All cells within tissues are exposed to mechanical stimuli and these forces regulate embryogenesis and tissue development and modulate tissue homeostasis. Tissue pathologies arise when cell and tissue level forces are corrupted such as in tissue fibrosis and in tumors. Aberrant cell and tissue level forces promote diseases including malignant transformation and metastasis and modulate cancer treatment response by altering membrane receptor signaling and chromatin organization. The research program in my laboratory aims to define these forces and then to understand how cell sense and respond to these forces at the subcellular, cellular and tissue level. The goal is to understand how force modulates cell and tissue fate during early embryogenesis (gastrulation) and tissue development (branching morphogenesis) and to clarify how these forces become deregulated in and contribute to breast, pancreatic and brain cancer(s). Our work focuses on clarifying how the mechanical stiffness and three dimensional organization of the extracellular matrix (ECM) (a noncellular component of the extracellular microenvironment) and the cells contractility synergistically influence cell growth, survival, migration and tissue-specific differentiation by modulating integrin transmembrane receptors and their crosstalk with receptor tyrosine kinases and GPCRs.
To delineate molecular mechanisms we use classic cell and molecular biology approaches (gain of function, loss of function; biochemical assays, array/ChIP seq etc) in combination with supra resolution imaging and quantitative analysis at the subcellular, cellular level and tissue level using three dimensional (3D) organotypic assays. Physiological relevance is explored using a series of unique transgenic, syngeneic and xenograft mice to study mammary tissue development and mammary, pancreatic and glioblastoma malignancy combined with intravital imaging, mechanical manipulations and quantitative analysis. We analyze and manipulate fresh breast, pancreatic and brain tumor biopsies in culture and in vivo to establish clinical translation.
Cancer Focused Projects:
1. Applying transgenic and syngeneic mouse models as well as human breast tumor biopsies, organotypic culture assays, mechanical manipulations in culture and in vivo and a unique 3D bioreactor to clarify the role of mechanical force in mammary tumor progression and treatment resistance - focusing on microRNAs, tissue inflammation, metabolic reprogramming combined with novel therapeutic strategies.
2. Using transgenic models and syngeneic manipulations to explore links between oncogenic transformation, tumor tension, and stromal desmoplasia in pancreatic tumor development and treatment resistance - focusing on tissue inflammation, stromal fibroblast contributions and tumor cell contractility.
3. Using xenograft, syngeneic and transgenic mouse models and intra vital imaging to define and understand the interplay between the unique forces that develop during brain tumor development and following therapy and glioblastoma aggression and recurrence - focusing on tissue inflammation and metabolic reprogramming.
4. Using human breast tumor biopsies and xenografts and mechanical manipulations in transgenic and immune compromised mice we are exploring the relationship between tissue tension and stem cell/progenitor cell expansion/commitment during malignant transformation of the mammary gland.
5. Exploring links between tissue tension, tissue inflammation and tumor aggression and histophenotype in human breast tumors.
6. Assessing the relationship in human patient tissue between tissue tension, microRNAs, mammographic density, obesity and risk to malignancy.
7. Examining the role of the tumor-associated glycocalyx and tumor metastasis and treatment resistance in culture and in vivo.
1. We are studying how tissue mechanics regulates embryogenesis using a unique in vitro model of human gastrulation.
2. We are exploring engineering approaches to optimize hepatocyte iPS expansion in culture and we are clarifying the role of cell mechanics and ECM stiffness on hepatocyte differentiation.
3. We are using unique transgenic mouse models in which cellular mechanosignaling is genetically enhanced or repressed to study mammary stem cell fate specification and mammary branching morphogenesis.
1. We are using genetic manipulations and glycomimetics combined with supra resolution imaging to explore how the glycocalyx regulates receptor tyrosine kinase receptor organization and signaling.
2. We are using 2 and 3D mechanically-tuned defined ECM substrates, biochemical assays and live imaging to study the impact of ECM stiffness on receptor tyrosine kinase receptor recycling
3. We are using scanning angle interference microscopy, single molecule force measurements, Atomic force microscopy and traction force microscopy combined with classic cell and molecular biology to explore the interplay between cell mechanics an epithelial to mesenchymal transition and motility phenotypes in 2 and 3D ECMs.
4. We are exploring the impact of tissue mechanics and tissue organization on chromatin structure, epigenetics and gene expression using genomics and molecular approaches (ChIP Seq/arrays/4C/etc) combined with live imaging and mechanical manipulations in 2 and 3D culture formats.
Students interested in a rotation project are encouraged to contact Dr. Weaver to discuss available projects.
The cancer glycocalyx mechanically primes integrin-mediated growth and survival. Paszek MJ, DuFort CC, Rossier O, Bainer R, Mouw JK, Godula K, Hudak JE, Lakins JN, Wijekoon AC, Cassereau L, Rubashkin MG, Magbanua MJ, Thorn KS, Davidson MW, Rugo HS, Park JW, Hammer DA, Giannone G, Bertozzi CR, Weaver VM. Nature. 2014 Jul 17;511(7509):319-25. doi: 10.1038/nature13535. Epub 2014 Jun 25. PMID: 25030168 [PubMed - indexed for MEDLINE]
Deconstructing signaling in three dimensions. Rubashkin MG, Ou G, Weaver VM. Biochemistry. 2014 Apr 8;53(13):2078-90. doi: 10.1021/bi401710d. Epub 2014 Mar 28. Review. PMID: 24649923 [PubMed - indexed for MEDLINE]
Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression. Mouw JK, Yui Y, Damiano L, Bainer RO, Lakins JN, Acerbi I, Ou G, Wijekoon AC, Levental KR, Gilbert PM, Hwang ES, Chen YY, Weaver VM. Nat Med. 2014 Apr;20(4):360-7. doi: 10.1038/nm.3497. Epub 2014 Mar 16. PMID: 24633304 [PubMed - indexed for MEDLINE]
Oncogenic targeting of BRM drives malignancy through C/EBPβ-dependent induction of α5 integrin. Damiano L, Stewart KM, Cohet N, Mouw JK, Lakins JN, Debnath J, Reisman D, Nickerson JA, Imbalzano AN, Weaver VM. Oncogene. 2014 May 8;33(19):2441-53. doi: 10.1038/onc.2013.220. Epub 2013 Jun 17. PMID: 23770848 [PubMed - indexed for MEDLINE] Free PMC Article
MT1-MMP-dependent control of skeletal stem cell commitment via a β1-integrin/YAP/TAZ signaling axis. Tang Y, Rowe RG, Botvinick EL, Kurup A, Putnam AJ, Seiki M, Weaver VM, Keller ET, Goldstein S, Dai J, Begun D, Saunders T, Weiss SJ. Dev Cell. 2013 May 28;25(4):402-16. doi: 10.1016/j.devcel.2013.04.011. Epub 2013 May 16. PMID: 23685250 [PubMed - indexed for MEDLINE] Free PMC Article
Exploring the link between human embryonic stem cell organization and fate using tension-calibrated extracellular matrix functionalized polyacrylamide gels. Lakins JN, Chin AR, Weaver VM. Methods Mol Biol. 2012;916:317-50. doi: 10.1007/978-1-61779-980-8_24. PMID: 22914951 [PubMed - indexed for MEDLINE]
Scanning angle interference microscopy reveals cell dynamics at the nanoscale. Paszek MJ, DuFort CC, Rubashkin MG, Davidson MW, Thorn KS, Liphardt JT, Weaver VM. Nat Methods. 2012 Jul 1;9(8):825-7. doi: 10.1038/nmeth.2077. PMID: 22751201 [PubMed - indexed for MEDLINE] Free PMC Article
In situ force mapping of mammary gland transformation. Lopez JI, Kang I, You WK, McDonald DM, Weaver VM. Integr Biol (Camb). 2011 Sep;3(9):910-21. doi: 10.1039/c1ib00043h. Epub 2011 Aug 15. PMID: 21842067 [PubMed - indexed for MEDLINE] Free PMC Article
Actomyosin-mediated cellular tension drives increased tissue stiffness and β-catenin activation to induce epidermal hyperplasia and tumor growth. Samuel MS, Lopez JI, McGhee EJ, Croft DR, Strachan D, Timpson P, Munro J, Schröder E, Zhou J, Brunton VG, Barker N, Clevers H, Sansom OJ, Anderson KI, Weaver VM, Olson MF. Cancer Cell. 2011 Jun 14;19(6):776-91. doi: 10.1016/j.ccr.2011.05.008. PMID: 21665151 [PubMed - indexed for MEDLINE] Free PMC Article
Balancing forces: architectural control of mechanotransduction. DuFort CC, Paszek MJ, Weaver VM. Nat Rev Mol Cell Biol. 2011 May;12(5):308-19. doi: 10.1038/nrm3112. Review. PMID: 21508987 [PubMed - indexed for MEDLINE] Free PMC Article
Engineering strategies to recapitulate epithelial morphogenesis within synthetic three-dimensional extracellular matrix with tunable mechanical properties. Miroshnikova YA, Jorgens DM, Spirio L, Auer M, Sarang-Sieminski AL, Weaver VM. Phys Biol. 2011 Apr;8(2):026013. doi: 10.1088/1478-3975/8/2/026013. Epub 2011 Mar 25. PMID: 21441648 [PubMed - indexed for MEDLINE] Free PMC Article
The extracellular matrix at a glance. Frantz C, Stewart KM, Weaver VM. J Cell Sci. 2010 Dec 15;123(Pt 24):4195-200. doi: 10.1242/jcs.023820. Review. No abstract available. PMID: 21123617 [PubMed - indexed for MEDLINE] Free PMC Article
Forcing form and function: biomechanical regulation of tumor evolution. Yu H, Mouw JK, Weaver VM. Trends Cell Biol. 2011 Jan;21(1):47-56. doi: 10.1016/j.tcb.2010.08.015. Epub 2010 Oct 1. Review. PMID: 20870407 [PubMed - indexed for MEDLINE] Free PMC Article
Dynamic interplay between the collagen scaffold and tumor evolution. Egeblad M, Rasch MG, Weaver VM. Curr Opin Cell Biol. 2010 Oct;22(5):697-706. doi: 10.1016/j.ceb.2010.08.015. Epub 2010 Sep 6. Review. PMID: 20822891 [PubMed - indexed for MEDLINE] Free PMC Article
HOXA9 regulates BRCA1 expression to modulate human breast tumor phenotype. Gilbert PM, Mouw JK, Unger MA, Lakins JN, Gbegnon MK, Clemmer VB, Benezra M, Licht JD, Boudreau NJ, Tsai KK, Welm AL, Feldman MD, Weber BL, Weaver VM. J Clin Invest. 2010 May;120(5):1535-50. doi: 10.1172/JCI39534. Epub 2010 Apr 12. PMID: 20389018 [PubMed - indexed for MEDLINE] Free PMC Article
Matrix crosslinking forces tumor progression by enhancing integrin signaling. Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, Fong SF, Csiszar K, Giaccia A, Weninger W, Yamauchi M, Gasser DL, Weaver VM. Cell. 2009 Nov 25;139(5):891-906. doi: 10.1016/j.cell.2009.10.027. PMID: 19931152 [PubMed - indexed for MEDLINE] Free PMC Article
Multiscale modeling of form and function. Engler AJ, Humbert PO, Wehrle-Haller B, Weaver VM. Science. 2009 Apr 10;324(5924):208-12. doi: 10.1126/science.1170107. Review. PMID: 19359578 [PubMed - indexed for MEDLINE]
A tense situation: forcing tumour progression. Butcher DT, Alliston T, Weaver VM. Nat Rev Cancer. 2009 Feb;9(2):108-22. doi: 10.1038/nrc2544. Review. PMID: 19165226 [PubMed - indexed for MEDLINE] Free PMC Article
Mechanics, malignancy, and metastasis: the force journey of a tumor cell. Kumar S, Weaver VM. Cancer Metastasis Rev. 2009 Jun;28(1-2):113-27. doi: 10.1007/s10555-008-9173-4. Review. PMID: 19153673 [PubMed - indexed for MEDLINE] Free PMC Article