., Wu, Y., Yang, B., Lala P.K. and Peng C. Nodal and activin receptor-like kinase (ALK) 7 inhibits proliferation and induce apoptosis in human trophoblast cells. J Biol Chem. 279 (30) 31277-31286, 2004.

  9. Nicola C., Timoshenko A.V., Dixon J., Lala P.K. and Chakraborty C. EP1 receptor-mediated migration of the first trimester human extravillous trophoblast: the role of intracellular calcium and calpain. J Clin Endocrinol Metab. 90(8), 4736-46, 2005.

  10. Zygmunt, M., McKinnon, T., Heer F., Lala, P.K. and Han, V.K.M. HCG increases trophoblast migration in vitro via the insulin-like growth factor-II/mannose-6 phosphate receptor. Mol Hum Reprod. 11(4):261-7. 2005.

  11. Timoshenko,A.V., Chakraborty C., Wagner G.F., and Lala, P.K. COX-2-mediated upregulation of the lymphangiogenic factor VEGF-C in human breast cancer. Brit. J. Cancer, 94 (8) 1154-63, 2006.

  12. Timoshenko, A.V., Rastogi,S. and Lala, P.K. Migration-promoting role of VEGF-C and VEGF-C binding receptors in human breast cancer cells. Brit. J. Cancer  97 (10), 1090-1098, 2007.

  13. Nicola, C., Chirpac,A., Lala, P.K. and Chakraborty,C  Roles of Rho guanosine  triphosphatase  A, Rho kinases and extracellular signal regulated kinases (1/2) in Prostaglandin E2-mediated migration of first trimester human extravillous trophoblast. Endocrinology. Epub 13 December, 2007, 149(3) 1243-51, 2008.

  14. Nicola, C., Lala, P.K. and Chakraborty, C. Prostaglandin(PG)E2-mediated migration of human trophoblast   requires Rac1 and Cdc42 GTPases.Biol. Reprod  78, 976-982, 2008.

  15. Ajayai, F., Congosa, N., Gaffey, T., Asman, Y.W., Watson, W., Baldi, A., Lala, P.K., Shridhar, V., Brost, B. and Chien, J. Elevated expression of serine protease HtrA1 inn preeclampsia and its role in trophoblast migration and invasion Amer J Obstet. Gynecol. 199, issue 5, 557.e1-557.e10, November 2008.

  16. Iacob D., Cai J., Tsonis M., Babwah A., Chakraborty C.,  Bhattacharjee R.N.  and Lala, P.K. Decorin-mediated inhibition of proliferation and migration of the human trophoblast via different tyrosine kinase receptors. Endocrinology 149(12) 6187-97, E pub August 14, 2008.

  17. Bhattacharjee, R.N, Timoshenko, A, Cai, J and Lala, P.K.  Relationship between Cyclo-oxygenase-2 and Human Epidermal Growth fector Receptor-2 in Vascular Endothelial Growth Factor-C upregulation and lymphangiogenesis in human breast cancer. Cancer Science, 101 (9) 2016-2032, Sept 2010 (epub .  July1, 2010.

  18. Timoshenko A.V, Kaltner H, André S, Gabius H-J and Lala P K. Differential stimulation of VEGF-C production by adhesion/growth-regulatory galectins and plant lectins in human breast cancer cells. Anticancer research, 30, 4829-4834, 2010.

  19. Khan, G.A., Gannareddy, G., Lala,  N , DiGugliemo, J and Lala, P.K.  Decorin is a novel VEGFR-2 binding antagonist for human extravillous trophoblast Molecular Endocrinology, E pub June 9, 2011; 25(8): 1431-1443.

  20. Majumder M, Tutunea-Fatan1 E, Xin X, Rodriguez-Torre M, Torres-Garcia J , Wiebe1 R,. Timoshenko AV, Bhattacharjee  RN, Chambers AF , Lala, PK  Co-expression of α9β1 integrin and VEGF-D confers lymphatic metastatic phenotype to a human breast cancer cell line MDA-MB-468LN. PLoS One  2012 7(4): e35094. doi:10.1371/journal.pone.0035094

  21. Xin X, Majumder M, Girish G, Mohindra V, Maruyama T and Lala P.K  Targeting COX-2 and EP4 to Control Tumor Growth, Angiogenesis, Lymphangiogenesis and Metastasis to the Lungs and Lymph Nodes in a Mouse Breast Cancer Model. Lab Investigation  (2012) 92, 1115–1128;doi:10.1038/labinvest.2012.90; published online 28 May 2012.

  22. Khan, G.A., Gannareddy, G., Lala,  N , DiGugliemo, J and Lala, P.K.  Decorin is a novel VEGFR-2 binding antagonist for human extravillous trophoblast Molecular Endocrinology, E pub June 9, 2011; 25(8): 1431-1443.

  23. Majumder M, Xin X and  Lala P K. A practical and sensitive method of quantitating lymphangiogenesis  in vivo. Lab Invest. 2013 May 27. doi: 10.1038/labinvest.2013.72. [Epub ahead of print]

  24. Majumder M, Xin X, Liu L, Girish GV, Lala PK. EP4 receptor as a novel target on cancer cells and macrophages to abrogate stem-like functions, lymphangiogenesis and lymphatic metastasis in a breast cancer model. Cancer Sci. 2014 Jun 30. doi: 10.1111/cas.12475. [Epub ahead of print] PMID:24981602.
 
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