Biology subjects

Sikandar, S. S.

Publications and source records attributed to Sikandar, S. S..

5 recordsLinked to original sources

bioRxiv2025

LMO2 regulates epithelial-mesenchymal plasticity of mammary epithelial cells

Cellular plasticity in mammary epithelial cells enables dynamic cell state changes essential for normal development but can be hijacked by breast cancer cells to drive tumor progression. However, the molecular factors that maintain cellular plasticity through the regulation of a hybrid cell state (epithelial/mesenchymal) are not fully defined. As LMO2 has been previously shown to regulate metastasis, here we determined the role of LMO2 in the normal mammary epithelial cells. Using lineage tracing and knockout mouse models we find that Lmo2 lineage-traced cells persist long-term in the mammary gland, both in the luminal and basal layer but have limited proliferative potential. Lmo2 loss does not impact mammary gland development, but acute deletion decreases in vivo reconstitution. Moreover, LMO2 knockdown in mouse and human mammary epithelial cells (MECs) reduces organoid formation. We find that LMO2 maintains a hybrid cell state in MECs and LMO2 knockdown promotes mesenchymal differentiation. Transcriptional profiling of LMO2 knockdown cells reveals significant enrichment in the epithelial-mesenchymal transition (EMT) pathway and upregulation of MCAM, a negative regulator of regenerative capacity in the mammary gland. Altogether, we show that LMO2 plays a role in maintaining cellular plasticity in MECs, adding insight into the normal differentiation programs hijacked by cancer cells to drive tumor progression.

developmental biology↗

bioRxiv2024

Pregnancy Reduces Il33+ Hybrid Progenitor Accumulation in the Aged Mammary Gland

Aging increases breast cancer risk while an early first pregnancy reduces a womans life-long risk. Several studies have explored the effect of either aging or pregnancy on mammary epithelial cells (MECs), but the combined effect of both remains unclear. Here, we interrogate the functional and transcriptomic changes at single cell resolution in the mammary gland of aged nulliparous and parous mice to discover that pregnancy normalizes age-related imbalances in lineage composition, while also inducing a differentiated cell state. Importantly, we uncover a minority population of Il33-expressing hybrid MECs with high cellular potency that accumulate in aged nulliparous mice but is significantly reduced in aged parous mice. Functionally, IL33 treatment of basal, but not luminal, epithelial cells from young mice phenocopies aged nulliparous MECs and promotes formation of organoids with Trp53 knockdown. Collectively, our study demonstrates that pregnancy blocks the age-associated loss of lineage integrity in the basal layer through a decrease in Il33+ hybrid MECs, potentially contributing to pregnancy-induced breast cancer protection.

developmental biology↗

bioRxiv2021

LMO2 is critical for early metastatic events in breast cancer

Metastasis is responsible for the majority of breast cancer-related deaths, however identifying the cellular determinants of metastasis has remained challenging. Here, we identified a minority population of immature THY1+/VEGFA+ tumor epithelial cells in human breast tumor biopsies that display angiogenic features and are marked by the expression of the oncogene, LMO2. Higher abundance of LMO2+ basal cells correlated with tumor endothelial content and predicted poor distant recurrence-free survival in patients. Using MMTV-PyMT/Lmo2CreERT2 mice, we demonstrated that Lmo2 lineage- traced cells have a higher propensity to metastasize. LMO2 knockdown in human breast tumors reduced lung metastasis by impairing intravasation, leading to a reduced frequency of circulating tumor cells. Mechanistically, we find that LMO2 binds to STAT3 and is required for STAT3 activation by TNF and IL6. Collectively, our study identifies a population of metastasis-initiating cells with angiogenic features and establishes the LMO2-STAT3 signaling axis as a therapeutic target in breast cancer metastasis. One sentence summaryLMO2 modulates STAT3 signaling in breast cancer metastasis.

cancer biology↗

bioRxiv2019

Single-cell transcriptional diversity is a hallmark of developmental potential

Single-cell RNA-sequencing (scRNA-seq) is a powerful approach for reconstructing cellular differentiation trajectories. However, inferring both the state and direction of differentiation without prior knowledge has remained challenging. Here we describe a simple yet robust determinant of developmental potential--the number of detectably expressed genes per cell-- and leverage this measure of transcriptional diversity to develop a new framework for predicting ordered differentiation states from scRNA-seq data. When evaluated on ~150,000 single-cell transcriptomes spanning 53 lineages and five species, our approach, called CytoTRACE, outperformed previous methods and ~19,000 molecular signatures for resolving experimentally-confirmed developmental trajectories. In addition, it enabled unbiased identification of tissue-resident stem cells, including cells with long-term regenerative potential. When used to analyze human breast tumors, we discovered candidate genes associated with less-differentiated luminal progenitor cells and validated GULP1 as a novel gene involved in tumorigenesis. Our study establishes a key RNA-based correlate of developmental potential and provides a new platform for robust delineation of cellular hierarchies (https://cytotrace.stanford.edu).

genomics↗

bioRxiv2018

CDK19 is a Regulator of Triple-Negative Breast Cancer Growth

Triple-negative breast cancer (TNBC) is a poor prognosis disease with no clinically approved targeted therapies. Here, using in vitro and in vivo RNA interference (RNAi) screens in TNBC patient-derived xenografts (PDX), we identify cyclin dependent kinase 19 (CDK19) as a potential therapeutic target. Using in vitro and in vivo TNBC PDX models, we validated the inhibitory effect of CDK19 knockdown on tumor initiation, proliferation and metastases. Despite this, CDK19 knockdown did not affect the growth of non-transformed mammary epithelial cells. Using CD10 and EpCAM as novel tumor initiating cell (TIC) markers, we found the EpCAMmed/high/CD10-/low TIC sub-population to be enriched in CDK19 and a putative cellular target of CDK19 inhibition. Comparative gene expression analysis of CDK19 and CDK8 knockdowns revealed that CDK19 regulates a number of cancer-relevant pathways, uniquely through its own action and others in common with CDK8. Furthermore, although it is known that CDK19 can act at enhancers, our CHIP-Seq studies showed that CDK19 can also epigenetically modulate specific H3K27Ac enhancer signals which correlate with gene expression changes. Finally, to assess the potential therapeutic utility of CDK19, we showed that both CDK19 knockdown and chemical inhibition of CDK19 kinase activity impaired the growth of pre-established PDX tumors in vivo. Current strategies inhibiting transcriptional co-factors and targeting TICs have been limited by toxicity to normal cells. Because of CDK19s limited tissue distribution and the viability of CDK19 knockout mice, CDK19 represents a promising therapeutic target for TNBC.

cancer biology↗