Clonal populations of a human TNBC model display significant functional heterogeneity and divergent growth dynamics in distinct contexts

Kuiken, Hendrik J.; Dhakal, Sabin; Selfors, Laura M.; Friend, Chandler M.; Zhang, Tian; Callari, Maurizio; Schackmann, Ron C.J.; Gray, G. Kenneth; Crowdis, Jett; Bhang, Hyo-eun C.; Baslan, Timour; Stegmeier, Frank; Gygi, Steven P.; Caldas, Carlos; Brugge, Joan S.

doi:10.1038/s41388-021-02075-y

Cited by 7 publications

(5 citation statements)

References 72 publications

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“…Consistent with a majority of studies unraveling a carcinogenic role of m6A modification in breast cancer, we have established here that RNA m6A methylation is required for IGF2BP3 to expedite the metastasis of TNBC 16,17 . The discrepancies in the reported function of m6A methylation in TNBC can probably be reconciled by the varied context of m6A readers and downstream signal pathways in these considerably heterogenous malignancies 18–20 . It is also likely that the redundancy in m6A writer and eraser categories enables the occurrence or removal of m6A modification specifically on individual transcripts, which is evidenced by the observation that the “synclastic” regulators of m6A modification can be inversely associated with the prognosis of TNBC patients 9,17 …”

Section: Discussionsupporting

confidence: 86%

“…16,17 The discrepancies in the reported function of m6A methylation in TNBC can probably be reconciled by the varied context of m6A readers and downstream signal pathways in these considerably heterogenous malignancies. [18][19][20] It is also likely that the redundancy in m6A writer and eraser categories enables the occurrence or removal of m6A modification specifically on individual transcripts, which is evidenced by the observation that the "synclastic" regulators of m6A modification can be inversely associated with the prognosis of TNBC patients. 9,17 IGF2BPs belong to a conserved RNA-binding protein family with imperative roles in ontogenesis.…”

Section: Discussionmentioning

confidence: 99%

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RNA m6A reader IGF2BP3 promotes metastasis of triple‐negative breast cancer via SLIT2 repression

Jiang

Zhao

et al. 2022

The FASEB Journal

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Triple-negative breast cancer (TNBC) is a group of fatal malignancies characterized by high metastatic capacity, the underlying mechanisms of which remain largely elusive. We have found here that insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) is highly expressed in TNBC and correlates clinically with distant metastasis-free survival of TNBC patients. IGF2BP3 promotes the migration and invasion capabilities of TNBC cells dependent upon cellular RNA N6-methyladenosine (m6A) modification. Mechanistically, IGF2BP3 binds to and destabilizes m6A-methylated mRNA of the extracellular matrix glycoprotein, SLIT2, impairs its downstream signaling via the cognate receptor ROBO1, and consequently triggers the activation of canonical PI3K/AKT and MEK/ERK pathways. The IGF2BP3/SLIT2 axis is critically involved in the regulation of TNBC metastasis in vivo. These findings shed light into the regulatory network of distant metastasis of breast cancer and provide rationale for targeting the m6A machinery in the treatment of TNBC.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

RNA m6A reader IGF2BP3 promotes metastasis of triple‐negative breast cancer via SLIT2 repression

Jiang

Zhao

et al. 2022

The FASEB Journal

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“…Epithelial-mesenchymal cooperation (EMC) is dynamic and responsive to changing environmental conditions, resulting in adaptive resistance, a challenge for optimal therapeutic intervention ( Labrie et al, 2019 ). Transient commensal clonal interactions of tumor can drive metastasis ( Naffar-Abu Amara et al, 2020 ), with significant functional heterogeneity ( Kuiken et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Integrins and Epithelial-Mesenchymal Cooperation in the Tumor Microenvironment of Muscle-Invasive Lethal Cancers

Harryman

Marr

Nagle

et al. 2022

Front. Cell Dev. Biol.

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Muscle-invasive lethal carcinomas traverse into and through this specialized biophysical and growth factor enriched microenvironment. We will highlight cancers that originate in organs surrounded by smooth muscle, which presents a barrier to dissemination, including prostate, bladder, esophageal, gastric, and colorectal cancers. We propose that the heterogeneity of cell-cell and cell-ECM adhesion receptors is an important driver of aggressive tumor networks with functional consequences for progression. Phenotype heterogeneity of the tumor provides a biophysical advantage for tumor network invasion through the tensile muscle and survival of the tumor network. We hypothesize that a functional epithelial-mesenchymal cooperation (EMC)exists within the tumor invasive network to facilitate tumor escape from the primary organ, invasion and traversing of muscle, and navigation to metastatic sites. Cooperation between specific epithelial cells within the tumor and stromal (mesenchymal) cells interacting with the tumor is illustrated using the examples of laminin-binding adhesion molecules—especially integrins—and their response to growth and inflammatory factors in the tumor microenvironment. The cooperation between cell-cell (E-cadherin, CDH1) and cell-ECM (α6 integrin, CD49f) expression and growth factor receptors is highlighted within poorly differentiated human tumors associated with aggressive disease. Cancer-associated fibroblasts are examined for their role in the tumor microenvironment in generating and organizing various growth factors. Cellular structural proteins are potential utility markers for future spatial profiling studies. We also examine the special characteristics of the smooth muscle microenvironment and how invasion by a primary tumor can alter this environment and contribute to tumor escape via cooperation between epithelial and stromal cells. This cooperative state allows the heterogenous tumor clusters to be shaped by various growth factors, co-opt or evade immune system response, adapt from hypoxic to normoxic conditions, adjust to varying energy sources, and survive radiation and chemotherapeutic interventions. Understanding the epithelial-mesenchymal cooperation in early tumor invasive networks holds potential for both identifying early biomarkers of the aggressive transition and identification of novel agents to prevent the epithelial-mesenchymal cooperation phenotype. Epithelial-mesenchymal cooperation is likely to unveil new tumor subtypes to aid in selection of appropriate therapeutic strategies.

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“…Many aspects of cancer biology, such as oncogenesis, therapy resistance, and metastasis are driven by the behavior of individual cells [1][2][3][4][5][6][7][8][9] . Often, these outcomes result from mutations in rare cells 10 ; however, it has become increasingly clear that non-genetic differences can also be responsible for these phenomena 11 .…”

Section: Introductionmentioning

confidence: 99%

Spatial transcriptomics reveals influence of microenvironment on intrinsic fates in melanoma therapy resistance

Boe,

Triandafillou,

Lazcano

et al. 2024

Preprint

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Resistance to cancer therapy is driven by both cell-intrinsic and microenvironmental factors. Previous work has revealed that multiple resistant cell fates emerge in melanoma following treatment with targeted therapy and that, in vitro, these resistant fates are determined by the transcriptional state of individual cells prior to exposure to treatment. What remains unclear is whether these resistant fates are shared across different genetic backgrounds and how, if at all, these resistant fates interact with the tumor microenvironment. Through spatial transcriptomics and single-cell RNA sequencing, we uncovered distinct resistance programs in melanoma cells shaped by both intrinsic cellular states and the tumor microenvironment. Consensus non-negative matrix factorization revealed shared intrinsic resistance programs across different cell lines, highlighting the presence of universal and unique resistance pathways. In patient samples, we demonstrated that these resistance programs coexist within individual tumors and associate with diverse immune signatures, suggesting that the tumor microenvironment and distribution of resistant fates are closely connected. Single-cell resolution spatial transcriptomics in xenograft models revealed both intrinsically determined and extrinsically influenced resistant fates. Overall, this work demonstrates that each therapy resistant fate coexists with a distinct immune microenvironment in tumors and that, in vivo, tissue features, such as regions of necrosis, can influence which resistant fate is adopted.

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Clonal populations of a human TNBC model display significant functional heterogeneity and divergent growth dynamics in distinct contexts

Cited by 7 publications

References 72 publications

RNA m6A reader IGF2BP3 promotes metastasis of triple‐negative breast cancer via SLIT2 repression

RNA m6A reader IGF2BP3 promotes metastasis of triple‐negative breast cancer via SLIT2 repression

Integrins and Epithelial-Mesenchymal Cooperation in the Tumor Microenvironment of Muscle-Invasive Lethal Cancers

Spatial transcriptomics reveals influence of microenvironment on intrinsic fates in melanoma therapy resistance

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