Associate Professor of Oncological Sciences and
Adjunct Associate Professor of Bioengineering and Adjunct Assistant Professor of Biology
B.A. University of California, Berkeley
Ph.D. University of California, San Francisco
Jody Rosenblatt's Lab Page
Jody Rosenblatt's PubMed Literature Search
We have identified a process all epithelia use to remove dying cells without disrupting barrier function called ‘cell extrusion’. We study extrusion using cell culture epithelia and zebrafish epidermis (see example of a dying extruding cell). To extrude, a cell destined to die produces and emits a bioactive lipid Sphingosine 1-Phosphate (S1P), which binds to a G-protein coupled receptor (S1P2) in the neighboring cells to form a contractile actin/myosin band that squeezes the cell out without disrupting the epithelial barrier (Gu et al, JCB 2011). Recently we have found that normal epithelial cell death depends on first extruding live cells.
Extrution-zebrafish epidermis Actin DNA caspase
Extrusion Misregulation and Cancer:
Although cells comprising the epithelium must act collectively to create a barrier for all of the organs they encase, they are constantly turning over via cell death and division. To maintain homeostasis, the numbers of cells that divide must match those that die. If too many cells accumulate, epithelial cancers (or carcinomas) result, whereas too much death results in poor barrier function (seen in asthma and colitis). Importantly, we have found that in vivo epithelia typically extrude live cells that eventually die, suggesting that extrusion drives cell death to control cell numbers during homeostasis (see schematic)(Eisenhoffer et al, Nature 2012). Live cells extrude at sites in the epithelia that become crowded (top gold cells) from other cells within the epithelium dividing and migrating (see crypt). Experimentally crowding cells also induces extrusion of live cells through a stretch-activated channel, Piezo 1. Blocking extrusion by disrupting the S1P-S1P2 pathway or Piezo 1 can lead to accumulation of cell masses in both cell culture and in zebrafish epidermis (see below). Similarly, aggressive tumors such as pancreatic and lung carcinomas, also lack the S1P2 receptor, critical for cell extrusion. We are currently finding small molecules that can rescue extrusion-mediated death and resolve these cell masses without affecting the barrier function in zebrafish. These inhibitors should provide important new clinical approaches to curing these deadly cancers.
Polarity of Extrusion
In tumors where cell death is blocked, extrusion could either suppress tumor formation (if cells are expelled out apically) or enable tumor cells to exit their primary sites and migrate to other sites (if they are extruded basally, below the epithelium). While most cells extrude apically into the lumen, some cells can extrude basally, back into the tissue the epithelium encases. Importantly, we have found that disrupting the tumor suppressor adenomatous polyposis coli (APC) or expressing oncogenic K-Ras drives extrusion predominantly basally, suggesting that shifting extrusion from apical to basal could be a common mechanism to promote tumor invasion. We are currently testing if disrupting the extrusion direction can promote invasion in zebrafish epidermis, where we can readily visualize all cell movements.
- Gudipaty SA and Rosenblatt J (2016) Epithelial Cell Extrusion: pathways and pathologies. Semin Cell Dev Biol May 19. pii: S1084-9521(16)30136-7.
- Eisenhoffer GT, Slattum G, Ruiz OE, Otsuna H, Bryan CD, Lopez J, Wagner DS, Bonkowsky JL, Chien CB, Dorsky RI, and Rosenblatt J (2016) A toolbox to study epidermal cell types in zebrafish. J Cell Sci May 5. pii: jcs.184341.
- Gu Y, Jill Shea J, Slattum GM, Firpo MA, Alexander M, Mulvihill SJ, Golubovskaya VM, and Rosenblatt J (2015) Defective apical extrusion signaling contributes to aggressive tumor hallmarks. Elife Jan 26; 4: e04069. doi: 10.7554/eLife.04069.
- Slattum GM and Rosenblatt J (2014) Tumour cell invasion: an emerging role for basal epithelial cell extrusion. Nature Reviews Cancer 14(7): 495-501.
- Slattum G, Gu Y, Sabbadini R, and Rosenblatt J (2014) Autophagy in oncogenic K-Ras promotes basal extrusion of epithelial cells by degrading S1P. Current Biology 24(1): 19-28.
- Eisenhoffer GT and Rosenblatt J (2013) Bringing balance by force: live cell extrusion controls epithelial cell numbers. Trends in Cell Biology 23(4): 185-92.
- Rosenblatt J (2012) Programmed cell death: a new way worms get rid of unwanted cells. Current Biology 22(19): R844-6. (Highlighted in Cell, and reviewed in Cell, Nature Reviews Molecular and Cell Biology, Current Biology, and médecine/sciences)
- Gu Y and Rosenblatt J (2012) New emerging roles for epithelial cell extrusion. Current Opinion in Cell Biology 24(6): 865-70.
- Eisenhoffer GT*, Loftus PD*, Yoshigi M, Otsuna H, Chien CB, Morcos PA, and Rosenblatt J (2012) Overcrowding induces extrusion of live cells to control epithelial cell numbers. Nature 484(7395): 546-9. (Highlighted in Cell, and reviewed in Cell, Nature Reviews Molecular and Cell Biology, Current Biology, and médecine/sciences)
- Marshall T, Delalande JM, Lloyd IE, and Rosenblatt J (2011) The tumor suppressor adenomatous polyposis coli controls the direction of epithelial cell extrusion. Molecular Biology of the Cell 22(21): 3962-70. (Highlighted in Science Signaling, and the American Society for Cell Biology Newsletter, and won the Molecular Biology of the Cell Paper of the Year)
- Gu Y, Forostyan T, Sabbadini RA, and Rosenblatt J (2011) Epithelial cell extrusion requires the sphingosine-1-phosphate receptor 2 pathway. Journal of Cell Biology 193(4): 667-76. (cover) (Highlighted in: The Journal of Cell Biology, Nature Cell Biology, and Faculty of 1000)
- Eisenhoffer GT and Rosenblatt J (2011) Live imaging of cell extrusion from the epidermis of developing zebrafish. Journal of Visualized Experiments Jun 27;(52). pii: 2689.
- Andrade D and Rosenblatt J (2011) Apoptotic regulation of epithelial cellular extrusion. Apoptosis 16(5): 491-501.
- Slattum G, McGee KM, and Rosenblatt J (2009) P115 RhoGEF and microtubules decide the direction apoptotic cells extrude from an epithelium. Journal of Cell Biology 186(5): 693-702. (cover) (Highlighted in Science, The Journal of Cell Biology, and Faculty of 1000)
- Rosenblatt J (2008) Mitosis: moesin and the importance of being round. Current Biology 18(7): 292-3.
- Rosenblatt J (2005) Spindle assembly: asters part their separate ways. Nature Cell Biology 7(3): 219-22.
- Rosenblatt J, Cramer LP, Baum B, and McGee KM (2004) Myosin II-dependent cortical movement is required for centrosome separation and positioning during mitotic spindle assembly. Cell 117(3): 361-372. (cover) (Highlighted in: Cell, The Journal of Cell Biology, Nature Cell Biology, and Faculty of 1000)
- Rosenblatt J, Raff MC, and Cramer LP (2001) An epithelial cell destined for apoptosis signals its neighbours to extrude it by an actin-and myosin-dependent mechanism. Current Biology 11(23): 1847–1857. (cover) (Highlighted in: Science, The Journal of Cell Biology, Current Biology, Current Opinion in Cell Biology, American Society for Cell Biology Press Book and noted as a ‘must read’ in Faculty of 1000)