Abstract
PTEN encodes a lipid phosphatase that is underexpressed in many cancers owing to deletions, mutations or gene silencing1–3. PTEN dephosphorylates phosphatidylinositol 3,4,5-triphosphate (PIP3), thereby opposing the activity of class I phosphatidylinositol 3-kinases (PI3Ks) that mediate growth and survival factors signaling through PI3K effectors such as AKT and mTOR2. To determine whether continued PTEN inactivation is required to maintain malignancy, we generated an RNAi-based transgenic mouse model that allows tetracycline-dependent regulation of PTEN in a time- and tissue-specific manner. Postnatal PTEN knockdown in the hematopoietic compartment produced highly disseminated T-cell leukemia (T-ALL). Surprisingly, reactivation of PTEN mainly reduced T-ALL dissemination but had little effect on tumor load in hematopoietic organs. Leukemia infiltration into the intestine was dependent on CCR9 G-protein coupled receptor (GPCR) signaling, which was amplified by PTEN loss. Our results suggest that in the absence of PTEN, GPCRs may play an unanticipated role in driving tumor growth and invasion in an unsupportive environment. They further reveal that the role of PTEN loss in tumor maintenance is not invariant and can be influenced by the tissue microenvironment, thereby producing a form of intratumoral heterogeneity that is independent of cancer genotype.
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