Intra-tumor molecular heterogeneity in breast cancer: definitions of measures and association with distant recurrence-free survival

Saha, Ashirbani; Harowicz, Michael R.; Cain, Elizabeth Hope; Hall, Allison; Hwang, E. Shelley; Marks, Jeffrey R.; Marcom, P. Kelly; Mazurowski, Maciej A.

doi:10.1007/s10549-018-4879-7

Cited by 11 publications

(6 citation statements)

References 39 publications

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“…The resulting cell embeddings (first 30 components, henceforth referred to as ‘PCA space’) were finally used to construct the Shared Nearest-Neighbors (SNN) graph (constructed from an initial k-NN search with k=30, as implemented in the buildSNNGraph() function from scran) that fed Louvain clustering (implemented in the cluster_louvain() function from igraph [74]. We chose the clustering solution upon inspection of other possible clustering solutions, each obtained from the Louvain partitioning of different SNN graphs (each constructed from different initial k-NN searches, with k in [5,10,15,20,30,50]. For each clustering solution, we evaluated: i) clusters compactness and separation, with the Davies-Boudain (DB) index [75].…”

Section: Methodsmentioning

confidence: 99%

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The breast cancer pro-metastatic phenotype requires concomitant hyper-activation of ECM remodeling and dsRNA-IFN1 signaling in rare clone cells

Roda

Cossa

Hillje

et al. 2022

Preprint

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The molecular determinants of breast cancer (BC) pro-metastatic phenotype are largely unknown. Here, we leveraged lentiviral barcoding coupled to single-cell RNA sequencing to trace clonal and transcriptional evolution during BC metastatization. We showed that metastases derive from rare pro-metastatic clones that are under-represented in primary tumors. Both low clonal-fitness and high metastatic-potential are independent of clonal origin. Differential expression and classification analyses revealed that the pro-metastatic phenotype is acquired in rare cells by concomitant hyper-activation of extracellular-matrix remodeling, dsRNA-interferon signaling, and stress-response pathways. Notably, genetic silencing of single pro-metastatic genes from different pathways significantly impairs migration in vitro and metastatization in vivo, with negligible effects on cell proliferation and tumor growth. In addition, gene-expression signatures from identified pro-metastatic genes predicts metastatic progression in BC patients, independently of known prognostic factors. This study elucidates previously unknown mechanisms of BC metastatization, and provides novel prognosis predictors and therapeutic targets for metastasis prevention.

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Section: Methodsmentioning

confidence: 99%

“…Seminal work showed that the potential of metastasis spreading in BC significantly correlates with the degree of genetic and/or phenotypic heterogeneity in the PT [9], [10], [11]. Early studies hypothesized that specific mutations in primary breast tumors are selected by the metastatic phenotype [12].…”

Section: Introductionmentioning

confidence: 99%

The breast cancer pro-metastatic phenotype requires concomitant hyper-activation of ECM remodeling and dsRNA-IFN1 signaling in rare clone cells

Roda

Cossa

Hillje

et al. 2022

Preprint

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show abstract

“…Breast cancer has been seriously endangering the public health because of its high incidence in women [ 1 , 2 ]. According to the expression of molecular markers (estrogen receptor, progesterone receptor, and HER2), breast cancer can be divided into several subtypes: luminal A, luminal B, HER2+, and triple-negative [ 3 ]. According to the different subtypes, there are different therapeutic strategies in clinic.…”

Section: Introductionmentioning

confidence: 99%

Cytokines, breast cancer stem cells (BCSCs) and chemoresistance

Chen¹,

Qin²,

Liu

2018

Clinical & Translational Med

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Chemotherapy resistance of breast cancer poses a great challenge to the survival of patients. During breast cancer treatment, the development of intrinsic and acquired drug resistance tends to further induce adverse prognosis, such as metastasis. In recent years, the progress of research on cytokine‐modulated tumor microenvironment and breast cancer stem cells (BCSCs) has shed light on defining the mechanisms of drug resistance gradually. In this review, we have discussed cytokine regulation on breast cancer chemoresistance. Cytokines can affect tumor cell behavior or reprogram tumor niche through specific signaling pathways, thereby regulating the progress of drug resistance. In addition, we summarized the mutually regulatory networks between cytokines and BCSCs in mediating chemoresistance. Cytokines in the tumor microenvironment can regulate the self‐renewal and survival of BCSCs in a variety of ways, sequentially promoting chemotherapeutic resistance. Therefore, the combinational treatment of BCSC targeting and cytokine blockade may have a positive effect on the clinical treatment of breast cancer.

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“…Likewise, another study quantifying the genetic intra-tumor diversity in patient-specific mutational profiles of more than 900 TCGA (The Cancer Genome Atlas) BC patients showed an inverse correlation between ITH and overall survival [ 152 , 153 ]. Moreover, the analysis of estrogen receptor expression across 970 different breast tumors revealed that patients with the most heterogeneous expression display an increased risk of distant metastases [ 154 ]. Thus, the co-existence of heterogeneous populations of cells within the same PT favors distant metastases, suggesting that different clones may develop cooperative interactions [ 155 , 156 ].…”

Section: Bc Intra-tumor Heterogeneity and Metastasismentioning

confidence: 99%

Beyond Genetics: Metastasis as an Adaptive Response in Breast Cancer

Ruscitto

Roda

Priami

et al. 2022

IJMS

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Metastatic disease represents the primary cause of breast cancer (BC) mortality, yet it is still one of the most enigmatic processes in the biology of this tumor. Metastatic progression includes distinct phases: invasion, intravasation, hematogenous dissemination, extravasation and seeding at distant sites, micro-metastasis formation and metastatic outgrowth. Whole-genome sequencing analyses of primary BC and metastases revealed that BC metastatization is a non-genetically selected trait, rather the result of transcriptional and metabolic adaptation to the unfavorable microenvironmental conditions which cancer cells are exposed to (e.g., hypoxia, low nutrients, endoplasmic reticulum stress and chemotherapy administration). In this regard, the latest multi-omics analyses unveiled intra-tumor phenotypic heterogeneity, which determines the polyclonal nature of breast tumors and constitutes a challenge for clinicians, correlating with patient poor prognosis. The present work reviews BC classification and epidemiology, focusing on the impact of metastatic disease on patient prognosis and survival, while describing general principles and current in vitro/in vivo models of the BC metastatic cascade. The authors address here both genetic and phenotypic intrinsic heterogeneity of breast tumors, reporting the latest studies that support the role of the latter in metastatic spreading. Finally, the review illustrates the mechanisms underlying adaptive stress responses during BC metastatic progression.

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Intra-tumor molecular heterogeneity in breast cancer: definitions of measures and association with distant recurrence-free survival

Abstract: Intra-tumor heterogeneity of ER receptor status may be a predictor of patient DRFS. Histopathologic data from multiple tissue samples may offer a view of tumor heterogeneity and assess recurrence risk.

Cited by 11 publications

References 39 publications

The breast cancer pro-metastatic phenotype requires concomitant hyper-activation of ECM remodeling and dsRNA-IFN1 signaling in rare clone cells

The breast cancer pro-metastatic phenotype requires concomitant hyper-activation of ECM remodeling and dsRNA-IFN1 signaling in rare clone cells

Cytokines, breast cancer stem cells (BCSCs) and chemoresistance

Beyond Genetics: Metastasis as an Adaptive Response in Breast Cancer

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