Abstract

SummaryThe two oncogenes KRas and Myc cooperate to drive tumorigenesis, but the mechanism underlying this remains unclear. In a mouse lung model of KRasG12D-driven adenomas, we find that co-activation of Myc drives the immediate transition to highly proliferative and invasive adenocarcinomas marked by highly inflammatory, angiogenic, and immune-suppressed stroma. We identify epithelial-derived signaling molecules CCL9 and IL-23 as the principal instructing signals for stromal reprogramming. CCL9 mediates recruitment of macrophages, angiogenesis, and PD-L1-dependent expulsion of T and B cells. IL-23 orchestrates exclusion of adaptive T and B cells and innate immune NK cells. Co-blockade of both CCL9 and IL-23 abrogates Myc-induced tumor progression. Subsequent deactivation of Myc in established adenocarcinomas triggers immediate reversal of all stromal changes and tumor regression, which are independent of CD4+CD8+ T cells but substantially dependent on returning NK cells. We show that Myc extensively programs an immune suppressive stroma that is obligatory for tumor progression.

Highlights

  • The 1983 discovery of oncogenic cooperation between activated Ras and Myc (Land et al, 1983) demonstrated the obligate interdependence of individual oncogenic mutations

  • Co-transgenic in vivo studies in mice demonstrated that oncogenic cooperation between Ras and Myc in diverse tissues (Alexander et al, 1989; Andres et al, 1988; Boxer et al, 2004; Compere et al, 1989; Podsypanina et al, 2008; Tran et al, 2008; Yaari et al, 2005) necessarily involves modulation of interactions between the tumor cells and their stroma

  • Activation of MycERT2 in 12-week-old indolent KRasG12D-driven lesions dramatically accelerated tumorigenesis over that in KRasG12D-only controls (Figures 1A, S1A, S2A, and S2B), resulting in highly proliferative, invasive tumors heavily infiltrated with leukocytes and with inchoate, nascent vasculature indicative of ongoing angiogenesis (Figures 1B–1D)

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Summary

Introduction

The 1983 discovery of oncogenic cooperation between activated Ras and Myc (Land et al, 1983) demonstrated the obligate interdependence of individual oncogenic mutations. Co-transgenic in vivo studies in mice demonstrated that oncogenic cooperation between Ras and Myc in diverse tissues (Alexander et al, 1989; Andres et al, 1988; Boxer et al, 2004; Compere et al, 1989; Podsypanina et al, 2008; Tran et al, 2008; Yaari et al, 2005) necessarily involves modulation of interactions between the tumor cells and their stroma. Both Ras and Myc are implicated in human non-small cell lung cancer (NSCLC). Even in NSCLC not overtly driven by mutations in Ras or Myc themselves, endogenous Ras and Myc both play prominent, even obligate, roles as downstream conduits for diverse upstream oncogenic drivers

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