Ken Lau, Ph.D.

Assistant Professor

ken.s.lau@vanderbilt.edu

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Faculty Appointments
Assistant Professor of Cell and Developmental Biology
Education
Ph.D., Proteomics and Bioinformatics , University of Toronto, Toronto, CanadaB.Sc., University of Toronto, Toronto, Canada
Office Address
2215 Garland Ave, MRB IV 10465J
Nashville, TN 37232
Research Description
Goal
The central goal of my lab is to understand how inflammatory microenvironments affect epithelial cell behaviors in the context of human diseases, specifically, in inflammatory bowel diseases and colorectal cancer. Aberrant cell specification is now recognized to be a major factor in various intestinal diseases. For example, dysfunctional Goblet and Paneth cells in the intestine contribute to barrier defects, while progenitor-like colorectal cancer cells are prone to therapeutic resistance and metastasis. Devising ways to control these aberrant behaviors may lead to effective therapeutic strategies to combat these complex diseases. My lab is interested in understanding the signaling mechanisms that control the differentiating cell populations in the intestine (defined loosely as transit amplifying cells) as they become exposed to various in vivo environments. We want to characterize the degree of heterogeneity and plasticity in such populations, and to leverage such properties for reversing pathological behaviors.

Approach
In live tissues, cells must integrate dynamic mixtures of environmental cues through their signaling networks to arrive at response decisions. To understand the multivariate problem of how the microenvironment interacts with cells, we use multiplex and high throughput experimental approaches to characterize the network states (numbers and types of cells, secreted protein factors, intracellular signaling, and transcriptional changes, over time) within in vivo tissue. Our model system is the intestine of the laboratory mouse, whose state is controlled by interactions between the epithelium, immune system, and microbiota very much like in human. We use the collected datasets over different experimental conditions to build data-driven mathematical models to quantitatively describe environment-cell input/output relationships and how these relationships are integrated over time to derive cellular outcomes. Because cell populations in in vivo tissues are not homogeneous, we will focus on generating data from single cells using techniques derived from flow cytometry and microscopy.

Training
I received my training at Massachusetts General Hospital and MIT under joint supervision of Dr. Kevin Haigis (a mouse geneticist) and Dr. Douglas Lauffenburger (a bioengineer). There, I performed pioneering work on combining system-level signaling analyses and mouse models of intestinal diseases. I then further expanded these studies into looking at immune-epithelial cell interaction, and global signaling changes in mice with oncogenic mutations in the Ras proteins. Overall, I found that multivariate analyses are necessary for predicting signal-response relationships, whereas exploring single pathways one at a time is not predictive in vivo. I aim to foster a highly interdisciplinary and collaborative atmosphere in my lab, with a key focus on learning principles that will be translatable to human patients.
Research Keywords
inflammation, colorectal cancer, differentiation, computational biology, systems biology, stem cells, apoptosis, cell death, epithelial biology, cell specification, signal transduction
Publications
Simmons AJ, Banerjee A, McKinley ET, Scurrah CR, Herring CA, Gewin LS, Masuzaki R, Karp SJ, Franklin JL, Gerdes MJ, Irish JM, Coffey RJ, Lau KS. Cytometry-based single-cell analysis of intact epithelial signaling reveals MAPK activation divergent from TNF-a-induced apoptosis in vivo. Mol. Syst. Biol. 2015 Oct; 11(10): 835. PMID: 26519361, PMCID: PMC4631206, ISSN: 1744-4292.

Lau KS, Schrier SB, Gierut J, Lyons J, Lauffenburger DA, Haigis KM. Network analysis of differential Ras isoform mutation effects on intestinal epithelial responses to TNF-a. Integr Biol (Camb) [print-electronic]. 2013 Nov; 5(11): 1355-65. PMID: 24084984, PMCID: PMC3966991, DOI: 10.1039/c3ib40062j, ISSN: 1757-9708.

Miraldi ER, Sharfi H, Friedline RH, Johnson H, Zhang T, Lau KS, Ko HJ, Curran TG, Haigis KM, Yaffe MB, Bonneau R, Lauffenburger DA, Kahn BB, Kim JK, Neel BG, Saghatelian A, White FM. Molecular network analysis of phosphotyrosine and lipid metabolism in hepatic PTP1b deletion mice. Integr Biol (Camb) [print-electronic]. 2013 Jul 7/24/2013; 5(7): 940-63. PMID: 23685806, PMCID: PMC3759823, DOI: 10.1039/c3ib40013a, ISSN: 1757-9708.

Lau KS, Cortez-Retamozo V, Philips SR, Pittet MJ, Lauffenburger DA, Haigis KM. Multi-scale in vivo systems analysis reveals the influence of immune cells on TNF-a-induced apoptosis in the intestinal epithelium. PLoS Biol [print-electronic]. 2012; 10(9): e1001393. PMID: 23055830, PMCID: PMC3463506, PII: PBIOLOGY-D-12-01984, DOI: 10.1371/journal.pbio.1001393, ISSN: 1545-7885.

Lau KS, Zhang T, Kendall KR, Lauffenburger D, Gray NS, Haigis KM. BAY61-3606 affects the viability of colon cancer cells in a genotype-directed manner. PLoS ONE [print-electronic]. 2012; 7(7): e41343. PMID: 22815993, PMCID: PMC3399817, PII: PONE-D-12-03440, DOI: 10.1371/journal.pone.0041343, ISSN: 1932-6203.

Lau KS, Juchheim AM, Cavaliere KR, Philips SR, Lauffenburger DA, Haigis KM. In vivo systems analysis identifies spatial and temporal aspects of the modulation of TNF-a-induced apoptosis and proliferation by MAPKs. Sci Signal. 2011; 4(165): ra16. PMID: 21427409, PMCID: PMC3963028, PII: 4/165/ra16, DOI: 10.1126/scisignal.2001338, ISSN: 1937-9145.

Mkhikian H, Grigorian A, Li CF, Chen HL, Newton B, Zhou RW, Beeton C, Torossian S, Tatarian GG, Lee SU, Lau K, Walker E, Siminovitch KA, Chandy KG, Yu Z, Dennis JW, Demetriou M. Genetics and the environment converge to dysregulate N-glycosylation in multiple sclerosis. Nat Commun. 2011; 2: 334. PMID: 21629267, PMCID: PMC3133923, PII: ncomms1333, DOI: 10.1038/ncomms1333, ISSN: 2041-1723.

Dennis JW, Lau KS, Demetriou M, Nabi IR. Adaptive regulation at the cell surface by N-glycosylation. Traffic [print-electronic]. 2009 Nov; 10(11): 1569-78. PMID: 19761541, PII: TRA981, DOI: 10.1111/j.1600-0854.2009.00981.x, ISSN: 1600-0854.

Lau KS, Haigis KM. Non-redundancy within the RAS oncogene family: insights into mutational disparities in cancer. Mol. Cells [print-electronic]. 2009 Oct 10/31/2009; 28(4): 315-20. PMID: 19812895, PMCID: PMC3976423, DOI: 10.1007/s10059-009-0143-7, ISSN: 0219-1032.

Lau KS, Dennis JW. N-Glycans in cancer progression. Glycobiology [print-electronic]. 2008 Oct; 18(10): 750-60. PMID: 18701722, PII: cwn071, DOI: 10.1093/glycob/cwn071, ISSN: 1460-2423.

Beheshti Zavareh R, Lau KS, Hurren R, Datti A, Ashline DJ, Gronda M, Cheung P, Simpson CD, Liu W, Wasylishen AR, Boutros PC, Shi H, Vengopal A, Jurisica I, Penn LZ, Reinhold VN, Ezzat S, Wrana J, Rose DR, Schachter H, Dennis JW, Schimmer AD. Inhibition of the sodium/potassium ATPase impairs N-glycan expression and function. Cancer Res. 2008 Aug 8/15/2008; 68(16): 6688-97. PMID: 18701493, PII: 68/16/6688, DOI: 10.1158/0008-5472.CAN-07-6833, ISSN: 1538-7445.

Lau KS, Khan S, Dennis JW. Genome-scale identification of UDP-GlcNAc-dependent pathways. Proteomics. 2008 Aug; 8(16): 3294-302. PMID: 18646010, DOI: 10.1002/pmic.200800208, ISSN: 1615-9861.

Katz D, Ito E, Lau KS, Mocanu JD, Bastianutto C, Schimmer AD, Liu FF. Increased efficiency for performing colony formation assays in 96-well plates: novel applications to combination therapies and high-throughput screening. BioTechniques. 2008 Feb; 44(2): ix-xiv. PMID: 18422490, PII: 000112757, DOI: 10.2144/000112757, ISSN: 0736-6205.

Mendelsohn R, Cheung P, Berger L, Partridge E, Lau K, Datti A, Pawling J, Dennis JW. Complex N-glycan and metabolic control in tumor cells. Cancer Res. 2007 Oct 10/15/2007; 67(20): 9771-80. PMID: 17942907, PII: 67/20/9771, DOI: 10.1158/0008-5472.CAN-06-4580, ISSN: 0008-5472.

Lau KS, Partridge EA, Grigorian A, Silvescu CI, Reinhold VN, Demetriou M, Dennis JW. Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation. Cell. 2007 Apr 4/6/2007; 129(1): 123-34. PMID: 17418791, PII: S0092-8674(07)00315-7, DOI: 10.1016/j.cell.2007.01.049, ISSN: 0092-8674.

Cheung J, Estivill X, Khaja R, MacDonald JR, Lau K, Tsui LC, Scherer SW. Genome-wide detection of segmental duplications and potential assembly errors in the human genome sequence. Genome Biol [print-electronic]. 2003; 4(4): R25. PMID: 12702206, PMCID: PMC154576, ISSN: 1474-760X.

Lau, KS, Mantas, M, Chass, GA, Ferretti, FH, Estrada M, Zamarbide G, Csizmadia, IG.. Ab initio and DFT conformational analysis of selected flavones: 5,7-dihydroxyflavone (chrysin) and 7,8-dihydroxyflavone. 2002.