Dr. Peeyush Lala
Professor-Emeritus (Active)
Ph.D. University of Calcutta
M.D. University of Calcutta
M.B.B.S. University of Calcutta
Office:M436 Medical Sciences Building
Phone: 519-661-3015
Fax: 519-661-3936
Email: pklala@uwo.ca
Visit: The Lala Lab
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.
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.
Publications:
For more publications, please visit Dr. Lala's Google Scholar page.
