Bcl-2 family genetic profiling reveals microenvironment-specific determinants of chemotherapeutic response

Justin R. Pritchard, Luke A. Gilbert, Corbin E. Meacham, Jennifer L. Ricks, Hai Jiang, Douglas A. Lauffenburger, Michael T. Hemann

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

The Bcl-2 family encompasses a diverse set of apoptotic regulators that are dynamically activated in response to various cell-intrinsic and -extrinsic stimuli. An extensive variety of cell culture experiments have identified effects of growth factors, cytokines, and drugs on Bcl-2 family functions, but in vivo studies have tended to focus on the role of one or two particular members in development and organ homeostasis. Thus, the ability of physiologically relevant contexts to modulate canonical dependencies that are likely to be more complex has yet to be investigated systematically. In this study, we report findings derived from a pool-based shRNA assay that systematically and comprehensively interrogated the functional dependence of leukemia and lymphoma cells upon various Bcl-2 family members across many diverse in vitro and in vivo settings. This approach permitted us to report the first in vivo loss of function screen for modifiers of the response to a front-line chemotherapeutic agent. Notably, our results reveal an unexpected role for the extrinsic death pathway as a tissue-specific modifier of therapeutic response. In particular, our findings show that particular tissue sites of tumor dissemination play critical roles in demarcating the nature and extent of cancer cell vulnerabilities and mechanisms of chemoresistance.

Original languageEnglish (US)
Pages (from-to)5850-5858
Number of pages9
JournalCancer research
Volume71
Issue number17
DOIs
StatePublished - Sep 1 2011

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Bcl-2 family genetic profiling reveals microenvironment-specific determinants of chemotherapeutic response'. Together they form a unique fingerprint.

  • Cite this

    Pritchard, J. R., Gilbert, L. A., Meacham, C. E., Ricks, J. L., Jiang, H., Lauffenburger, D. A., & Hemann, M. T. (2011). Bcl-2 family genetic profiling reveals microenvironment-specific determinants of chemotherapeutic response. Cancer research, 71(17), 5850-5858. https://doi.org/10.1158/0008-5472.CAN-11-1014