Pan-cancer single-cell RNA-seq identifies recurring programs of cellular heterogeneity

Kinker, Gabriela Sarti; Greenwald, Alissa C.; Tal, Rotem; Orlova, Zhanna; Cuoco, Michael S.; McFarland, James M.; Warren, Allison; Rodman, Christopher; Roth, Jennifer A.; Bender, Samantha; Kumar, Bhavna; Rocco, James W.; Fernandes, Pedro Augusto Carlos Magno; Mader, Christopher C.; Keren‐Shaul, Hadas; Plotnikov, A.N.; Barr, Haim; Tsherniak, Aviad; Rozenblatt-Rosen, Orit; Krizhanovsky, Valery; Puram, Sidharth V.; Regev, Aviv; Tirosh, Itay

doi:10.1038/s41588-020-00726-6

Cited by 286 publications

(307 citation statements)

References 61 publications

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“…Our data add to a growing body of research 18,[47][48][49][50] showing that even genetically homogenous populations of tumor cells consist of subpopulations at diverse differentiation states that are also different with respect to their state of oncogene dependency. Stochastic fluctuations in the levels of key proteins from pathways that have crosstalk with the oncogenic pathway and differentiation state-specific epigenetic modifications represent possibly related mechanisms that lead to diverse states of drug tolerance 2,51,52 .…”

Section: Discussionsupporting

confidence: 55%

Epigenetic modulation reveals differentiation state specificity of oncogene addiction

et al. 2021

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Hyperactivation of the MAPK signaling pathway motivates the clinical use of MAPK inhibitors for BRAF-mutant melanomas. Heterogeneity in differentiation state due to epigenetic plasticity, however, results in cell-to-cell variability in the state of MAPK dependency, diminishing the efficacy of MAPK inhibitors. To identify key regulators of such variability, we screen 276 epigenetic-modifying compounds, individually or combined with MAPK inhibitors, across genetically diverse and isogenic populations of melanoma cells. Following single-cell analysis and multivariate modeling, we identify three classes of epigenetic inhibitors that target distinct epigenetic states associated with either one of the lysine-specific histone demethylases Kdm1a or Kdm4b, or BET bromodomain proteins. While melanocytes remain insensitive, the anti-tumor efficacy of each inhibitor is predicted based on melanoma cells’ differentiation state and MAPK activity. Our systems pharmacology approach highlights a path toward identifying actionable epigenetic factors that extend the BRAF oncogene addiction paradigm on the basis of tumor cell differentiation state.

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Section: Discussionsupporting

confidence: 55%

Epigenetic modulation reveals differentiation state specificity of oncogene addiction

et al. 2021

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“…RHEGs open the possibility of making more specific claims about intratumor heterogeneity beyond cell stress, cell cycle, cell proteostasis, and cell type (9). A recent scRNA-seq study documented twelve such recurrently heterogeneous programs in a large panel of cell lines (59). Although genes in these programs overlap significantly with RHEGs (p < 10 -8 by hypergeometric test), they only comprise ~9% of the RHEG set overall.…”

Section: Discussionmentioning

confidence: 99%

Pan-cancer Drivers are Recurrent Transcriptional Regulatory Heterogeneities in Early-stage Luminal Breast Cancer

Singh

Sutcliffe

Repich

et al. 2020

Preprint

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The authors declare no potential conflicts of interest. Running title: Stochastic profiling of luminal breast cancer by 10cRNA-seqThe heterogeneous composition of solid tumors is known to impact disease progression and response to therapy. Malignant cells coexist in different regulatory states that can be accessed transcriptomically by single-cell RNA sequencing, but these methods have many caveats related to sensitivity, noise, and sample handling. We revised a statistical fluctuation analysis called stochastic profiling to combine with 10-cell RNA sequencing, which was designed for laser-capture microdissection (LCM) and extended here for immuno-LCM. When applied to a cohort of late-onset, early-stage luminal breast cancers, the integrated approach identified thousands of candidate regulatory heterogeneities. Intersecting the candidates from different tumors yielded a relatively stable set of 710 recurrent heterogeneously expressed genes (RHEGs) that were significantly variable in >50% of patients. RHEGs were not confounded by dissociation artifacts, cell cycle oscillations, or driving mutations for breast cancer. Rather, we detected RHEG enrichments for epithelial-to-mesenchymal transition genes and, unexpectedly, the latest pan-cancer assembly of driver genes across cancer types other than breast.Heterogeneous transcriptional regulation conceivably provides a faster, reversible mechanism for malignant cells to sample the effects of potential oncogenes or tumor suppressors on cancer hallmarks. Statement of significanceProfiling intratumor heterogeneity of luminal breast carcinoma cells identifies a recurrent set of genes suggesting sporadic activation of pathways known to drive other types of cancer.

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“…Indeed, scRNA-seq has been used to demonstrate the presence of multiple cell populations within a tumor, each belonging to a distinct molecular group [49][50][51]. Furthermore, Kinker and colleagues have used scRNA-seq to investigate the ability of cultured cell lines to recapitulate the heterogeneity observed among malignant cells in human tumors [52]. They profiled 198 cancer cell lines from 22 cancer types and identified 12 expression programs as being heterogenous across multiple cancer cell lines.…”

Section: Strategies For Identifying Tumor Heterogeneitymentioning

confidence: 99%

Tumor Heterogeneity: A Great Barrier in the Age of Cancer Immunotherapy

El-Sayes

Vito

Mossman

2021

Cancers

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Throughout the history of oncology research, tumor heterogeneity has been a major hurdle for the successful treatment of cancer. As a result of aberrant changes in the tumor microenvironment such as high mutational burden, hypoxic conditions and abnormal vasculature, several malignant subpopulations often exist within a single tumor mass. Therapeutic intervention can also increase selective pressure towards subpopulations with acquired resistance. This phenomenon is often the cause of relapse in previously responsive patients, drastically changing the expected outcome of therapy. In the case of cancer immunotherapy, tumor heterogeneity is a substantial barrier as acquired resistance often takes the form of antigen escape and immunosuppression. In an effort to combat intrinsic resistance mechanisms, therapies are often combined as a multi-pronged approach to target multiple pathways simultaneously. These multi-therapy regimens have long been a mainstay of clinical oncology with chemotherapy cocktails but are more recently being investigated in the emerging landscape of immunotherapy. Furthermore, as high throughput technology becomes more affordable and accessible, researchers continue to deepen their understanding of the factors that influence tumor heterogeneity and shape the TME over the course of treatment regimens. In this review, we will investigate the factors that give rise to tumor heterogeneity and the impact it has on the field of immunotherapy. We will discuss how tumor heterogeneity causes resistance to various treatments and review the strategies currently being employed to overcome this challenging clinical hurdle. Finally, we will outline areas of research that should be prioritized to gain a better understanding of tumor heterogeneity and develop appropriate solutions.

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Pan-cancer single-cell RNA-seq identifies recurring programs of cellular heterogeneity

Cited by 286 publications

References 61 publications

Epigenetic modulation reveals differentiation state specificity of oncogene addiction

Epigenetic modulation reveals differentiation state specificity of oncogene addiction

Pan-cancer Drivers are Recurrent Transcriptional Regulatory Heterogeneities in Early-stage Luminal Breast Cancer

Tumor Heterogeneity: A Great Barrier in the Age of Cancer Immunotherapy

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