Stem cell-like transcriptional reprogramming mediates metastatic resistance to mTOR inhibition

Abstract

Inhibitors of the mechanistic target of rapamycin (mTOR) are currently used to treat advanced metastatic breast cancer. However, whether an aggressive phenotype is sustained through adaptation or resistance to mTOR inhibition remains unknown. Here, complementary studies in human tumors, cancer models and cell lines reveal transcriptional reprogramming that supports metastasis in response to mTOR inhibition. This cancer feature is driven by EVI1 and SOX9. EVI1 functionally cooperates with and positively regulates SOX9, and promotes the transcriptional upregulation of key mTOR pathway components (REHB and RAPTOR) and of lung metastasis mediators (FSCN1 and SPARC). The expression of EVI1 and SOX9 is associated with stem cell-like and metastasis signatures, and their depletion impairs the metastatic potential of breast cancer cells. These results establish the mechanistic link between resistance to mTOR inhibition and cancer metastatic potential, thus enhancing our understanding of mTOR targeting failure.

EVI1 as a Prognostic and Predictive Biomarker of Clear Cell Renal Cell Carcinoma

“…A high level of expression of EVI1 in this subtype-but not in the other KIRC subtypes (CC-e.1-2) and complete cohort-was found to be significantly associated with poorer outcome, as measured by a multivariate (including age, gender, and tumor stage) Cox regression analysis of progression-free interval (PFI; Figure 2B). The CC-e.3 subtype was identified by TCGA as the subgroup with a higher relative level of expression of markers of the epithelial-mesenchymal transition [30], which is consistent with the functional associations of EVI1 described in some cancer settings [6,7,15]. Indeed, EVI1 expression in CC-e.3 tumors was found to be positively co-expressed with several metastasis-, invasion-and integrin-related curated gene sets ( Supplementary Table S2).…”

“…In addition to myeloid leukemia, overexpression of EVI1 has been associated with aggressive phenotypes of breast cancer, colorectal, lung, ovarian, pancreatic, and prostate cancer [5][6][7][8][9][10][11][12][13].…”

“…Abnormal overexpression of EVI1 and, therefore, activation of its underlying transcriptional program, are involved in up to a quarter of pediatric acute myeloid leukemia (AML), and influence prognosis and response to chemotherapy in this setting [3,4]. More recently, an oncogenic role for EVI1 has been broadened to include several epithelial cancers, similarly associated with aggressive features [5][6][7][8][9][10][11][12][13]. Analyses of genomic alterations across cancers have shown that chromosome 3q26.2, which harbors EVI1, is amplified in a variety of epithelial cancer types [14].…”

“…In intestinal epithelial cells, oncogenic EVI1 overactivates PI3K-AKT signaling in response to TGFβ-mediated and taxol-mediated apoptosis [6]. In breast cancer, overexpression of EVI1 is associated with poor prognosis [8], stem cell-like and lung-metastatic features, and resistance to allosteric mTOR inhibition [7]. Cancer stem cell-like and metastatic cells rely on enhanced mTOR activity, and EVI1 maintains this signaling by transcriptional upregulation of key pathway components and metastatic mediators [7].…”

DLG5 suppresses breast cancer stem cell‐like characteristics to restore tamoxifen sensitivity by inhibiting TAZ expression

“…CSCs can self‐renew and differentiate to different types of mature cancer cells, leading to the development and progression of malignant tumours . BCSCs are major players of drug resistance and can promote the development of TAM resistance in breast cancer by increasing their stemness . In this study, we found that DLG5 silencing increased the frequency of CD44 + /CD24 − and ALDH + BCSCs, the formation of mammospheres, anchorage‐independent growing clonogenicity and Oct4 and c‐MYC expression in ER + MCF7 cells while induction of DLG5 overexpression decreased them in TAM‐resistant LCC2 cells.…”