Plasticity underlies tumor progression: role of Nodal signaling

Abstract

The transforming growth factor beta (TGFβ) superfamily member Nodal is an established regulator of early embryonic development, with primary roles in endoderm induction, left-right asymmetry and primitive streak formation. Nodal signals through TGFβ family receptors at the plasma membrane and induces signaling cascades leading to diverse transcriptional regulation. While conceptually simple, the regulation of Nodal and its molecular effects are profoundly complex and context dependent. Pioneering work by developmental biologists has characterized the signaling pathways, regulatory components, and provided detailed insight into the mechanisms by which Nodal mediates changes at the cellular and organismal levels. Nodal is also an important factor in maintaining pluripotency of embryonic stem cells through regulation of core transcriptional programs. Collectively, this work has led to an appreciation for Nodal as a powerful morphogen capable of orchestrating multiple cellular phenotypes. Although Nodal is not active in most adult tissues, its re-expression and signaling have been linked to multiple types of human cancer, and Nodal has emerged as a driver of tumor growth and cellular plasticity. In vitro and in vivo experimental evidence has demonstrated that inhibition of Nodal signaling reduces cancer cell aggressive characteristics, while clinical data have established associations with Nodal expression and patient outcomes. As a result, there is great interest in the potential targeting of Nodal activity in a therapeutic setting for cancer patients that may provide new avenues for suppressing tumor growth and metastasis. In this review, we evaluate our current understanding of the complexities of Nodal function in cancer and highlight recent experimental evidence that sheds light on the therapeutic potential of its inhibition.

Targeting melanoma with front-line therapy does not abrogate Nodal-expressing tumor cells

“…9,[13][14][15][16][17][18] Our findings, as well as those by others, have shown significant levels of Nodal expression in a variety of virulent neoplasms, including melanoma, breast, prostate, ovary, and ovarian cancers in association with advanced disease. 19 Because Nodal expression is not typically observed in most normal adult tissues, it has the potential as a promising new targetable molecule during the late stages of cancer progression.…”

NODAL/TGFβ signalling mediates the self-sustained stemness induced by PIK3CAH1047R homozygosity in pluripotent stem cells

“…Specifically, NODAL re-expression has previously been linked to aggressive features such as invasion and metastasis in a range of cancers(reviewed in Refs. ( 24, 41 )), and associated with poor prognosis in breast cancer ( 42 – 45 ). Given the high prevalence of PIK3CA H1047R in breast cancers (35.4 %; cBioPortal non-overlapping breast cancer studies, accessed August 2019) ( 3 ), we next stratified the breast invasive carcinoma (BRCA) dataset in The Cancer Genome Atlas (TCGA) according to PIK3CA H1047R allele dosage and conducted targeted analysis of NODAL, NANOG, POU5F1 and MYC expression, comparing tumors with multiple PIK3CA H1047R copies to those with a single copy.…”

EGFR signaling promotes inflammation and cancer stem-like activity in inflammatory breast cancer

“…As shown in Supplementary Figure 5A , we selected 5 top target genes—SNAI1, SNAI2, Zeb2, Nodal, and ITGA5—that were downregulated by celecoxib treatment. We further validated the change in Nodal, a molecule in the TGFβ superfamily involved in regulating cell “stemness” [ 23 – 28 ]. Stimulation of SUM149 cells with PGE 2 and PGF 2a increased Nodal expression at the mRNA level in SUM149 cells (Figure 5A ), whereas celecoxib treatment decreased Nodal expression at the mRNA level in SUM149 cells (Figure 5B ) and KPL-4 cells ( Supplementary Figure 5B ).…”