Phenotypic plasticity during metastatic colonization

Jehanno, Charly; Vulin, Milica; Richina, Veronica; Richina, Federica; Bentires‐Alj, Mohamed

doi:10.1016/j.tcb.2022.03.007

Cited by 32 publications

(33 citation statements)

References 135 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The dormancy-colonization switch is an example of behavioral plasticity in cancer ( 214 ) that includes reversible EMT/MET and the sequential acquisition of stemness-related characteristics ( 119, 214–217 ). Indeed, dormant DTCs resemble stem cells, particularly in their retention of self-renewal ability while being quiescent ( 39, 88, 144, 218 ).…”

Section: Therapeutic Management Of Dormant Metastases: Current Landscapementioning

confidence: 99%

Breast Cancer Metastatic Dormancy and Relapse: An Enigma of Microenvironment(s)

et al. 2022

View full text Add to dashboard Cite

Multiple factors act in concert to define the fate of disseminated tumor cells (DTCs) to enter dormancy or develop overt metastases. Here, we review these factors in the context of three stages of the metastatic cascade that impact DTCs. First, cells can be programmed within the primary tumor microenvironment to promote or inhibit dissemination, and the primary tumor can condition a premetastatic niche. Then, cancer cells from the primary tumor spread through hematogenous and lymphatic routes, and the primary tumor sends cues systematically to regulate the fate of DTCs. Finally, DTCs home to their metastatic site, where they are influenced by various organ-specific aspects of the new microenvironment. We discuss these factors in the context of breast cancer, where about one third of patients develop metastatic relapse. Finally, we discuss how the standard-of-care options for breast cancer might affect the fate of DTCs.

show abstract

Section: Therapeutic Management Of Dormant Metastases: Current Landscapementioning

confidence: 99%

Breast Cancer Metastatic Dormancy and Relapse: An Enigma of Microenvironment(s)

et al. 2022

View full text Add to dashboard Cite

show abstract

“…To overcome the quiescence-mediating signals in the remote organ [ 10 ], and to generate a metastatic lesion, the cell must re-acquire its epithelial properties through the activation of the mesenchymal-to-epithelial transition (MET) program, which enables proliferation, generation of macro-metastases, and cancer recurrence [ 11 ]. Thus, metastatic cells exhibit plasticity (epithelial–mesenchymal plasticity—EMP), and cells that co-express both epithelial and mesenchymal properties in varying degrees (known as E/M hybrids) are considered to have the greatest metastatic and aggressive potential [ 12 , 13 , 14 ]. EMT markers, such as reduced E-cadherin expression and increased vimentin expression, as well as increased EMT transcription factors (EMT-TFs), such as Snail/SNAI1, Slug/SNAI2, Zeb1, or Twist1, were shown to drive the EMT program, repress the epithelial markers, and induce a more mesenchymal phenotype associated with dormancy [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…Tumor mass dormancy describes a balance between cells that proliferate and cells that die by apoptosis, so that the small cluster of DTCs or micro-metastasis remains in a stable size and does not generate a detectable macro-metastatic lesion. This can be the result of a lack of sufficient blood supply (angiogenic dormancy) or pressure exerted by the immune response [ 12 , 17 ]. Cellular and tumor-mass dormancies are influenced by interactions with the surrounding tissue and stroma cells in the metastatic niche, through signals mediated by soluble factors or transmembranal proteins.…”

Section: Introductionmentioning

confidence: 99%

Knocking-Down CD147/EMMPRIN Expression in CT26 Colon Carcinoma Forces the Cells into Cellular and Angiogenic Dormancy That Can Be Reversed by Interactions with Macrophages

et al. 2023

View full text Add to dashboard Cite

Metastasis in colorectal cancer is responsible for most of the cancer-related deaths. For metastasis to occur, tumor cells must first undergo the epithelial-to-mesenchymal transition (EMT), which is driven by the transcription factors (EMT-TFs) Snail, Slug twist1, or Zeb1, to promote their migration. In the distant organs, tumor cells may become dormant for years, until signals from their microenvironment trigger and promote their outgrowth. Here we asked whether CD147/EMMPRIN controls entry and exit from dormancy in the aggressive and proliferative (i.e., non-dormant) CT26 mouse colon carcinoma cells, in its wild-type form (CT26-WT cells). To this end, we knocked down EMMPRIN expression in CT26 cells (CT26-KD), and compared their EMT and cellular dormancy status (e.g., proliferation, pERK/pP38 ratio, vimentin expression, expression of EMT-TFs and dormancy markers), and angiogenic dormancy (e.g., VEGF and MMP-9 secretion, healing of the wounded bEND3 mouse endothelial cells), to the parental cells (CT26-WT). We show that knocking-down EMMPRIN expression reduced the pERK/pP38 ratio, enhanced the expression of vimentin, the EMT-TFs and the dormancy markers, and reduced the proliferation and angiogenic potential, cumulatively indicating that cells were pushed towards dormancy. When macrophages were co-cultured with both types of CT26 cells, the CT26-WT cells increased their angiogenic potential, but did not change their proliferation, state of EMT, or dormancy, whereas the CT26-KD cells exhibited values mostly similar to those of the co-cultured CT26-WT cells. Addition of recombinant TGFβ or EMMPRIN that simulated the presence of macrophages yielded similar results. Combinations of low concentrations of TGFβ and EMMPRIN had a minimal additive effect only in the CT26-KD cells, suggesting that they work along the same signaling pathway. We conclude that EMMPRIN is important as a gatekeeper that prevents cells from entering a dormant state, and that macrophages can promote an exit from dormancy.

show abstract

“…The cellular plasticity arising from the transitions between epithelial and mesenchymal states has been recognized as instrumental to metastatic progression[5]. The characterization of cancer cells at different stages of the metastatic cascade in terms of canonical EMT markers and TFs has recently given rise to the concept of partial EMT[10, 27, 28].…”

Section: Discussionmentioning

confidence: 99%

Single-cell analysis reveals inter- and intratumour heterogeneity in metastatic breast cancer

Hamelin¹,

Obradović²,

Sethi³

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Metastasis is the leading cause of cancer-related deaths of breast cancer patients. Some cancer cells in a tumour go through successive steps, referred to as the metastatic cascade, and give rise to metastases at a distant site. We know that the plasticity and heterogeneity of cancer cells play critical roles in metastasis but the precise underlying molecular mechanisms remain elusive. Here we aimed to identify molecular mechanisms of metastasis during colonization, one of the most important yet poorly understood steps of the cascade. We performed single-cell RNA-Seq (scRNA-Seq) on tumours and matched lung macrometastases of patient-derived xenografts of breast cancer. After correcting for confounding factors such as the cell cycle and the percentage of detected genes (PDG), we identified cells in three states in both tumours and metastases. Gene-set Enrichment Analysis revealed biological processes specific to proliferation and invasion in two states. Our findings suggest that these states are a balance between epithelial-to-mesenchymal (EMT) and mesenchymal-to-epithelial transitions (MET) traits that results in so-called partial EMT phenotypes. Analysis of the top Differentially Expressed Genes (DEGs) between these cell states revealed a common set of partial EMT Transcriptions Factors (TFs) controlling gene expression, including ZNF750, OVOL2, TP63, TFAP2C and HEY2. Our data suggest that the TFs related to EMT delineate different cell states in tumours and metastases. The results highlight the marked interpatient heterogeneity of breast cancer but identify common features of single cells from five models of metastatic breast cancer.

show abstract

Phenotypic plasticity during metastatic colonization

Cited by 32 publications

References 135 publications

Breast Cancer Metastatic Dormancy and Relapse: An Enigma of Microenvironment(s)

Breast Cancer Metastatic Dormancy and Relapse: An Enigma of Microenvironment(s)

Knocking-Down CD147/EMMPRIN Expression in CT26 Colon Carcinoma Forces the Cells into Cellular and Angiogenic Dormancy That Can Be Reversed by Interactions with Macrophages

Single-cell analysis reveals inter- and intratumour heterogeneity in metastatic breast cancer

Contact Info

Product

Resources

About