Dysregulation of Stemness Pathways in HPV Mediated Cervical Malignant Transformation Identifies Potential Oncotherapy Targets

Abstract

Human papillomavirus (HPV) infection is associated with a range of malignancies that affect anogenital and oropharyngeal sites. α-HPVs dominantly infect basal epithelial cells of mucosal tissues, where they dysregulate cell division and local immunity. The cervix is one of the mucosal sites most susceptible to HPV infections. It consists of anatomically diverse regions, and the majority of cervical intraepithelial neoplasia and cancers arise within the cervical squamo-columnar junction where undifferentiated basal progenitor cells with stem cell properties are found. The cancer stem cell theory particularly associates tumorigenesis, invasion, dissemination, and metastasis with cancer cells exhibiting stem cell properties. In this perspective, we discuss evidence of a cervical cancer stem cell niche and explore the association of stemness related genes with 5-year survival using a publicly available transcriptomic dataset of a cervical cancer cohort. We report that poor prognosis in this cohort correlates with overexpression of a subset of stemness pathway genes, a majority of which regulate the central Focal Adhesion pathway, and are also found to be enriched in the HPV infection pathway. These observations support therapeutic targeting of stemness genes overexpressed by mucosal cells infected with high-risk HPVs.

Immune-Inhibitory Gene Expression is Positively Correlated with Overall Immune Activity and Predicts Increased Survival Probability of Cervical and Head and Neck Cancer Patients

“…Absence of MHC class I gene expression by tumors could also be associated with a “cold” tumor phenotype, but we did not identify any survival associated MHC class I genes in this data set. We speculate that patients with “cold” CESC and HNSCC tumors might benefit from a multi-step therapy approach ( Frazer and Chandra, 2019 ) by: 1) conversion of “cold” to “hot” tumors using local radiation therapy to induce immunogenic cell death, and/or intra-tumor application of adjuvant (if achievable), 2) priming of a systemic tumor-targeted T cell response using HPV oncoprotein targeted vaccination for HPV + CESC and HNSCC ( Chandra et al, 2017 ), 3) immune checkpoint inhibition to prolong tumor- and therapy-induced immune responses, 4) promotion of T cell homing to the tumor by blockade of TGFβ ( Mariathasan et al, 2018 ), 5) anti-angiogenesis therapy by VEGF blockage, and 6) inhibition of tumor cell dissemination by targeting the central focal adhesion pathway ( Budhwani et al, 2020 ). Proof of principle studies have shown that “cold” to “hot” tumor conversion can be achieved, for example by intra-tumor delivery of oncolytic viruses such as Talimogene laherparpvec (T-VEC), an engineered herpes simplex virus which selectively infects cancer cells and expresses the dendritic cell attractant granulocyte-macrophage colony-stimulating factor (GM-CSF) ( Johnson et al, 2015 ).…”

p63 Directs Subtype-Specific Gene Expression in HPV+ Head and Neck Squamous Cell Carcinoma

“…The distribution of p63 peaks relative to the transcriptional start sites revealed that, in both cell lines, p63 preferentially targets intragenic and distal regulatory regions, which are likely to act as enhancer sites ( Figure 2C and Supplementary Figure 3C ). A DAVID-based pathway analysis of the genes associated with the top 2,500 p63 ChIP-seq peaks revealed several important pathways, including those deemed important in HPV-associated cancers, such as focal adhesion, p53, and Rap1 signaling pathways ( Figure 2D ) ( 53 , 54 ). Interestingly, focal adhesion pathways are enriched in the subtype of HPV+ HNSCC tumors with high p63 expression levels ( 11 , 14 , 51 ).…”

N6-methyladenosine modification of CENPK mRNA by ZC3H13 promotes cervical cancer stemness and chemoresistance

“…Stemness, chemoresistance, metastasis, and tumor size are known to contribute to cancer recurrence and poor prognosis in cervical cancer patients [ 29 , 30 ]. Notably, m 6 A RNA methylation has been recently shown to play an important role in controlling biological processes required for the development and progression of human cancers, such as cell stemness, drug resistance, metastasis, and proliferation [ 31 ].…”