Biology subjects

Khou, S.

Publications and source records attributed to Khou, S..

3 recordsLinked to original sources

bioRxiv2025

Neoplastic immune mimicry is a generalizable phenomenon in breast cancer and epithelial CD69 enables early tumor progression

Dedifferentiation programs are commonly enacted during breast cancer progression to enhance tumor cell fitness. Increased cellular plasticity within the neoplastic compartment of tumors correlates with disease aggressiveness, often culminating in greater resistance to cytotoxic therapies or augmented metastatic potential. Here we report that subpopulations of dedifferentiated neoplastic breast epithelial cells express canonical leukocyte cell surface receptor proteins and have thus named this cellular program "immune mimicry." We document neoplastic cells engaging in immune mimicry within public human breast tumor single-cell RNA-seq datasets, histopathological breast tumor specimens, breast cancer cell lines, as well as in murine transgenic and cell line-derived mammary cancer models. Immune-mimicked neoplastic cells harbor hallmarks of dedifferentiation and are enriched in treatment-resistant and high-grade breast tumors. We corroborated these observations in aggressive breast cancer cell lines where anti-proliferative cytotoxic chemotherapies drove epithelial cells toward immune mimicry. Moreover, in subsequent proof-of-concept studies, we demonstrate that expression of the CD69 leukocyte activation protein by neoplastic cells confers a proliferative advantage that facilitates early tumor growth and therefore conclude that neoplastic breast epithelial cells upregulating leukocyte surface receptors potentiate malignancy. Moving forward, neoplastic immune mimicry should be evaluated for prognostic utility in additional breast cancer cohorts to determine its potential for patient stratification. Future research should evaluate correlates with distal metastases, progression-free survival, overall survival, and therapeutic response/resistance. Statement of SignificanceNeoplastic breast epithelial cells express surface receptors canonically attributed to leukocytes and are associated with therapy resistance and aggressive tumor behavior.

cancer biology↗

bioRxiv2022

Tumor cell intrinsic RIG-I activation is sufficient to drive immune mediated tumor rejection

Targeting cytosolic nucleic acid sensors is a potent approach to drive type I interferon responses and anti-tumor immunity. Recent evidence suggests that activation of retinoic acid inducible gene-I (RIG-I) using synthetic hairpin RNA agonists decreases tumor progression in multiple preclinical models. However, the role of tumor cell intrinsic RIG-I in shaping tumor cell fates and the host immune microenvironment remains unclear. Here, we show that RIG-I expression is correlated with better overall survival and a distinct immune gene signature in specific human cancers including colorectal cancer. Activation of RIG-I in breast and colorectal cancer cells is sufficient to drive tumor cell death in vitro and significantly delay tumor growth in vivo in multiple preclinical models. Importantly, the efficacy of tumor cell RIG-I activation is lost in immune deficient mice suggesting the requirement of immune responses for this effect. We observe that tumor cell intrinsic RIG-I activation elicits a robust cellular and molecular immune response. We show that tumor cell RIG-I activation also leads to induction of specific immune checkpoints including PD-L1. Using a publicly available database, we found that RIG-I expression serves as an excellent prognostic marker for responders to checkpoint immunotherapy, particularly PD-L1/PD-1 across cancers. Finally, combination of tumor cell intrinsic RIG-I activation with anti-PD-L1 led to a synergistic decrease in tumor growth in a colorectal tumor model. Our findings suggest that tumor cell intrinsic RIG-I can be targeted to enhance anti-tumor immune responses and highlights a potential strategy for anti-cancer vaccines that can invigorate the immune system.

cancer biology↗

bioRxiv2022

DNA damage-induced lncRNA MEG9 impacts angiogenesis

Endothelial cells are highly responsive to environmental changes that allow them to adapt to intrinsic and extrinsic stimuli and switch their transcriptome accordingly to go back to vascular homeostasis. Our previous data demonstrated that small non-coding-RNAs respond quickly to genotoxic stressors and determined endothelial cell fate and DNA damage response. To further understand the contribution of non-coding-RNAs, we profiled differentially expressed long non-coding RNAs in response to genotoxic stress and compared them to pro-angiogenic growth factor signaling. We identified the Maternally expressed gene 9 (MEG9) as a cytoprotective lncRNA in the endothelium. Gain and Loss-of-function studies indicate that MEG9 prevents endothelial cells from cell death, suggesting that MEG9 responses to genotoxic stress can be an adaptive and protective mechanism. Consistent with this phenotype, the knockdown of MEG9 decreases growth factor-dependent angiogenesis in a 3D fibrin gel angiogenesis assay. Deletion of the MEG9 ortholog, Mirg, in mice results in increased vascular leak in Matrigel plugs and a sex and age-dependent decrease in platelets. Mechanistically, we observed that both MEG9 knockdown in vitro and Mirg-deleted mice in vivo activated common pathways, including apoptosis, clotting, and inflammation. Indeed, the proinflammatory adhesion molecule ICAM1 was significantly increased in human and mouse endothelial cells in a MEG9-dependent manner, supporting the increased vascular permeability observed on MEG9 deficient cells. Taken together, our findings illustrate how genotoxic stress responses through dynamic modulation of lncRNAs, such as MEG9, trigger adaptive mechanisms to maintain endothelial function, while loss of these molecules contributes to maladaptive responses and endothelial cell dysfunction.

cell biology↗