R-3 Repository :: Browsing by Author "Liu, Xin"

Browsing by Author "Liu, Xin"

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A collagen glucosyltransferase drives lung adenocarcinoma progression in mice
(Springer Nature, 2021) Guo, Hou-Fu; Bota-Rabassedas, Neus; Terajima, Masahiko; Leticia Rodriguez, B.; Gibbons, Don L.; Chen, Yulong; Banerjee, Priyam; Tsai, Chi-Lin; Tan, Xiaochao; Liu, Xin; Yu, Jiang; Tokmina-Roszyk, Michal; Stawikowska, Roma; Fields, Gregg B.; Miller, Mitchell D.; Wang, Xiaoyan; Lee, Juhoon; Dalby, Kevin N.; Creighton, Chad J.; Phillips, George N.Jr.; Tainer, John A.; Yamauchi, Mitsuo; Kurie, Jonathan M.
Cancer cells are a major source of enzymes that modify collagen to create a stiff, fibrotic tumor stroma. High collagen lysyl hydroxylase 2 (LH2) expression promotes metastasis and is correlated with shorter survival in lung adenocarcinoma (LUAD) and other tumor types. LH2 hydroxylates lysine (Lys) residues on fibrillar collagen’s amino- and carboxy-terminal telopeptides to create stable collagen cross-links. Here, we show that electrostatic interactions between the LH domain active site and collagen determine the unique telopeptidyl lysyl hydroxylase (tLH) activity of LH2. However, CRISPR/Cas-9-mediated inactivation of tLH activity does not fully recapitulate the inhibitory effect of LH2 knock out on LUAD growth and metastasis in mice, suggesting that LH2 drives LUAD progression, in part, through a tLH-independent mechanism. Protein homology modeling and biochemical studies identify an LH2 isoform (LH2b) that has previously undetected collagen galactosylhydroxylysyl glucosyltransferase (GGT) activity determined by a loop that enhances UDP-glucose-binding in the GLT active site and is encoded by alternatively spliced exon 13 A. CRISPR/Cas-9-mediated deletion of exon 13 A sharply reduces the growth and metastasis of LH2b-expressing LUADs in mice. These findings identify a previously unrecognized collagen GGT activity that drives LUAD progression.
An Efficient Gauss-Newton Algorithm for Symmetric Low-Rank Product Matrix Approximatins
(2014-05) Liu, Xin; Wen, Zaiwen; Zhang,Yin
We derive and study a Gauss-Newton method for computing the symmetric low-rank product (SLRP) XXT, where X / Rnkfor k
Cancer-Associated Fibroblasts Induce a Collagen Cross-link Switch in Tumor Stroma
(American Association for Cancer Research, 2016) Pankova, Daniela; Chen, Yulong; Terajima, Masahiko; Schliekelman, Mark J.; Baird, Brandi N.; Fahrenholtz, Monica; Sun, Li; Gill, Bartley J.; Vadakkan, Tegy J.; Kim, Min P.; Ahn, Young-Ho; Roybal, Jonathon D.; Liu, Xin; Cuentas, Edwin Roger Parra; Rodriguez, Jaime; Wistuba, Ignacio I.; Creighton, Chad J.; Gibbons, Don L.; Hicks, John M.; Dickinson, Mary E.; West, Jennifer L.; Grande-Allen, K. Jane; Hanash, Samir M.; Yamauchi, Mitsuo; Kurie, Jonathan M.; Bioengineering
Intratumoral collagen cross-links heighten stromal stiffness and stimulate tumor cell invasion, but it is unclear how collagen cross-linking is regulated in epithelial tumors. To address this question, we used KrasLA1 mice, which develop lung adenocarcinomas from somatic activation of a KrasG12D allele. The lung tumors in KrasLA1 mice were highly fibrotic and contained cancer-associated fibroblasts (CAF) that produced collagen and generated stiffness in collagen gels. In xenograft tumors generated by injection of wild-type mice with lung adenocarcinoma cells alone or in combination with CAFs, the total concentration of collagen cross-links was the same in tumors generated with or without CAFs, but coinjected tumors had higher hydroxylysine aldehyde–derived collagen cross-links (HLCC) and lower lysine-aldehyde–derived collagen cross-links (LCCs). Therefore, we postulated that an LCC-to-HLCC switch induced by CAFs promotes the migratory and invasive properties of lung adenocarcinoma cells. To test this hypothesis, we created coculture models in which CAFs are positioned interstitially or peripherally in tumor cell aggregates, mimicking distinct spatial orientations of CAFs in human lung cancer. In both contexts, CAFs enhanced the invasive properties of tumor cells in three-dimensional (3D) collagen gels. Tumor cell aggregates that attached to CAF networks on a Matrigel surface dissociated and migrated on the networks. Lysyl hydroxylase 2 (PLOD2/LH2), which drives HLCC formation, was expressed in CAFs, and LH2 depletion abrogated the ability of CAFs to promote tumor cell invasion and migration.
Contextual cues from cancer cells govern cancer-associated fibroblast heterogeneity
(Cell Press, 2021) Bota-Rabassedas, Neus; Banerjee, Priyam; Niu, Yichi; Cao, Wenjian; Luo, Jiayi; Xi, Yuanxin; Tan, Xiaochao; Sheng, Kuanwei; Ahn, Young-Ho; Lee, Sieun; Parra, Edwin Roger; Rodriguez-Canales, Jaime; Albritton, Jacob; Weiger, Michael; Liu, Xin; Guo, Hou-Fu; Yu, Jiang; Rodriguez, B. Leticia; Firestone, Joshua J.A.; Mino, Barbara; Creighton, Chad J.; Solis, Luisa M.; Villalobos, Pamela; Raso, Maria Gabriela; Sazer, Daniel W.; Gibbons, Don L.; Russell, William K.; Longmore, Gregory D.; Wistuba, Ignacio I.; Wang, Jing; Chapman, Harold A.; Miller, Jordan S.; Zong, Chenghang; Kurie, Jonathan M.; Bioengineering
Cancer cells function as primary architects of the tumor microenvironment. However, the molecular features of cancer cells that govern stromal cell phenotypes remain unclear. Here, we show that cancer-associated fibroblast (CAF) heterogeneity is driven by lung adenocarcinoma (LUAD) cells at either end of the epithelial-to-mesenchymal transition (EMT) spectrum. LUAD cells that have high expression of the EMT-activating transcription factor ZEB1 reprogram CAFs through a ZEB1-dependent secretory program and direct CAFs to the tips of invasive projections through a ZEB1-driven CAF repulsion process. The EMT, in turn, sensitizes LUAD cells to pro-metastatic signals from CAFs. Thus, CAFs respond to contextual cues from LUAD cells to promote metastasis.
An Efficient Gauss--Newton Algorithm for Symmetric Low-Rank Product Matrix Approximations
(Society for Industrial and Applied Mathematics, 2015) Liu, Xin; Wen, Zaiwen; Zhang, Yin
We derive and study a Gauss--Newton method for computing a symmetric low-rank product $XX^{{T}}$, where $X \in{\mathbb{R}}^{n\times k}$ for $k
Fibulin-2 Is a Driver of Malignant Progression in Lung Adenocarcinoma
(Public Library of Science, 2013) Baird, Brandi N.; Schliekelman, Mark J.; Ahn, Young-Ho; Chen, Yulong; Roybal, Jonathon D.; Gill, Bartley J.; Mishra, Dhruva K.; Erez, Baruch; O'Reilly, Michael; Yang, Yanan; Patel, Mayuri; Liu, Xin; Thilaganathan, Nishan; Larina, Irina V.; Dickinson, Mary E.; West, Jennifer L.; Gibbons, Don L.; Liu, Diane D.; Kim, Min P.; Hicks, John M.; Wistuba, Ignacio I.; Hanash, Samir M.; Kurie, Jonathan M.; Bioengineering
The extracellular matrix of epithelial tumors undergoes structural remodeling during periods of uncontrolled growth, creating regional heterogeneity and torsional stress. How matrix integrity is maintained in the face of dynamic biophysical forces is largely undefined. Here we investigated the role of fibulin-2, a matrix glycoprotein that functions biomechanically as an inter-molecular clasp and thereby facilitates supra-molecular assembly. Fibulin-2 was abundant in the extracellular matrix of human lung adenocarcinomas and was highly expressed in tumor cell lines derived from mice that develop metastatic lung adenocarcinoma from co-expression of mutant K-ras and p53. Loss-offunction experiments in tumor cells revealed that fibulin-2 was required for tumor cells to grow and metastasize in syngeneic mice, a surprising finding given that other intra-tumoral cell types are known to secrete fibulin-2. However, tumor cells grew and metastasized equally well in Fbln2-null and -wildtype littermates, implying that malignant progression was dependent specifically upon tumor cellderived fibulin-2, which could not be offset by other cellular sources of fibulin-2. Fibulin-2 deficiency impaired the ability of tumor cells to migrate and invade in Boyden chambers, to create a stiff extracellular matrix in mice, to cross-link secreted collagen, and to adhere to collagen. We conclude
Limited Memory Block Krylov Subspace Optimization for Computing Dominant Singular Value Decompositions
(2012-03) Liu, Xin; Wen, Zaiwen; Zhang, Yin
In many data-intensive applications, the use of principal component analysis (PCA) and other related techniques is ubiquitous for dimension reduction, data mining or other transformational purposes. Such transformations often require efficiently, reliably and accurately computing dominant singular value decompositions (SVDs) of large unstructured matrices. In this paper, we propose and study a subspace optimization technique to significantly accelerate the classic simultaneous iteration method. We analyze the convergence of the proposed algorithm, and numerically compare it with several state-of-the-art SVD solvers under the MATLAB environment. Extensive computational results show that on a wide range of large unstructured matrices, the proposed algorithm can often provide improved efficiency or robustness over existing algorithms.
Limited Memory Block Krylov Subspace Optimization for Computing Dominant Singular Value Decompositions
(SIAM, 2013) Liu, Xin; Wen, Zaiwen; Zhang, Yin
In many data-intensive applications, the use of principal component analysis and other related techniques is ubiquitous for dimension reduction, data mining, or other transformational purposes. Such transformations often require efficiently, reliably, and accurately computing dominant singular value decompositions (SVDs) of large and dense matrices. In this paper, we propose and study a subspace optimization technique for significantly accelerating the classic simultaneous iteration method. We analyze the convergence of the proposed algorithm and numerically compare it with several state-of-the-art SVD solvers under the MATLAB environment. Extensive computational results show that on a wide range of large unstructured dense matrices, the proposed algorithm can often provide improved efficiency or robustness over existing algorithms.
Modeling the Plasma Convection in Saturn's Inner Magnetosphere
(2013-09-16) Liu, Xin; Hill, Thomas W.; Toffoletto, Frank R.; Lenardic, Adrian
Saturn's magnetosphere is unique in the solar system. The rotation-driven convection consists of alternating channels of cool plasma from an interior source moving outward and hot plasma from outside moving inward, making Saturn’s inner magnetosphere a dynamical region. This thesis describes work on developing numerical models to simulate the plasma convection pattern in Saturn's inner magnetosphere. Chapter 2 introduces the numerical Rice Convection Model (RCM), a multi-fluid model that was originally developed for Earth’s magnetosphere. We adapt it for Saturn’s conditions in this thesis. In Chapter 3, we show results of initial RCM simulation runs, in which only cool plasma from the interior source is considered. We also include the Coriolis force and the pickup effect. Because the cool plasma is much denser than the hot plasma and always dominant in determining the convection pattern, it is important and necessary to investigate it first. Chapter 4 compares several cool plasma source models and determines the one that produces the best simulation results when compared to Cassini spacecraft observations. In Chapter 5, we add the finite temperature and associated plasma pressure of the cool plasma. The effect of ionospheric Pedersen conductance is also investigated. Finally in Chapter 6, we add hot plasma at the outer boundary, and simulate the V-shape signatures of the injection-dispersion events, which are considered the most definitive evidence of rotation-driven convection in Saturn's inner magnetosphere. Our simulations conform to the observed fact that wider, slower outflow channels of cooler, denser plasma alternate with narrower, faster inflow channels of hotter, more tenuous plasma. Comparisons between simulated and observed results show great consistency.
Pro-metastatic collagen lysyl hydroxylase dimer assemblies stabilized by Fe2+-binding
(Springer Nature, 2018) Guo, Hou-Fu; Tsai, Chi-Lin; Terajima, Masahiko; Tan, Xiaochao; Banerjee, Priyam; Miller, Mitchell D.; Liu, Xin; Yu, Jiang; Byemerwa, Jovita; Alvarado, Sarah K.; Kaoud, Tamer S.; Dalby, Kevin N.; Bota-Rabassedas, Neus; Chen, Yulong; Yamauchi, Mitsuo; Tainer, John A.; Phillips, George N.Jr.; Kurie, Jonathan M.
Collagen lysyl hydroxylases (LH1-3) are Fe2+- and 2-oxoglutarate (2-OG)-dependent oxygenases that maintain extracellular matrix homeostasis. High LH2 levels cause stable collagen cross-link accumulations that promote fibrosis and cancer progression. However, developing LH antagonists will require structural insights. Here, we report a 2 Å crystal structure and X-ray scattering on dimer assemblies for the LH domain of L230 in Acanthamoeba polyphaga mimivirus. Loop residues in the double-stranded β-helix core generate a tail-to-tail dimer. A stabilizing hydrophobic leucine locks into an aromatic tyrosine-pocket on the opposite subunit. An active site triad coordinates Fe2+. The two active sites flank a deep surface cleft that suggest dimerization creates a collagen-binding site. Loss of Fe2+-binding disrupts the dimer. Dimer disruption and charge reversal in the cleft increase Km and reduce LH activity. Ectopic L230 expression in tumors promotes collagen cross-linking and metastasis. These insights suggest inhibitor targets for fibrosis and cancer.
Trace-Penalty Minimization for Large-scale Eigenspace Computation
(2013-02) Wen, Zaiwen; Yang, Chao; Liu, Xin; Zhang, Yin
The Rayleigh-Ritz (RR) procedure, including orthogonalization, constitutes a major bottleneck in computing relatively high-dimensional eigenspaces of large sparse matrices. Although operations involved in RR steps can be parallelized to an extent, their parallel scalability, limited by some inherent sequentiality, is lower than dense matrix-matrix multiplications. The primary motivation of this paper is to develop a methodology that reduces the use of the RR procedure in exchange for matrix-matrix multiplications. We propose an unconstrained penalty model and establish its equivalence to the eigenvalue problem. This model enables us to deploy gradient-type algorithms heavily dominated by dense matrixmatrix multiplications. Although the proposed algorithm does not necessarily reduce the total number of arithmetic operations, it leverages highly optimized operations on modern high performance computers to achieve parallel scalability. Numerical results based on a preliminary implementation, parallelized using OpenMP, show that our approach is promising.

Browsing by Author "Liu, Xin"

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