Discrete Molecular Classes of Ovarian Cancer Suggestive of Unique Mechanisms of Transformation and Metastases

Abstract

Purpose: Tumor heterogeneity and subsistence of high-grade serous ovarian adenocarcinoma (HGSC) classes can be speculated from clinical incidences suggesting passive tumor dissemination versus active invasion and metastases.Experimental Design: We explored this theme toward tumor classification through two approaches of gene expression pattern clustering: (i) derivation of a core set of metastases-associated genes and (ii) resolution of independent weighted correlation networks. Further identification of appropriate cell and xenograft models was carried out for resolution of class-specific biologic functions.Results: Both clustering approaches achieved resolution of three distinct tumor classes, two of which validated in other datasets. Networks of enriched gene modules defined biologic functions of quiescence, cell division-differentiation-lineage commitment, immune evasion, and cross-talk with niche factors. Although deviant from normal homeostatic mechanisms, these class-specific profiles are not totally random. Preliminary validation of these suggests that Class 1 tumors survive, metastasize in an epithelial-mesenchymal transition (EMT)-independent manner, and are associated with a p53 signature, aberrant differentiation, DNA damage, and genetic instability. These features supported by association of cell-specific markers, including PAX8, PEG3, and TCF21, led to the speculation of their origin being the fimbrial fallopian tube epithelium. On the other hand, Class 2 tumors activate extracellular matrix-EMT-driven invasion programs (Slug, SPARC, FN1, THBS2 expression), IFN signaling, and immune evasion, which are prospectively suggestive of ovarian surface epithelium associated wound healing mechanisms. Further validation of these etiologies could define a new therapeutic framework for disease management.

Lysophosphatidic Acid Initiates Epithelial to Mesenchymal Transition and Induces β-Catenin-mediated Transcription in Epithelial Ovarian Carcinoma

“…Ovarian cancers typically display both epithelial and mesenchymal characteristics, and the mesenchymal marker vimentin is widely expressed in human tumor specimens (16). Recent molecular profiling studies support these findings, showing up-regulation of EMT and EMT-associated invasion programs in primary ovarian tumors and their matched metastases (65,66). Snail is a key inducer of EMT and functions as a negative regulator of E-cadherin transcription.…”

SPANXA suppresses EMT by inhibiting c-JUN/SNAI2 signaling in lung adenocarcinoma

“…The epithelial cells lose cell–cell junctions by down-regulating E-cadherin (CDH1) while acquiring a mesenchymal phenotype, which is characterized by up-regulated mesenchymal proteins, including vimentin (VIM), N-cadherin (CDH2) and fibronectin (FN1). This process is triggered by various signaling pathways controlled by a set of transcription factors, including SNAI1/2, HEY1, TWIST and ZEB1/2 [4–6]. In lung cancer, SNAI2/SLUG is known as a critical EMT inducer that suppresses CDH1 expression and metastasis [7, 8].…”

Functional Balance between TCF21-Slug defines phenotypic plasticity and sub-classes in high-grade serous ovarian cancer

“…Data from our previous study 16 identified class-specific association of thirteen transcription factors (TFs; Supplementary Table1); AIF1,ETV7 were excluded from further analysis due to experimental complexities of assessing immunomodulation. Promoter occupancies between the remaining TFs derived from known consensus DNA binding sequences (Figs.1a,S1a) predicted co-regulation of Tcf21,Gata4,Peg3,Gli1 and Foxl2 that correlated positively with each other and negatively with Snai2 (Slug) in the TCGA dataset ( Fig.S1b).…”

“…One of these exhibited co-operative cell migration (CCM), another undergoes epithelialmesenchymal transition (EMT) while Class3 presents with mixed features 12,16 . Correlating these with other studies using the same datasets suggested CCM-Class tumors to present as P/D/iE sub-class, EMT-Class tumors as M/IR/iM while the heterogeneous Class3 tumors possibly represent IR/D phenotypes.…”