Biology subjects

Lakins, J. N.

Publications and source records attributed to Lakins, J. N..

5 recordsLinked to original sources

bioRxiv2025

NCOR2 represses MHC class I molecule expression to drive metastatic progression of breast cancer

Metastatic progression depends upon the ability of disseminated tumor cells to evade immune surveillance. MHC molecule expression facilitates T cell recognition and activation to permit the eradication of metastatic tumor cells. We identified nuclear corepressor 2 (NCOR2) as a key epigenetic regulator of MHC class I molecule expression on breast tumor cells. Patients with triple negative breast cancers (TNBC) that expressed high levels of NCOR2 also exhibited reduced metastasis free survival and decreased MHC class I expression, and the metastatic lesions in patients with TNBC had high nuclear NCOR2 and reduced CD8 T cell levels and activity. Genetically and experimentally reducing NCOR2 expression in tumor cells permitted interferon gamma upregulation of MHC class I, and potentiated CD8 T cell activity and induction of apoptosis to repress metastatic progression of disseminated breast cancer cells. These studies provide evidence to support NCOR2 as a targetable epigenetic regulator of metastasis towards which therapies could be developed to reduce patient mortality.

cancer biology↗

bioRxiv2023

Tissue tension permits β-catenin phosphorylation to drive mesoderm specification in human embryonic stem cells.

The role of morphogenetic forces in cell fate specification is an area of intense interest. Our prior studies suggested that the development of high cell-cell tension in human embryonic stem cells (hESC) colonies permits the Src-mediated phosphorylation of junctional {beta}-catenin that accelerates its release to potentiate Wnt-dependent signaling critical for initiating mesoderm specification. Using an ectopically expressed nonphosphorylatable mutant of {beta}-catenin (Y654F), we now provide direct evidence that impeding tension-dependent Src-mediated {beta}-catenin phosphorylation impedes the expression of Brachyury (T) and the epithelial-to-mesenchymal transition (EMT) necessary for mesoderm specification. Addition of exogenous Wnt3a or inhibiting GSK3{beta} activity rescued mesoderm expression, emphasizing the importance of force dependent Wnt signaling in regulating mechanomorphogenesis. Our work provides a framework for understanding tension-dependent {beta}-catenin/Wnt signaling in the self-organization of tissues during developmental processes including gastrulation.

developmental biology↗

bioRxiv2022

Mechanosensitive hormone signaling promotes mammary progenitor expansion and breast cancer progression

Tissue stem-progenitor cell frequency has been implicated in tumor risk and progression. Tissue-specific factors linking stem-progenitor cell frequency to cancer risk and progression remain ill defined. Using a genetically engineered mouse model that promotes integrin mechanosignaling with syngeneic manipulations, spheroid models, and patient-derived xenografts we determined that a stiff extracellular matrix and high integrin mechanosignaling increase stem-progenitor cell frequency to enhance breast tumor risk and progression. Studies revealed that high integrin-mechanosignaling expands breast epithelial stem-progenitor cell number by potentiating progesterone receptor-dependent RANK signaling. Consistently, we observed that the stiff breast tissue from women with high mammographic density, who exhibit an increased lifetime risk for breast cancer, also have elevated RANK signaling and a high frequency of stem-progenitor epithelial cells. The findings link tissue fibrosis and integrin mechanosignaling to stem-progenitor cell frequency and causally implicate hormone signaling in this phenotype. Accordingly, inhibiting RANK signaling could temper the tumor promoting impact of fibrosis on breast cancer and reduce the elevated breast cancer risk exhibited by women with high mammographic density. SummaryElevated mechano-signaling and matrix stiffness promote progesterone and RANK mediated expansion of mammary progenitors and breast cancer risk and progression.

cancer biology↗

bioRxiv2020

Inflammation promotes tumor aggression by stimulating stromal cell-dependent collagen crosslinking and stromal stiffening

Collagen deposition and stromal stiffening accompany malignancy, compromise treatment, and promote tumor aggression. Clarifying the molecular nature of and the factors that regulate extracellular matrix stiffening in tumors should identify biomarkers to stratify patients for therapy and therapeutic interventions to improve outcome. We profiled lysyl hydroxylase- and lysyl oxidase-mediated collagen crosslinks and quantified the greatest abundance of total and complex collagen crosslinks in more aggressive human breast cancer subtypes with the stiffest stroma. These tissues also harbored the highest number of tumor-associated macrophages (TAM), whose therapeutic ablation not only reduced metastasis, but also concomitantly decreased accumulation of collagen crosslinks and stromal stiffening. Epithelial-targeted expression of the crosslinking enzyme lysyl oxidase had no impact on collagen crosslinking in PyMT mammary tumors, whereas stromal cell targeting did. Consistently, stromal cells in microdissected human tumors expressed the highest level of collagen crosslinking enzymes. Immunohistochemical analysis of a cohort of breast cancer patient biopsies revealed that stromal expression of lysyl hydroxylase two, an enzyme that induces hydroxylysine aldehyde-derived collagen crosslinks and stromal stiffening correlated significantly disease specific mortality. The findings link tissue inflammation, stromal cell-mediated collagen crosslinking and stiffening to tumor aggression and identify lysyl hydroxylase two as a novel stromal biomarker. SignificanceWe show infiltrating macrophages induce stromal fibroblast, and not epithelial, expression of collagen crosslinking enzymes that drive tumor stiffening. Stromal enzyme LH2 is significantly upregulated in breast cancer patients with the stiffest stroma, the most trivalent HLCCs and the worst prognosis, underscoring its potential as a biomarker and therapeutic target.

cancer biology↗

bioRxiv2020

Mechanics regulate human embryonic stem cell self-organization to specify mesoderm

Embryogenesis is directed by morphogens that induce differentiation within a defined tissue geometry. Tissue organization is mediated by cell-cell and cell-extracellular matrix (ECM) adhesions and is modulated by cell tension and tissue-level force. Whether cell tension regulates development by directly influencing morphogen signaling remains unclear. Human embryonic stem cells (hESCs) exhibit an intrinsic capacity for self-organization that motivates their use as a tractable model of early human embryogenesis. We engineered patterned substrates that enhance cell-cell interactions to direct the self-organization of cultured hESCs into "gastrulation-like" nodes. Tissue geometries that generate local nodes of high cell-cell tension and induce these self-organized tissue nodes drive BMP4-dependent gastrulation by enhancing phosphorylation and nuclear translocation of {beta}-catenin to promote Wnt signaling and mesoderm specification. The findings underscore the interplay between tissue organization, cell tension, and morphogen-dependent differentiation, and demonstrate that cell- and tissue-level forces directly regulate cell fate specification in early human development. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/943076v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@e21aaeorg.highwire.dtl.DTLVardef@45c41forg.highwire.dtl.DTLVardef@4ee902org.highwire.dtl.DTLVardef@a3837d_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG HighlightsO_LISubstrates that enhance cell-cell adhesion promote hESC self-organization C_LIO_LITissue nodes exhibiting high tension are predisposed to gastrulation induction C_LIO_LIColony geometry dictates the localization of tension nodes to specify mesoderm C_LIO_LITension activates {beta}-catenin and stimulates Wnt signaling to induce mesoderm C_LI In BriefEngineered substrates that promote cell-cell adhesion and reconstitute epiblast tissue organization facilitate "gastrulation-like" morphogenesis in cultured hESCs. Tissue geometries that foster localized regions of high cell-cell tension potentiate BMP4-dependent mesoderm specification by enhancing phosphorylation and nuclear translocation of {beta}-catenin to promote Wnt signaling.

developmental biology↗