Robert Blelloch, MD, PhD

Co-Director, Developmental & Stem Cell Biology Graduate Program
Professor
Department of Urology
+1 415 476-2838

Our laboratory is interested in determining the molecular mechanisms that regulate stem cell differentiation and de-differentiation and how these mechanisms become deregulated in cancer.  Since starting the lab in 2006, we have been largely focusing on the role of post-transcriptional regulators including microRNAs (miRNAs) and RNA binding proteins (RBPs).

Embryonic Stem Cells
We have shown that a specific family of miRNAs, which we call the ESCC family, is a powerful inducer and stabilizer of the mammalian embryonic stem cell (ESC) fate.  We found that this family suppresses hundreds of downstream mRNA targets. By following a subset of these targets, we now know that the ESCC miRNAs function in part by directing the unique cell cycle structure, the epithelial state, and the epigenetic state of ESCs. We are currently dissecting the role of all the ESCC miRNA downstream targets in pluripotency. In parallel, we have uncovered other miRNAs that have the opposite function to the ESCC miRNAs in that they promote differentiation.  Indeed the differentiating miRNAs are antagonized by the ESCC miRNAs.  We are dissecting the mechanisms of these miRNAs in ESC differentiation.  Furthermore, we are studying the roles of the ESCC miRNAs in vivo. The ESCC miRNAs are expressed from two genetic loci. We are using genetic tools to understand their role in mammalian development.

Somatic Stem and Germ Cells
The lab is also studying the role of small RNAs in other stem cell types and in vivo developmental stages. In particular, we are studying miRNA roles in trophoblast stem cells, glial progenitor cells, and oocytes. We recently made the surprising finding that miRNA function is globally suppressed in mammalian oocytes. We are following up this finding by trying to understand how and why all miRNA function is temporarily inactivated during this critical developmental time window. Simultaneously, we discovered that another class of small RNAs, endogenous siRNA (endo-siRNAs) are essential for oocyte meiosis. We are currently dissecting the specific endo-siRNAs and targets responsible for meiotic progression.

Prostate Cancer
Finally, we are studying the roles of miRNAs in cancer with a particular focus on prostate cancer. We have discovered that miRNAs are essential for the progression of prostate cancer from a hyperplastic to dysplastic lesion. Similar to our ESC work, we are using genomic approaches to uncover the miRNA-mRNA networks in order to dissect the molecular pathways required for progression. Furthermore, we have been analyzing miRNA signatures in the serum of prostate cancer patients, identifying miRNAs that prospectively identify patients at risk for progression and determine how they will respond to specific therapies.

Research Summary: 
Molecular basis of stem cell self-renewal, differentiation and contribution to cancer

Websites

Featured Publications: 

Suppression of Exosomal PD-L1 Induces Systemic Anti-tumor Immunity and Memory.

Cell

Poggio M, Hu T, Pai CC, Chu B, Belair CD, Chang A, Montabana E, Lang UE, Fu Q, Fong L, Blelloch R

The eutheria-specific miR-290 cluster modulates placental growth and maternal-fetal transport.

Development (Cambridge, England)

Paikari A, D Belair C, Saw D, Blelloch R

The impact of microRNAs on transcriptional heterogeneity and gene co-expression across single embryonic stem cells.

Nature communications

Gambardella G, Carissimo A, Chen A, Cutillo L, Nowakowski TJ, di Bernardo D, Blelloch R

FOXD3 Regulates Pluripotent Stem Cell Potential by Simultaneously Initiating and Repressing Enhancer Activity.

Cell stem cell

Krishnakumar R, Chen AF, Pantovich MG, Danial M, Parchem RJ, Labosky PA, Blelloch R

miR-302 Is Required for Timing of Neural Differentiation, Neural Tube Closure, and Embryonic Viability.

Cell reports

Parchem RJ, Moore N, Fish JL, Parchem JG, Braga TT, Shenoy A, Oldham MC, Rubenstein JL, Schneider RA, Blelloch R

Two miRNA clusters reveal alternative paths in late-stage reprogramming.

Cell stem cell

Parchem RJ, Ye J, Judson RL, LaRussa MF, Krishnakumar R, Blelloch A, Oldham MC, Blelloch R