Dr. Peeyush Lala
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
M436 Medical Sciences Building
Visit: The Lala Lab
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.
Mechanisms at the fetal-maternal interface regulating placental development and functione:
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 (fetal growth restriction or FGR) and also a serious pregnancy-associated disorder in the mother called preeclampsia (PE). 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 underlying the actions of decorin (DCN), an invasion-inhibitory molecule, produced by a specialized cell layer of the pregnant uterus, where EVT cells invade. DCN was found to control trophoblast growth and invasion by binding to multiple tyrosine kinase receptors, in particular, type 2 VEGF receptor. DCN binding to this receptor restrains blood vessel formation by vascular endothelial cells, and invasions of the uterus by EVT cells. We also discovered that DCN overproduction by decidual cells results in a hypo-invasive placenta, and is causally associated with PE. Furthermore, elevated levels of DCN in the maternal plasma during the second trimester is a predictive biomarker of this disease before clinical signs appear. We are conducting a larger prospective study to test this biomarker in predicting PE and FGR. We are also exploring the role of DCN in trophoblast differentiation from trophoblast Stem /progenitor cells, and creating a mouse model of PE by genetically induced decorin overproduction in the decidua, that can be exploited for prevention and intervention of PE with drugs blocking DCN action.
Mechanisms in COX-2 mediated breast cancer progression:
Our past research on the mechanisms of cancer growth and spread (metastasis) identified tumor-derived Prostaglandin (PG) E2 as a culprit blocking activation of cancer fighting immune cells. This led to a new protocol of immunotherapy (1988-92) combining indomethacin (a PGE2 blocking drug) and interleukin-2 (IL2, an immune activating factor) for treating certain human cancers (such as melanomas and kidney cancer) with success. Subsequently tumor-derived Nitric Oxide (NO) was found to be another culprit, so that NO-blocking drugs also exhibited anti-cancer effects. However we found that they were less safe than PGE2 blocking drugs. Present research focuses on human breast cancer. It revolves around our discoveries that aberrant expression of Cyclooxygenase (COX)-2 (an enzyme responsible for high PGE2 production) by cancer 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) an induction and sustenance of stem-like cells which defy traditional therapies and cause recurrence. We have discovered that all of the above cancer-promoting/sustaining events result from activation of the PGE receptor type 4 (EP4) on tumor and host cells, and that selective EP4 antagonists can mitigate all these events in breast cancer-bearing mice resulting in profound antitumor and anti-metastatic effects without any toxicity. We have discovered two small RNA (micro-RNA) molecules induced by COX-2 overexpression in breast cancer were oncogenic, SLC-promoting and detectable in patients’ blood. Thus they may serve as potential biomarkers to monitor breast cancer therapy with EP4 antagonists. We further discovered that CBEB-2, a common gene target of both miRNAs is a tumor-suppressor gene in breast cancer, which when knocked-down in breast epithelial cells makes them cancerous. Thus mutational inactivation of this gene may potentially lead to breast cancer. Recently drugs blocking immune check points (PD-1 on immune cells and its ligand PD-L1 on cancer cells) have shown promising effects in certain solid tumors. On the basis of the findings that actions of EP4 antagonists utilize different mechanisms than those of immune check point inhibitors and they complement each other, we are currently planning a human trial of advanced breast cancer patients with EP4 antagonists in combination with immune check point inhibitors.
Google Scholar Citations:
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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]
- Lala N, Girish G V, Cloutier-Bosworth A and Lala P K. Mechanisms in Decorin regulation of Vascular Endothelial Growth Factor-induced Human Trophoblast Migration and Acquisition of Endothelial Phenotype. Biology of Reproduction (2012) 87(3):59, 1–14 ; before print June 13, 2012, doi: 10.1095/biolreprod.111.097881
- Majumder M, Xin X, Lala PK. 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
- Majumder M, Xin X, Liu L, Girish GV and Lala PK. Prostaglandin E2 receptor EP4 as the common target on cancer cells and macrophages to abolish angiogenesis, lymphangiogenesis, metastasis, and stem-like cell functions. Cancer Science 105 (2014) 1142–1151.
- Tutunea-Fatan Elena, Majumder, Mousumi Xin, Xiping and Lala Peeyush K, The Role of CCL21/CCR7 Chemokine Axis in Breast Cancer Induced Lymphangiogenesis. Molecular Cancer (2015) 14:35 DO10.1186/s12943-015-0306-4.
- Majumder M, Landman E, Liu L, Hess D and Lala P.K. COX2 Elevates Oncogenic miR526bin Breast Cancer by EP4 Activation. Molecular Cancer Research (2015) 13(6) 1022-1033, Published Online March 2, 2015; doi: 10.1158/1541-7786.MCR-14-0543
- Lala, P.K. and Nandi, P. (2016) Mechanisms of trophoblast migration, endometrial angiogenesis in preeclampsia: the role of decorin. (Invited and commissioned review).Cell adhesion & migration, Vol. 10, nos. 1–2, 1–15. 2015, Published on line; http://dx.doi.org/10.1080/19336918.2015.1106669
- Nandi P, Siddiqui MF and Lala PK (2015) Restraint of trophoblast invasion of the uterus by decorin : role in preeclampsia. American J. Reprod. Immunol. 2016 Mar; 75(3):351-60, doi:10.1111/aji.12449, 2015.
- Siddiqui MF. Nandi P, Girish GV, Nygard K, Eastabrook G, de Vrijer B, Han VKM, Lala PK, (2016) Decorin over-expression by decidual cells in preeclampsia: a potential blood biomarker. American J Obstet Gynecol. 2016 Sep;215 (3):361.e1-361.e15. doi: 10.1016/j.ajog.2016.03.020. Epub 2016 Mar 19. PMID: 27001218
- Majumder M, Xin X, Liu L, Tutunea-Fatan E, Rodriguez-Torres M, Vincent K, Postovit L-M, Hess D, and Lala PK, COX-2 Induces Breast Cancer Stem Cells via EP4/PI3K/AKT/NOTCH/WNT Axis. Stem cells. 34:2290–2305(2016)
- Nandi P, Girish GV, Majumder M, Xin X, Tutunea-Fatan E and Lala, PK.PGE2 promotes breast cancer-associated lymphangiogenesis by activation of EP4 receptor on lymphatic endothelial cells.(2017) BMC Cancer, 017 Jan 5;17(1):11. doi: 10.1186/s12885-016-3018-2.PMID: 28056899