Zhang Z, Chen J, Ma R, Xu C, Lu Y, Zhou J, Xia K, Lu P. Targeting Tumor Heterogeneity by Breaking a Stem Cell and Epithelial Niche Interaction Loop. Adv Sci (Weinh). (In Press)
Mammary glands lacking Ocln exhibit retarded epithelial branching, owing to reduced cell proliferation and surface expansion. Interestingly, Ocln regulates mitotic spindle orientation and function, and its loss leads to a range of defects, including prolonged prophase and failed nuclear and/or cytoplasmic division. Mechanistically, OCLN binds to the RabGTPase-11 adaptor FIP5 and recruits recycling endosomes to the centrosome to participate in spindle assembly and function. FIP5 loss recapitulates Ocln null, leading to prolonged prophase, reduced cell proliferation, and retarded epithelial branching.
Ma R, Feng D, Chen J, Zhou J, Xia K, Kong X, Hu G, Lu P. Targeting Tumor Heterogeneity by Breaking a Stem Cell and Epithelial Niche Interaction Loop. Adv Sci (Weinh). 2024 May 6:e2307452. doi: 10.1002/advs.202307452. Epub ahead of print. PMID: 38708713.
Cancer heterogeneity, including intra-tumor heterogeneity, poses as a major hurdle to limit the effectiveness of current targeted therapies. Ma et al. demonstrate that an FGF-BMP signaling positive feedback loop integrates interactions among mammary gland stem cells, luminal epithelial and stromal fibroblast niche components not only in organ regeneration, but also cancer progression. Targeting this interaction loop, for example by reduced function of one or more of its components blocks organ regeneration and breast cancer progression. The results thus have profound implications on targeting cancer heterogeneity and overcoming drug resistance in next generation of targeted therapies.
Li J, Ma R, Wang X, Lu Y, Chen J, Feng D, Zhou J, Xia K, Klein O, Xie H, Lu P. Sprouty genes regulate activated fibroblasts in mammary epithelial development and breast cancer. Cell Death Dis. 2024 Apr 10;15(4):256. doi: 10.1038/s41419-024-06637-2. PMID: 38600092
As a major component of the tumor microenvironment, cancer associated fibroblasts (CAFs) have several molecular distinct subtypes that are presumed to be functionally different. However, their embryonic origins and the basis of subtype interactions have remained unknown. We found that mammary stromal fibroblast lacking Spry1, 2, & 4 show sensitized signaling activities of multiple RTKs, increased FGF ligand production and ECM remodeling enzyme activities, and consequently overactive epithelial invasion. Single cell transcriptomic analyses show that multiple molecularly distinct subgroups give rise to one functionally essential subtype, which has the strongest ability to stimulate epithelial invasion and branching. This functional subgroup is over-represented when EGFR signaling is excessive due to loss of Sprouty function, e.g., when Sprouty genes are knocked out or downregulated in cancer, and its over-representation promotes breast cancer progression. Together, our data highlight the multi-origin nature of an essential functional subtype of the mammary fibroblasts, and that its regulation is essential for development and cancer progression.
Liu J, Zhang Y, Zhou Y, Wang QQ, Ding K, Zhao S, Lu P, Liu J, Cytoophidia couple adipose architecture and metabolism. Cellular and Molecular Life Sciences. 2022 Oct 1;79(10):534.
Ma R, Gong D, You H, Xu C, Lu Y, Bergers G, Werb Z, Klein OD, Petritsch CK, Lu P. LGL1 binds to Integrin β1 and inhibits downstream signaling to promote epithelial branching in the mammary gland. Cell Rep. 2022 Feb 15;38(7):110375. PMID: 35172155.
Epithelial branching morphogenesis in vertebrates uses a distinct mode than in invertebrates, and this process is regulated by the polarity protein LGL1. Moreover, LGL1 determines directional migration of mammary epithelial tissue by regulating the integrin β1 signaling pathway.
Lu Y, Zhou T, Xu C, Wang R, Feng D, Li J, Wang X, Kong Y, Hu G, Kong X, Lu P. Occludin is a target of Src kinase and promotes lipid secretion by binding to BTN1a1 and XOR. PLoS Biol. 2022 Jan 18;20(1):e3001518.PMID: 35041644
Occludin null mice show defective lipid metabolism. Occludin is a downstream target of Src kinase, and promotes lipid droplet secretion by binding to regulatory proteins BTN1a1 and XOR.
Lu Y, Deng R, You H, Lu P. 3D in vitro culture system to study collective migration in mammary organoid epithelium. STAR Protoc. 2021 Aug 27;2(3):100778. PMID: 34485944
Lu P, Lu Y. Born to Run? Diverse Modes of Epithelial Migration. Front Cell Dev Biol. 2021 Aug 12;9:704939. PMID: 34540829
Lu Y, Deng R, You H, Xu Y, Antos C, Sun J, Klein OD, Lu P. Asymmetric Stratification-Induced Polarity Loss and Coordinated Individual Cell Movements Drive Directional Migration of Vertebrate Epithelium. Cell Rep. 2020 Oct 13;33(2):108246. PMID: 33053348
Collective migration of mammary epithelium is a unique and multi-stage process that, unlike previously reported collective systems, uses novel mechanisms to determine migration direction and generate driving force. The results of this study open new doors to understanding the process of collective cell migration and provide new insight in understanding cancer metastasis.
Zhang Z, Sun W, Shi T, Lu P, Zhuang M, Liu JL. Capturing RNA-protein interaction via CRUIS. Nucleic Acids Res. 2020 May 21;48(9):e52. PMID: 32140725
Based on the RNA-targeted Cas enzyme and the adjacent enzyme labeling system PUP-IT, we developed a new method for capturing RNA-binding proteins on specific RNAs.
Zhou T, Lu Y, Xu C, Wang R, Zhang L, Lu P. Occludin protects secretory cells from ER stress by facilitating SNARE-dependent apical protein exocytosis. Proc Natl Acad Sci U S A. 2020 Mar 3;117(9):4758-4769. PMID: 32051248
Occludin does not function as a barrier in epithelial tissue as expected. It instead plays a vital role in the production and secretion of milk proteins, an extremely fundamental cell behavior. It localizes on secretory vesicles and interacts with SNARE proteins to enhance secretion efficiency of proteins, thereby ensuring milk production during lactation.
Shi T, Yao L, Han Y, Hao P, Lu P. Quantitative Phosphoproteomics Reveals System-Wide Phosphorylation Network Altered by Spry in Mouse Mammary Stromal Fibroblasts. Int J Mol Sci. 2019 Oct 30;20(21):5400. PMID: 31671542
Elucidated the effects of protein phosphorylation in mammary fibroblasts lacking Spry 1, 2, 4.
Lu P, Zhou T, Xu C, Lu Y. Mammary stem cells, where art thou? Wiley Interdiscip Rev Dev Biol. 2019 Nov;8(6):e357. PMID: 31322329.
Koledova Z, Lu P. A 3D Fibroblast-Epithelium Co-culture Model for Understanding Microenvironmental Role in Branching Morphogenesis of the Mammary Gland. Methods Mol Biol. 2017;1501:217-231. PMID: 27796955.
Yao L, Lu P, Ling EA. Melatonin Suppresses Toll Like Receptor 4-Dependent Caspase-3 Signaling Activation Coupled with Reduced Production of Proinflammatory Mediators in Hypoxic Microglia. PLoS One. 2016 Nov 3;11(11):e0166010. PMID: 27812200
Koledova Z, Zhang X, Streuli C, Clarke RB, Klein OD, Werb Z, Lu P. SPRY1 regulates mammary epithelial morphogenesis by modulating EGFR-dependent stromal paracrine signaling and ECM remodeling. Proc Natl Acad Sci U S A. 2016 Sep 27;113(39):E5731-40. PMID: 27621461
First in vivo proof that Spry1 regulates EGF but not FGF signaling pathway. Moreover, mammary epithelial and fibroblasts ensure the communication of these two important cell subsets through the feedback loop of Spry2-regulated FGF and Spry1-regulated EGF signaling pathway, respectively, to promote the normal development of the mammary gland.
Werb Z, Lu P. The Role of Stroma in Tumor Development. Cancer J. 2015 Jul-Aug;21(4):250-3. PMID: 26222075
Zhang X, Martinez D, Koledova Z, Qiao G, Streuli CH, Lu P. FGF ligands of the postnatal mammary stroma regulate distinct aspects of epithelial morphogenesis. Development. 2014 Sep;141(17):3352-62. Epub 2014 Jul 30. PMID: 25078648
FGF2 and FGF10 have different functions on epithelial tissue in the mammary stroma: FGF2 mainly promotes the proliferation of epithelial cells and extension of ducts, while FGF10 mainly promotes directional migration of epithelial tissue.
Zhang X, Qiao G, Lu P. Modulation of fibroblast growth factor signaling is essential for mammary epithelial morphogenesis. PLoS One. 2014 Apr 9;9(4):e92735. PMID: 24718286
Howard BA, Lu P. Stromal regulation of embryonic and postnatal mammary epithelial development and differentiation. Semin Cell Dev Biol. 2014 Jan-Feb;25-26:43-51. PMID: 24445189
Kim EJ, Jung HS, Lu P. Pleiotropic functions of fibroblast growth factor signaling in embryonic mammary gland development. J Mammary Gland Biol Neoplasia. 2013 Jun;18(2):139-42. PMID: 23613170
Lu P, Weaver VM, Werb Z. The extracellular matrix: a dynamic niche in cancer progression. J Cell Biol. 2012 Feb 20;196(4):395-406. PMID: 22351925
Detailed review of the role of the extracellular matrix (ECM) in cancer. It has so far been cited for over 3000 times in the last 10 years.
Lu P, Takai K, Weaver VM, Werb Z. Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb Perspect Biol. 2011 Dec 1;3(12):a005058. PMID: 21917992
Another review of ECM role with over 2000 citations.
Lu P, Werb Z. Patterning mechanisms of branched organs. Science. 2008 Dec 5;322(5907):1506-9. PMID: 19056977
A classic review of epithelial branching morphogenesis. It describes how branched organs form by utilizing conserved or organ-specific cellular and molecular biology for branching morphogenesis.
Lu P, Ewald AJ, Martin GR, Werb Z. Genetic mosaic analysis reveals FGF receptor 2 function in terminal end buds during mammary gland branching morphogenesis. Dev Biol. 2008 Sep 1;321(1):77-87. PMID: 18585375
Used a novel genetic-based mosaic analysis and found that FGFR2 promotes the invasion of mammary epithelium into the fat pad by regulating proliferation of luminal cells in terminal buds during mammary epithelial branch morphogenesis.
Lu P, Yu Y, Perdue Y, Werb Z. The apical ectodermal ridge is a timer for generating distal limb progenitors. Development. 2008 Apr;135(8):1395-405. PMID: 18359901
Lu P, Sternlicht MD, Werb Z. Comparative mechanisms of branching morphogenesis in diverse systems. J Mammary Gland Biol Neoplasia. 2006 Oct;11(3-4):213-28. PMID: 17120154
Sternlicht MD, Kouros-Mehr H, Lu P, Werb Z. Hormonal and local control of mammary branching morphogenesis. Differentiation. 2006 Sep;74(7):365-81. PMID: 16916375
Lu P, Minowada G, Martin GR. Increasing Fgf4 expression in the mouse limb bud causes polysyndactyly and rescues the skeletal defects that result from loss of Fgf8 function. Development. 2006 Jan;133(1):33-42. PMID: 16308330.
