John M. Lamar, PhD
Areas of Study
- Albany Medical College2008PhD
- Albany Medical College2006MS
- SUNY Geneseo2000BS
The Lamar Lab studies cancer metastasis, which is responsible for greater than 90% of all cancer mortality. Metastasis involves the spread of cancer cells from the primary tumor to distant organs and their subsequent survival and growth in this new tissue environment. This occurs through a complicated cascade of events that requires the cells gain a number of adaptations. One way that cancer cells adapt is by altering the expression of key genes that influence cellular processes important for metastasis. These changes in gene expression can alter the behavior of the cancer cells or influence their ability to sense and respond to cues they receive from the tissue microenvironment. We aim to identify molecular pathways that promote metastasis and test if they could be targeted to help treat metastatic disease. We study this in breast cancer and cutaneous melanoma. We have also recently begun researching a rare vascular sarcoma called Epitheliod Hemangioendothelioma (EHE).
Our work on metastasis has focused heavily on the Hippo Pathway and its two effectors, Yes-associated protein (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ). Normally, the Hippo Pathway is a critical regulator of organ size and tissue development in vertebrates. However, dysregulation of the Hippo Pathway can lead to abnormal activation YAP or TAZ, which promotes cancer development, tumor progression, and metastasis. Indeed, Dr. Lamar's previous work in breast cancer and melanoma was the first paper to show that aberrant activation of YAP is a potent driver of metastasis (Lamar et al. 2012). As we summarized in a recent review (Warren et al. 2019), numerous papers have subsequently found that YAP or TAZ activation can drive metastasis in many cancer types. A major focus of our lab is to understand how activation of YAP and TAZ promotes metastasis and to identify ways to target the Hippo-YAP/TAZ pathway to treat metastatic disease.
Identification of Novel Regulators of YAP and TAZ
Although YAP and TAZ are activated in a significant percentage of human cancers, mutations in YAP and TAZ or Hippo Pathway genes are not common in most cancer types. This suggests that other oncogenic alterations may be activating YAP or TAZ to promote cancer development and drive metastasis. We aim to identify pathways that can be targeted in cancer cells to inhibit YAP and TAZ activity and determine how these pathways activate YAP and TAZ in metastatic cells. This includes trying to understand how changes in the microenvironmental cues that cancer cells experience influence YAP/TAZ regulatory pathways. In one example, we found that oncogenic activation of SRC promotes YAP/TAZ activity in breast cancer and melanoma cells and that inhibition of this SRC-YAP/TAZ pathway can prevent metastasis formation (Lamar et al 2019). Current projects in the lab are focused on novel regulators of YAP and TAZ that we identified using RNAI screens (Xiao et al. 2020).
Identify YAP/TAZ-TEAD Target Genes Driving Tumor Progression and Metastasis
Although its now clear that YAP and TAZ activation can drive tumor progression and metastasis, YAP/TAZ target genes mediating these effects are still not fully elucidated in many cancer types. We have identified numerous genes regulated by YAP and TAZ in metastatic cell lines and aim to determine which of these genes is important for YAP/TAZ-mediated cancer progression and metastasis. We will use CRISPR/CAS and miR30-based RNAi to knock out or knock down these YAP target genes and test if this influences tumor progression or metastasis using in vitro and in vivo assays of cell migration and invasion, proliferation, survival, transformation, tumor growth, and metastasis. We will then determine the mechanism through which each identified gene influences YAP/TAZ-dependent pro-tumorigenic and pro-metastatic processes.
We have recently begun studying a vascular sarcoma called Epithelioid Hemangioendothelioma (EHE). Though exceedingly rare, EHE can occur in patients of all ages. It often has a long indolent phase before suddenly becoming aggressive, and there are very few effective treatments for aggressive disease. More than 90% of all EHEs have a chromosomal translocation that fuses the WWTR1 gene (which encodes TAZ) with the CAMTA1 gene and its now clear that the resulting TAZ-CAMTA1 fusion protein is the causal oncogene in EHE. In the remaining 10% of EHEs a YAP-TFE3 fusion appears to be the causal mutation. Though research on EHE is very limited, its now clear that both the TAZ-CAMTA1 and YAP-TFE3 fusion proteins drive tumorigenesis because they behave like a highly active forms of TAZ and YAP. However, the CAMTA1 and TFE3 portions of the fusions also play important roles in EHE development and progression. Since EHEs are addicted to the fusion proteins, therapies that inhibit the activity of these fusion proteins would be extremely effective treatments for EHE. We have identified several proteins that regulate TAZ-CAMTA1, and current work is focused on understanding the mechanism of regulation and using this to identify pathways that can be exploited therapeutically to treat EHE.
Seavey C.N., Pobbati A.V., Hallett A., Ma S., Reynolds J.P., Kanai R., Lamar J.M., Rubin B.P. WWTR1(TAZ)-CAMTA1 gene fusion is sufficient to dysregulate YAP/TAZ signaling and drive epithelioid hemangioendothelioma tumorigenesis. Genes Dev. 2021 Apr 1;35(7-8):512-527 (Epub) PMID: 33766982
Miskin, R.P.; Warren, J.S.A.; Ndoye, A.; Wu, L.; Lamar, J.M.; DiPersio, C.M. Integrin alpha3beta1 promotes invasive and metastatic properties of breast cancer cells through induction of the brn-2 transcription factor. Cancers (Basel) 2021, 13. PMC7866210
Lu, Y.W.; Martino, N.; Gerlach, B.D.; Lamar, J.M.; Vincent, P.A.; Adam, A.P.; Schwarz, J.J. Mef2 (myocyte enhancer factor 2) is essential for endothelial homeostasis and the atheroprotective gene expression program. Arterioscler Thromb Vasc Biol 2021, 41, 1105-1123. PMID: 33406884
Benjamin, D.C.; Kang, J.H.; Hamza, B.; King, E.M.; Lamar, J.M.; Manalis, S.R.; Hynes, R.O. Yap enhances tumor cell dissemination by promoting intravascular motility and reentry into systemic circulation. Cancer Res 2020, 80, 3867-3879. PMC7501173
View John M. Lamar's articles on the National Institute of Health's PubMed website.