Philip Beachy, PhD

My lab studies the function of Hedgehog proteins and other extracellular signals in morphogenesis (pattern formation) and in injury repair and regeneration (pattern maintenance). We study how the distribution of such signals is regulated in tissues, how cells perceive and respond to distinct concentrations of signals, and how such signaling pathways arose in evolution. We also study the normal roles of such signals in stem-cell physiology and their abnormal roles in the formation and expansion of cancer stem cells.

The Ernest and Amelia Gallo Professor in the School of Medicine, Professor of Developmental Biology and, by courtesy, of Chemical and Systems Biology

Publications

  • Neuronal delivery of Hedgehog directs spatial patterning of taste organ regeneration. Proceedings of the National Academy of Sciences of the United States of America Lu, W. J., Mann, R. K., Nguyen, A., Bi, T., Silverstein, M., Tang, J. Y., Chen, X., Beachy, P. A. 2018; 115 (2): E200–E209

    Abstract

    How organs maintain and restore functional integrity during ordinary tissue turnover or following injury represents a central biological problem. The maintenance of taste sensory organs in the tongue was shown 140 years ago to depend on innervation from distant ganglion neurons, but the underlying mechanism has remained unknown. Here, we show that Sonic hedgehog (Shh), which encodes a secreted protein signal, is expressed in these sensory neurons, and that experimental ablation of neuronal Shh expression causes loss of taste receptor cells (TRCs). TRCs are also lost upon pharmacologic blockade of Hedgehog pathway response, accounting for the loss of taste sensation experienced by cancer patients undergoing Hedgehog inhibitor treatment. We find that TRC regeneration following such pharmacologic ablation requires neuronal expression of Shh and can be substantially enhanced by pharmacologic activation of Hedgehog response. Such pharmacologic enhancement of Hedgehog response, however, results in additional TRC formation at many ectopic sites, unlike the site-restricted regeneration specified by the projection pattern of Shh-expressing neurons. Stable regeneration of TRCs thus requires neuronal Shh, illustrating the principle that neuronal delivery of cues such as the Shh signal can pattern distant cellular responses to assure functional integrity during tissue maintenance and regeneration.

    View details for DOI 10.1073/pnas.1719109115

    View details for PubMedID 29279401

    View details for PubMedCentralID PMC5777079

  • Hedgehog mediated degradation of Ihog adhesion proteins modulates cell segregation in Drosophila wing imaginal discs NATURE COMMUNICATIONS Hsia, E. C., Zhang, Y., Tran, H., Lim, A., Chou, Y., Lan, G., Beachy, P. A., Zheng, X. 2017; 8: 1275

    Abstract

    The Drosophila Hedgehog receptor functions to regulate the essential downstream pathway component, Smoothened, and to limit the range of signaling by sequestering Hedgehog protein signal within imaginal disc epithelium. Hedgehog receptor function requires both Patched and Ihog activity, the latter interchangeably encoded by interference hedgehog (ihog) or brother of ihog (boi). Here we show that Patched and Ihog activity are mutually required for receptor endocytosis and degradation, triggered by Hedgehog protein binding, and causing reduced levels of Ihog/Boi proteins in a stripe of cells at the anterior/posterior compartment boundary of the wing imaginal disc. This Ihog spatial discontinuity may contribute to classically defined cell segregation and lineage restriction at the anterior/posterior wing disc compartment boundary, as suggested by our observations that Ihog activity mediates aggregation of otherwise non-adherent cultured cells and that loss of Ihog activity disrupts wing disc cell segregation, even with downstream genetic rescue of Hedgehog signal response.

    View details for DOI 10.1038/s41467-017-01364-z

    View details for Web of Science ID 000414245600006

    View details for PubMedID 29097673

    View details for PubMedCentralID PMC5668237

  • Stromal Gli2 activity coordinates a niche signaling program for mammary epithelial stem cells SCIENCE Zhao, C., Cai, S., Shin, K., Lim, A., Kalisky, T., Lu, W., Clarke, M. F., Beachy, P. A. 2017; 356 (6335): 284-?
  • The Stromal Niche for Epithelial Stem Cells: A Template for Regeneration and a Brake on Malignancy. Cancer cell Roberts, K. J., Kershner, A. M., Beachy, P. A. 2017; 32 (4): 404–10

    Abstract

    Stromal restraint of cancer growth and progression-emerging as a widespread phenomenon in epithelial cancers such as bladder, pancreas, colon, and prostate-appears rooted in stromal cell niche activity. During normal tissue repair, stromal niche signals, often Hedgehog-induced, promote epithelial stem cell differentiation as well as self-renewal, thus specifying a regenerating epithelial pattern. In the case of cancerous tissue, stromal cell-derived differentiation signals in particular may provide a brake on malignant growth. Understanding and therapeutic harnessing of the role of stroma in cancer restraint may hinge on our knowledge of the signaling programs elaborated by the stromal niche.

    View details for DOI 10.1016/j.ccell.2017.08.007

    View details for PubMedID 29017054

    View details for PubMedCentralID PMC5679442

  • Rapid, direct activity assays for Smoothened reveal Hedgehog pathway regulation by membrane cholesterol and extracellular sodium. Proceedings of the National Academy of Sciences of the United States of America Myers, B. R., Neahring, L., Zhang, Y., Roberts, K. J., Beachy, P. A. 2017; 114 (52): E11141–E11150

    Abstract

    Hedgehog signaling specifies tissue patterning and renewal, and pathway components are commonly mutated in certain malignancies. Although central to ensuring appropriate pathway activity in all Hedgehog-responsive cells, how the transporter-like receptor Patched1 regulates the seven-transmembrane protein Smoothened remains mysterious, partially due to limitations in existing tools and experimental systems. Here we employ direct, real-time, biochemical and physiology-based approaches to monitor Smoothened activity in cellular and in vitro contexts. Patched1-Smoothened coupling is rapid, dynamic, and can be recapitulated without cilium-specific proteins or lipids. By reconstituting purified Smoothened in vitro, we show that cholesterol within the bilayer is sufficient for constitutive Smoothened activation. Cholesterol effects occur independently of the lipid-binding Smoothened extracellular domain, a region that is dispensable for Patched1-Smoothened coupling. Finally, we show that Patched1 specifically requires extracellular Na+ to regulate Smoothened in our assays, raising the possibility that a Na+ gradient provides the energy source for Patched1 catalytic activity. Our work suggests a hypothesis wherein Patched1, chemiosmotically driven by the transmembrane Na+ gradient common to metazoans, regulates Smoothened by shielding its heptahelical domain from cholesterol, or by providing an inhibitor that overrides this cholesterol activation.

    View details for DOI 10.1073/pnas.1717891115

    View details for PubMedID 29229834

    View details for PubMedCentralID PMC5748227