Single cell transcriptomic heterogeneity in invasive ductal and lobular breast cancer cells

Chen, Fangyuan; Ding, Kai; Priedigkeit, Nolan; Elangovan, Ashuvinee; Levine, Kevin M.; Carleton, Neil; Savariau, Laura; Atkinson, Jennifer M.; Oesterreich, Steffi; Lee, Adrian V.

doi:10.1101/2020.02.21.959023

Cited by 5 publications

(6 citation statements)

References 71 publications

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“…5B). As expected, dormant cells suspend oestrogen and confirm the Pre-Adapted dormancy signature we have previously identified (Chen et al, 2021;Hong et al, 2019). As expected, dormant cells also suspend metabolic activities (glycolysis and oxidative phosphorylation), G2M checkpoint and MYC signalling, in agreement with quiescence (Rehman et al, 2021).…”

Section: Figure 2 Longitudinal Tracing Via Transcriptional Barcodes a Schematic Representation Ofsupporting

confidence: 88%

Unperturbed dormancy recording reveals stochastic awakening strategies in endocrine treated breast cancer cells

Rosano

Sofyalı

Dheman

et al. 2021

Preprint

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Hormone dependent breast cancer (HDBC) is the most commonly diagnosed tumor type in women. Adjuvant endocrine therapies (ET) have been the cornerstone in the clinical management of HDBC patients for over forty years. A vast proportion of HDBC patients incur long periods of clinical dormancy following ET, with tumour awakening appearing at a steady pace for up to 25 years (Pan et al., 2017). Extensive genomic studies have demonstrated that 15-30% of clinical relapses develop recurrent genomic changes which contribute to drug resistance (i.e. ESR1 activating mutations) (Bertucci et al., 2019; Magnani et al., 2017; Razavi et al., 2018). However, even in these cases, there is no conclusive evidence around the pre-existence vs. de novo nature of these events. We previously showed that ETs can trigger and select for dormancy in subpopulations of breast cancer (Hong et al., 2019). In this work we took two novel approaches to investigate the dormancy and awakening roadmap of HDBC cells at unprecedented detail. Firstly, we leveraged a rare cohort of n=5 patients which were treated with primary adjuvant ETs in the absence of surgery (TRACING-HT) to dissect the contribution of genomic aberrations to tumor awakening. Next, we developed a first of its kind evolutionary study in vitro to systematically annotate cancer cells adaptive strategies at single cell level in unperturbed systems during a period of several months (TRADITIOM). Collectively our data suggest that ETs steer HDBC cells into an inherently unstable dormant state. Over time, routes to awakening emerge sporadically and spontaneously in single lineages. Each dormant cell retains an intrinsic awakening probability which we propose is a function of epigenetic decay. Awakening occurs without an external trigger and involves multiple apparent endpoint phenotypes that cannot be fully explained by conventional Darwinian genetic selection processes. Finally, our data show that common genetic hits associated with resistance happen downstream of awakening. Overall, our data have uncovered previously unsuspected roles for stochastic nongenetic events during dormancy with profound clinical implications.

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Section: Figure 2 Longitudinal Tracing Via Transcriptional Barcodes a Schematic Representation Ofsupporting

confidence: 88%

Unperturbed dormancy recording reveals stochastic awakening strategies in endocrine treated breast cancer cells

Rosano

Sofyalı

Dheman

et al. 2021

Preprint

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“…Cells were plated the day before addition of 1 μg/ml doxycycline (Sigma Aldrich). Knockout of E-cadherin was performed as previously described 63 by utilizing the Gene Knockout Kit (V1) from Synthego (Redwood City, California) and cells were used as pools.…”

Section: Methodsmentioning

confidence: 99%

Proteomic and transcriptomic profiling identifies mediators of anchorage-independent growth and roles of inhibitor of differentiation proteins in invasive lobular carcinoma

Tasdemir

Ding

Savariau

et al. 2020

Sci Rep

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Invasive lobular carcinoma (ILC) is a histological subtype of breast cancer with distinct molecular and clinical features from the more common subtype invasive ductal carcinoma (IDC). ILC cells exhibit anchorage-independent growth in ultra-low attachment (ULA) suspension cultures, which is largely attributed to the loss of E-cadherin. In addition to anoikis resistance, herein we show that human ILC cell lines exhibit enhanced cell proliferation in ULA cultures as compared to IDC cells. Proteomic comparison of ILC and IDC cell lines identified induction of PI3K/Akt and p90-RSK pathways specifically in ULA culture in ILC cells. Further transcriptional profiling uncovered unique upregulation of the inhibitors of differentiation family transcription factors ID1 and ID3 in ILC ULA culture, the knockdown of which diminished the anchorage-independent growth of ILC cell lines through cell cycle arrest. We find that ID1 and ID3 expression is higher in human ILC tumors as compared to IDC, correlated with worse prognosis uniquely in patients with ILC and associated with upregulation of angiogenesis and matrisome-related genes. Altogether, our comprehensive study of anchorage independence in human ILC cell lines provides mechanistic insights and clinical implications for metastatic dissemination of ILC and implicates ID1 and ID3 as novel drivers and therapeutic targets for lobular breast cancer.

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“…The scRNA-seq technique has become a powerful tool for the elucidation of intra-tumor and intra-cell line heterogeneity in breast cancer ( 2 , 23 ). Estrogen regulation generally involves not only individual molecules but also molecular networks.…”

Section: Discussionmentioning

confidence: 99%

“…The transcriptional regulation of estrogen receptor (ER) is an intricate network of signaling and functional processes that is still largely unknown at the single cell level. Recently, the intra-cell line heterogeneity of breast cancer has been comprehensively characterized through single-cell RNA sequencing (scRNA-seq), revealing transcriptomic subpopulations within cell lines ( 2 ). Therefore, investigating the heterogeneity of estrogen regulation at the single cell level could shed more light on estrogen mechanisms and potential breast cancer therapeutics.…”

Section: Introductionmentioning

confidence: 99%

Inferring Cell Subtypes and LncRNA Function by a Cell-Specific CeRNA Network in Breast Cancer

Chen

Zeng

et al. 2021

Front. Oncol.

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Single-cell RNA sequencing is a powerful tool to explore the heterogeneity of breast cancer. The identification of the cell subtype that responds to estrogen has profound significance in breast cancer research and treatment. The transcriptional regulation of estrogen is an intricate network involving crosstalk between protein-coding and non-coding RNAs, which is still largely unknown, particularly at the single cell level. Therefore, we proposed a novel strategy to specify cell subtypes based on a cell-specific ceRNA network (CCN). The CCN was constructed by integrating a cell-specific RNA-RNA co-expression network (RCN) with an existing ceRNA network. The cell-specific RCN was built based on single cell expression profiles with predefined reference cells. Heterogeneous cell subtypes were inferred by enriching RNAs in CCN to the estrogen response hallmark. Edge biomarkers were identified in the early estrogen response subtype. Topological analysis revealed that NEAT1 was a hub lncRNA for the early response subtype, and its ceRNAs could predict patient survival. Another hub lncRNA, DLEU2, could potentially be involved in GPCR signaling, based on CCN. The CCN method that we proposed here facilitates the inference of cell subtypes from a network perspective and explores the function of hub lncRNAs, which are promising targets for RNA-based therapeutics.

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Single cell transcriptomic heterogeneity in invasive ductal and lobular breast cancer cells

Cited by 5 publications

References 71 publications

Unperturbed dormancy recording reveals stochastic awakening strategies in endocrine treated breast cancer cells

Unperturbed dormancy recording reveals stochastic awakening strategies in endocrine treated breast cancer cells

Proteomic and transcriptomic profiling identifies mediators of anchorage-independent growth and roles of inhibitor of differentiation proteins in invasive lobular carcinoma

Inferring Cell Subtypes and LncRNA Function by a Cell-Specific CeRNA Network in Breast Cancer

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