Professor Emeritus, Anatomy and Cell Biology
Dr. Peeyush Lala is a Professor Emeritus in the Department of Anatomy and Cell Biology whose research mainly focuses on the cellular origins of common diseases and disorders that affect the placenta, such as preeclampsia, as well as breast cancer.
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.
Lawson Health Research Institute Profile
Dr Lala has published over 206 peer-reviewed articles and 360 conference abstracts. . He served on the editorial board of numerous reputed Biomedical journals such as the Experimental Hematology, Leukemia research, American journal of Anatomy, American journla of Reproductive Immunology, Placenta, Biology of Reproduction, cancer Metastasis Reviews. He received long term funding from the Medical Research Council of Canada (currently renamed CIHR) and the National cancer Institute of Canada (currently renamed CCSRI), and substantial funding from other agencies such as the NIH -USA, US-DOD (Breast Cancer Program), Lalor Foundation USA, Cancer Research Society, The Breast Caner Society of Canada, the Canadian Breast Cancer Foundation and the Ontario Institute of Cancer research. He served on the grants review panels of the MRC (CIHR), NIH (USA), NCIC, CRS, Cannaught Foundation and the CBCF, and also as an external reviewer to the US-Israel Science and Technology Foundation, cancer Research campaign (UK), Austrian science Foundation, Swiss National Foundation, AIRC, Itay, Welcome Foundation, UK, sheffield Hospital charitable Trust, Cambridge University Research Funds, and a s a member of the Site Visit teams of the NIH. He has served as the President of the Canadian Association of Anatomists, Cell Biologists and Neurobiologists, the Vice President of the American Society of reproductive Immunology and a founding member and organizer of the International Federation of Placental associations (IFPA) Meetings. He has been a plenary speaker at many internationla meetings in Reproduction and Cancer.
Dr Lala has received many prestigious awards including the J.C.B. Grant Senior Scientist award of the Canadian Association of Anatomists, Cell Biologists and Neurobiologists (1990), and Research Excellence Award of the Faculty of Medicine, UWO (1996). In 2001, he was honoured by his peers and past trainees with an international symposium at Queens University, sponsored by the CIHR, held in tribute to his unique contributions building the bridge between the fields of reproductive and cancer biology. For his five decades of outstanding contributions to biomedical research and education, in June 2013, the University of Western Ontario bestowed its highest honor to Dr Lala by awarding him the Doctor of Science degree, honoris causa at its annual convocation where he addressed the graduating students receiving their undergraduate and graduate degrees in bio-medical sciences (video).
Professional and Academic Experience
Following a short period of teaching career in Pathology in Calcutta University (1959-1962), Dr. Lala started his independent research career in 1963 at the Argonne National Laboratory in USA wherefrom he moved as a faculty member at the University of California Medical Centre in San Francisco (1964). In 1967, he moved to Canada initially as a research scientist at the Chalk River Nuclear Laboratories and then a faculty member at the Department of Anatomy & Cell Biology, McGill University in Montreal (1968), where he became a full professor in 1977. In 1983, he relocated to the University of Western Ontario as the Chair of the Department of Anatomy & Cell Biology (1983-1993). He is also cross-appointed at the Department of Oncology since 1990. Currently he is a Professor-emeritus with a fully active, well-funded research lab and some teaching responsibilities for senior medical students. He has trained some forty-five graduate students and eighteen post-doctoral fellows many of whom are independent scientists.
Research Group: Cancer; Children's Health
Research Interest Area: Fetal and Newborn Health; Reproduction and pregnancy
Research Overview
Research in his 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.
Research Focus: Development of the human placenta; Placental influence on the fetus and the newborn; Intra-uterine growth restriction of the fetus; Preeclampsia; Breast cancer; Molecular targets for breast cancer therapy, prevention and intervention; Prevention of breast cancer metastasis.
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About Peeyush Lala
Dr. Peeyush Lala is a Professor Emeritus in the Department of Anatomy and Cell Biology whose research mainly focuses on the cellular origins of common diseases and disorders that affect the placenta, such as preeclampsia, as well as breast cancer.
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.
Lawson Health Research Institute Profile
Dr Lala has published over 206 peer-reviewed articles and 360 conference abstracts. . He served on the editorial board of numerous reputed Biomedical journals such as the Experimental Hematology, Leukemia research, American journal of Anatomy, American journla of Reproductive Immunology, Placenta, Biology of Reproduction, cancer Metastasis Reviews. He received long term funding from the Medical Research Council of Canada (currently renamed CIHR) and the National cancer Institute of Canada (currently renamed CCSRI), and substantial funding from other agencies such as the NIH -USA, US-DOD (Breast Cancer Program), Lalor Foundation USA, Cancer Research Society, The Breast Caner Society of Canada, the Canadian Breast Cancer Foundation and the Ontario Institute of Cancer research. He served on the grants review panels of the MRC (CIHR), NIH (USA), NCIC, CRS, Cannaught Foundation and the CBCF, and also as an external reviewer to the US-Israel Science and Technology Foundation, cancer Research campaign (UK), Austrian science Foundation, Swiss National Foundation, AIRC, Itay, Welcome Foundation, UK, sheffield Hospital charitable Trust, Cambridge University Research Funds, and a s a member of the Site Visit teams of the NIH. He has served as the President of the Canadian Association of Anatomists, Cell Biologists and Neurobiologists, the Vice President of the American Society of reproductive Immunology and a founding member and organizer of the International Federation of Placental associations (IFPA) Meetings. He has been a plenary speaker at many internationla meetings in Reproduction and Cancer.
Dr Lala has received many prestigious awards including the J.C.B. Grant Senior Scientist award of the Canadian Association of Anatomists, Cell Biologists and Neurobiologists (1990), and Research Excellence Award of the Faculty of Medicine, UWO (1996). In 2001, he was honoured by his peers and past trainees with an international symposium at Queens University, sponsored by the CIHR, held in tribute to his unique contributions building the bridge between the fields of reproductive and cancer biology. For his five decades of outstanding contributions to biomedical research and education, in June 2013, the University of Western Ontario bestowed its highest honor to Dr Lala by awarding him the Doctor of Science degree, honoris causa at its annual convocation where he addressed the graduating students receiving their undergraduate and graduate degrees in bio-medical sciences (video).
Professional and Academic Experience
Following a short period of teaching career in Pathology in Calcutta University (1959-1962), Dr. Lala started his independent research career in 1963 at the Argonne National Laboratory in USA wherefrom he moved as a faculty member at the University of California Medical Centre in San Francisco (1964). In 1967, he moved to Canada initially as a research scientist at the Chalk River Nuclear Laboratories and then a faculty member at the Department of Anatomy & Cell Biology, McGill University in Montreal (1968), where he became a full professor in 1977. In 1983, he relocated to the University of Western Ontario as the Chair of the Department of Anatomy & Cell Biology (1983-1993). He is also cross-appointed at the Department of Oncology since 1990. Currently he is a Professor-emeritus with a fully active, well-funded research lab and some teaching responsibilities for senior medical students. He has trained some forty-five graduate students and eighteen post-doctoral fellows many of whom are independent scientists.
Research Group: Cancer; Children's Health
Research Interest Area: Fetal and Newborn Health; Reproduction and pregnancy
Research Overview
Research in his 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.
Research Focus: Development of the human placenta; Placental influence on the fetus and the newborn; Intra-uterine growth restriction of the fetus; Preeclampsia; Breast cancer; Molecular targets for breast cancer therapy, prevention and intervention; Prevention of breast cancer metastasis.
| Present | Professor Emeritus, Western University ‐ Department of Anatomy and Cell Biology | |
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Disciplines
Cell Biology and Anatomy