Transition to invasive breast cancer is associated with progressive changes in the structure and composition of tumor stroma

Risom, Tyler; Glass, David R.; Averbukh, Inna; Liu, Candace C.; Baranski, Alex; Kagel, Adam; McCaffrey, Erin; Greenwald, Noah F.; Rivero-Gutiérrez, Belén; Strand, Siri H.; Varma, Sushama; Kong, Alex; Keren, Leeat; Srivastava, Sanvesh; Zhu, Chunfang; Khair, Zumana; Veis, Deborah J.; DeSchryver, Katherine; Vennam, Sujay; Maley, Carlo C.; Hwang, E. Shelley; Marks, Jeffrey R.; Bendall, Sean C.; Colditz, Graham A.; West, Robert B.; Angelo, Michael

doi:10.1016/j.cell.2021.12.023

Cited by 230 publications

(215 citation statements)

References 50 publications

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“…The mechanisms inducing the forces that myoepithelial cells exert on cancer cells of the luminal epithelial layer remain to be investigated. Most recently, morphometric quantifications comparing the myoepithelium of patients with ductal carcinoma in situ have shown that progressors have a thicker continuous myoepithelium [41], perhaps in response to aggressive luminal phenotypes. tumor.…”

Section: Trends In Cancermentioning

confidence: 99%

Tissue architecture in tumor initiation and progression

et al. 2022

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Section: Trends In Cancermentioning

confidence: 99%

Tissue architecture in tumor initiation and progression

et al. 2022

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“…In addition, we observe many active marks both within the CDS, and 5’ to the 3UTR start (Figure S4A). As we were interested in the state of the cells in 2D organoids in relation to zonal SON 3UTR/CDS expression, we examined histone mark and other marker expression across the organoids, as a cellular measure of transcriptional activity (Risom et al, 2022; Vogelauer et al, 2000). Remarkably, most showed non-random, concentric expression in the 2D organoids (Fig.…”

Section: Resultsmentioning

confidence: 99%

Differential expression of Nanog 3UTR and coding region mRNA components defines an embryonic stem cell niche

Yang

Gozali

et al. 2022

Preprint

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The known molecular heterogeneity among pluripotent embryonic stem cells (ESCs) in culture may be maladaptive or a beneficial determinant of normal biology. In other systems such as hair and intestine, normal and dynamic heterogeneity among stem cells is necessary for balancing stem cell division and quiescence in order to maintain the stem cell pool. In ESCs, Sox2, Oct4 and Nanog (the SON genes) critically regulate pluripotency but their role in stem cell heterogeneity or pool maintenance is not clear. We previously reported an additional level of gene expression, the unexpected differential expression of mRNA coding region (CDS) and cognate 3′untranslated region (3UTR) components, often revealing novel developmental patterns. Here we show dramatic, patterned, concentric, differential expression of pluripotent gene 3UTR and CDS mRNA components in both undifferentiated ESCs in culture and in developing human and mouse embryos. This differential expression reveals robust pluripotent ESC heterogeneity that provides the underpinnings of a previously unrecognized ESC cell niche structure. A hallmark of the niche is the presence of cells expressing high levels of Nanog 3UTR but only low or no Nanog CDS at structure perimeters, We used a novel bioinformatic approach combining the 3UTR to CDS ratio and gene expression, and identified unique ESC clusters. High Nanog 3UTR cells have lower cell cycle activity and higher quiescence than other ESCs and express a distinct complement of cellular histone marks. These quiescent perimeter cells exchange with interior domains, opening the possibility that they act as cell replenishment reservoirs in the niche or the embryo. Functionally, the Nanog 3UTR, independent of its CDS, is critical, as its selective deletion decreases ESC cell division while increasing trophectoderm markers. Lastly, self-organization of ESCs according to pluripotent gene differential 3UTR and CDS expression is modified by activin signaling, indicating extrinsic modulation of the niche structure. Pluripotent embryonic stem cells, actively display regulated, dynamic differential expression of SON gene mRNA components, allowing the formation of a heterogenous, ordered, stem cell niche bordered by quiescent hub stem cells, thus illuminating the role of SON genes in pluripotent embryonic stem cell pool maintenance. More generally this suggests that differential mRNA component expression may widely define cell types that exist in non-permanent, different states in either development or disease.

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“…A recent study performed comparative profiling of DCIS epithelium and its microenvironment in samples from DCIS patients with or without subsequent invasive relapse (Risom et al, 2022). Their data indicated that patients with increased stromal cell infiltration, desmoplasia, and ECM remodeling were less likely to relapse to invasive disease (Risom et al, 2022). This study brings forward the intriguing notion of increased stromal desmoplasia correlating with a good prognosis in DCIS, contrary to its widely accepted role in tissue stiffening and cancer progression in IBC (Piersma et al, 2020; Schedin and Keely, 2011).…”

Section: Discussionmentioning

confidence: 99%

Filopodia-mediated basement membrane assembly at pre-invasive tumor boundaries

Peuhu

Jacquemet

Scheele

et al. 2021

Preprint

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The mechanisms triggering the transition from in situ tumors to invasive carcinomas are poorly understood. The process involves breaching tumor-containing basement membranes (BM) and cancer cell invasion into the tumor stroma. Myosin-X (MYO10) is a filopodia-inducing protein frequently overexpressed in metastatic breast cancer. Here, we investigated the contribution of MYO10 to invasive breast tumor progression. We found that downregulation of MYO10 expression reduces breast cancer cell protrusions and migration in vitro. In addition, it attenuates protrusive activity and cell motility in early-stage breast cancer xenografts, which is in line with MYO10’s established pro-invasive function. However, MYO10 depletion also promoted the local dispersal of increasingly basal-like tumor cells into the tumor stroma in vivo, resembling the transition from in situ to invasive tumors. MYO10-depleted tumors exhibited compromised BM structures, which correlated with increased mRNA expression but the reduced assembly of BM proteins surrounding the xenograft. Furthermore, MYO10-depleted 3D spheroids were defective in extracellular matrix (ECM) assembly around the spheroids, indicating a functional role for MYO10 in ECM deposition. Altogether, our data support a model where tumor cell protrusive activity, induced by MYO10, contributes to anti-invasive ECM organization at the in situ stages of breast cancer but promotes cell motility in advanced invasive breast cancer.

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Transition to invasive breast cancer is associated with progressive changes in the structure and composition of tumor stroma

Cited by 230 publications

References 50 publications

Tissue architecture in tumor initiation and progression

Tissue architecture in tumor initiation and progression

Differential expression of Nanog 3UTR and coding region mRNA components defines an embryonic stem cell niche

Filopodia-mediated basement membrane assembly at pre-invasive tumor boundaries

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