Physiologically activated mammary fibroblasts promote postpartum mammary cancer

Guo, Qiuchen; Minnier, Jessica; Burchard, Julja; Chiotti, Kami; Spellman, Paul T.; Schedin, Pepper

doi:10.1172/jci.insight.89206

Cited by 49 publications

(59 citation statements)

References 92 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…7C). Overall, we found pathways associated with the multifunctional aspects of involution (TGFβ axis) 47,48 ; networks associated with an immune suppressive ecosystem (Cxcl12 and Dpp4 axis) 32,49 and ECM remodelling (IGF axis) 50 (Fig. 7C).…”

Section: Characterisation Of the Cell-to-cell Interactions Involved Imentioning

confidence: 93%

“…The involution process involves cell apoptosis and tissue remodelling, the latter of which is orchestrated by stromal and immune cells 31 . Among these cell types, fibroblasts have a critical role in the extracellular matrix remodelling and immune suppression during involution 32 . Thus, we further explored the role of cancer-associated fibroblasts (CAFs) in aberrant involution in our model.…”

Section: Characterisation Of Cancer-associated Fibroblasts In Pymt Tumentioning

confidence: 99%

“…Mammary involuting fibroblasts have unique properties that include a high production of fibrillar collagen, ECM remodelling and immune suppression through monocyte recruitment 32 . This specialised class of fibroblast involved in involution are characterised by the expression of Col1a1, Cxcl12, Tgfb1 and Mmp3.…”

Section: Cafs From Pymt/elf5 Mammary Tumours Show Features Of Mimicrymentioning

confidence: 99%

See 2 more Smart Citations

Single cell transcriptomics reveals involution mimicry during the specification of the basal breast cancer subtype

Valdés-Mora

Salomon

Gloss

et al. 2019

Preprint

View full text Add to dashboard Cite

Both luminal and basal breast cancer subtypes originate in the mammary luminal progenitor cell compartment. Basal breast cancer is associated with younger age, early relapse, and high mortality rate. Here we used unbiased droplet-based single-cell RNAseq to elucidate the cellular basis of tumour progression during the specification of the basal breast cancer subtype from the luminal progenitor population. Basal-like cancer cells resembled the alveolar lineage that is specified upon pregnancy and showed molecular features indicative of an interaction with the tumour microenvironment (TME) including EMT, hypoxia, lactation and involution. Involution signatures in luminal breast cancer tumours with alveolar lineage features were associated with worse prognosis and features of basal breast cancer. Our highresolution molecular characterisation of the tumour ecosystem also revealed a highly interactive cell-cell network reminiscent of an involution process. This involution mimicry involves malignant education of cancer-associated fibroblasts and myeloid cell recruitment to support tissue remodelling and sustained inflammation. Our study shows how luminal breast cancer acquires a post-lactation developmental program to shift molecular subtype and promote tumour progression, with potential to explain the increased risk of cancer during the post-partum period.

show abstract

Section: Characterisation Of the Cell-to-cell Interactions Involved Imentioning

confidence: 93%

Section: Characterisation Of Cancer-associated Fibroblasts In Pymt Tumentioning

confidence: 99%

Section: Cafs From Pymt/elf5 Mammary Tumours Show Features Of Mimicrymentioning

confidence: 99%

See 1 more Smart Citation

Single cell transcriptomics reveals involution mimicry during the specification of the basal breast cancer subtype

Valdés-Mora

Salomon

Gloss

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…We first looked at the expression of the satellite cell marker Pax7, and see that there is no expression of Pax7 in the single fiber transcriptome despite its presence in whole muscle samples ( Figure 4D). We also analyzed markers for fibroblasts, namely Col1a1 and Thy1 (14,15). As expected for these genes, they are expressed in the whole muscle, but not expressed in the single fiber ( Figure 5A,B).…”

Section: Comparative Analysis Of Whole Muscle and Single Myofiber Rnamentioning

confidence: 61%

High Resolution Genome Wide Expression Analysis of Single Myofibers Using SMART-Seq

Blackburn

Lazure

Corchado

et al. 2019

Preprint

View full text Add to dashboard Cite

Skeletal muscle is a heterogeneous tissue. Individual myofibers that make up muscle tissue exhibit variation in their metabolic and contractile properties. Although there are biochemical and histological assays to study myofiber heterogeneity, efficient methods to analyze the whole transcriptome of individual myofibers are lacking. We have developed single myofiber RNA-Seq (smfRNA-Seq) to analyze the whole transcriptome of individual myofibers by combining single fiber isolation with Switching Mechanisms at 5' end of RNA Template (SMART) technology. Our method provides high-resolution genome wide expression profiles of single myofibers. Using smfRNA-Seq, we have analyzed the differences in the transcriptome of young and old myofibers to validate the effectiveness of this new method. Using smfRNA-Seq, we performed comparative gene expression analysis between single myofibers from young and old mice. Our data suggests that aging leads to significant changes in the expression of metabolic and structural genes in myofibers. Our data suggests that smfRNA-Seq is a powerful tool to study developmental, disease and age-related dynamics in the composition of skeletal muscle.

show abstract

“…We further demonstrate that SEMA7A is involved in an additional, but not unrelated, signaling axis that may alter the tumor microenvironment through fibroblast mediated production of collagen. Our previous results have shown that collagen deposition occurs during postpartum mammary gland involution(4) and fibroblasts are uniquely activated during postpartum involution to display pro-tumorigenic activity(13). In addition, a single pregnancy is sufficient to convert the high collagen content of the postpartum breast into pro-tumorigenic collagen(48).…”

Section: Discussionmentioning

confidence: 99%

Postpartum breast cancer progression is driven by semaphorin 7a mediated invasion and survival

Tarullo

Hill

Hansen

et al. 2019

Preprint

View full text Add to dashboard Cite

Breast cancer (BC) remains the second leading cause of cancer related deaths in women in the US --mainly due to metastatic disease. Thus, understanding how BC progresses is of the utmost importance to developing new strategies to block metastasis. Young women diagnosed with BC generally have poor prognosis due to increased rates of metastasis. Additionally, women who are within 5 years of most recent child-birth at diagnosis are ~3 times more likely to develop metastasis than age and stage matched nulliparous women. We define these cases as postpartum breast cancers (PPBC) and propose that the unique biology of the postpartum mammary gland drives tumor progression and metastasis. Semaphorin 7a (SEMA7A) is a unique member of the Semaphorin family as it is the only GPI-anchored member that can be shed into the extracellular environment. Our published results show that SEMA7A expression is associated with decreased overall survival in BC patient cohorts and revealed roles for SEMA7A in breast tumor cell growth, motility, invasion, and tumor associated-lymphangiogenesis all of which are also increased in pre-clinical models of PPBC. However, whether primary SEMA7A driver PPBC progression remains largely unexplored. We utilized a pre-clinical of PPBC with breast cancer cells where we silenced or overexpressed SEMA7A. Our results show that silencing of SEMA7A decreases tumor growth in postpartum hosts while overexpression increases growth in nulliparous hosts to rates closer to those observed in postpartum hosts. Further, we show that SEMA7A effects multiple pro-metastatic tumor attributes such as cell survival, tumor associated COX-2 expression, fibronectin deposition, and fibroblast-mediated collagen deposition in the tumor microenvironment regardless of whether the host is nulliparous or postpartum. Finally, we show that co-expression of SEMA7A/Collagen/COX2/FN mRNA predicts for increased metastasis in breast and ovarian cancer cohorts. These studies suggest SEMA7A as a key mediator of general BC progression and that targeting SEMA7A alone or in combination may open avenues for novel therapeutic strategies to prevent BC progression to metastasis. INTRODUCTION:Postpartum breast cancers (PPBC), or breast cancers diagnosed within 5-10 years of last childbirth, are nearly three times as likely to become metastatic and result in death from breast cancer 1-3 . Specifically, PPBC patients diagnosed within five years of last competed pregnancy exhibit 70% distant metastasis free five-year survival (DMFS) rates 1 that are further decreased to 50% after ten years 2 . Using this definition, PPBC may account over half of breast cancers diagnosed in women aged <45 in two independent cohorts. Using a pre-clinical model of PPBC we have shown that noninvasive breast tumor cells, MCF10DCIS, become invasive and metastatic if they are implanted into mouse mammary tissues during the normal physiological process of postpartum mammary gland involution 4 . The MCF10DCIS model closely resembles ductal carcinoma in situ (DCIS) and progresse...

show abstract

Physiologically activated mammary fibroblasts promote postpartum mammary cancer

Cited by 49 publications

References 92 publications

Single cell transcriptomics reveals involution mimicry during the specification of the basal breast cancer subtype

Single cell transcriptomics reveals involution mimicry during the specification of the basal breast cancer subtype

High Resolution Genome Wide Expression Analysis of Single Myofibers Using SMART-Seq

Postpartum breast cancer progression is driven by semaphorin 7a mediated invasion and survival

Contact Info

Product

Resources

About