Stromal integrin α11 regulates PDGFRβ signaling and promotes breast cancer progression

Primac, Irina; Maquoi, Erik; Blacher, Silvia; Heljasvaara, Ritva; Deun, Jan Van; Smeland, Hilde Ytre-Hauge; Canale, Annalisa; Louis, Thomas; Stuhr, Linda Elin Birkhaug; Sounni, Nor Eddine; Cataldo, Didier; Pihlajaniemi, Taina; Péqueux, Christel; Wever, Olivier De; Gullberg, Donald; Noël, Agnès

doi:10.1172/jci125890

Cited by 117 publications

(97 citation statements)

References 76 publications

(77 reference statements)

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“…Our study is consistent with other studies showing a relative loss of PDGFRα+ CAFs during breast cancer progression in mice (Bartoschek et al, 2018;Raz et al, 2018). Our findings support the notion that PDGFRβ may primarily be a marker of CAFs while PDGFRα may mark more resting fibroblasts (Paulsson et al, 2009;Primac et al, 2019;Östman, 2017).…”

Section: A Switch In Pdgfr Subtype Between Normal and Tumour Tissuesupporting

confidence: 93%

“…A multitude of markers have been proposed as CAF markers, including but not limited to: alpha smooth muscle actin (αSMA), fibroblast activation protein alpha (FAPα), fibroblast specific protein-1 (FSP1/S100A4), vimentin, Podoplanin (PDPN), platelet derived growth factor receptor alpha and beta (PDGFRα and PDGFRβ), CD90 (Thy.1), neuron glial antigen 2 (NG2), Caveolin-1 (Kalluri, 2016), and recently integrin a11 (Primac et al, 2019;Schnittert et al, 2019). As these markers are also expressed on other cell types in the TME, it remains unclear to what extend these markers truly represent the total level of CAFs within the TME.…”

Section: Six Caf Markers Combined Capture the Majority Of Lin-cellsmentioning

confidence: 99%

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Deciphering the temporal heterogeneity of cancer-associated fibroblast subpopulations in breast cancer

Venning

Zornhagen

Wullkopf

et al. 2020

Preprint

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Cancer-associated fibroblasts (CAFs) comprise a heterogeneous population of stromal cells within the tumour microenvironment. CAFs exhibit both tumour-promoting and tumour-suppressing functions, making them exciting targets for improving cancer treatments. A careful identification and characterisation of the CAF heterogeneity is thus necessary before implementing CAFtargeted strategies in cancer. With that in mind, we developed a flow cytometry strategy based on exclusion of non-CAF cells and successfully employed it to explore the temporal heterogeneity of CAFs in two models of triple-negative breast cancer (4T1 and 4T07). Analysing 128 murine tumours we identified 5-6 main CAF subpopulations and numerous minor ones based on the analysis of alpha smooth muscle actin, fibroblast activation protein alpha, platelet derived growth factor receptor alpha and beta, CD26/DPP4 and podoplanin. All markers showed temporal changes, and CD26+ CAFs emerged as a large novel subpopulation. These results form the foundation needed for the future elucidation of tumour-promoting CAF subpopulations.

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Section: A Switch In Pdgfr Subtype Between Normal and Tumour Tissuesupporting

confidence: 93%

Section: Six Caf Markers Combined Capture the Majority Of Lin-cellsmentioning

confidence: 99%

Deciphering the temporal heterogeneity of cancer-associated fibroblast subpopulations in breast cancer

Venning

Zornhagen

Wullkopf

et al. 2020

Preprint

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“…The cooperation between HGFR and α2β1 integrin has been shown to regulate the innate immune response upon mast cell adhesion to collagen type I (279). Furthermore, we have recently shown that integrin α11 associates to PDGFRβ in cancer associated fibroblasts and activates its JNK downstream signaling (280).…”

Section: Mechanistic Insights Into Collagen-binding Integrin Signalingmentioning

confidence: 92%

Reciprocal Interplay Between Fibrillar Collagens and Collagen-Binding Integrins: Implications in Cancer Progression and Metastasis

et al. 2020

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Cancers are complex ecosystems composed of malignant cells embedded in an intricate microenvironment made of different non-transformed cell types and extracellular matrix (ECM) components. The tumor microenvironment is governed by constantly evolving cell-cell and cell-ECM interactions, which are now recognized as key actors in the genesis, progression and treatment of cancer lesions. The ECM is composed of a multitude of fibrous proteins, matricellular-associated proteins, and proteoglycans. This complex structure plays critical roles in cancer progression: it functions as the scaffold for tissues organization and provides biochemical and biomechanical signals that regulate key cancer hallmarks including cell growth, survival, migration, differentiation, angiogenesis, and immune response. Cells sense the biochemical and mechanical properties of the ECM through specialized transmembrane receptors that include integrins, discoidin domain receptors, and syndecans. Advanced stages of several carcinomas are characterized by a desmoplastic reaction characterized by an extensive deposition of fibrillar collagens in the microenvironment. This compact network of fibrillar collagens promotes cancer progression and metastasis, and is associated with low survival rates for cancer patients. In this review, we highlight how fibrillar collagens and their corresponding integrin receptors are modulated during cancer progression. We describe how the deposition and alignment of collagen fibers influence the tumor microenvironment and how fibrillar collagen-binding integrins expressed by cancer and stromal cells critically contribute in cancer hallmarks.

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“…Furthermore, the metastatic pathways associated with genome instability (Path1, RNA LVI clone; Path 3, RNA LN1 clone), shared biological processes related to the cell cycle and oxidative stress, indicative of rapid proliferation and the involvement of hypoxia in the development of these clones. Metastatic pathways involving primary cancer cells (Path 1, RNA LVI clone; Path 2, RNA LN2 clone), were associated with biological processes related to "blood vessel development", "epithelial cell migration", and "regulation of cell adhesion", all of which have been previously reported as related to tumor cell invasion and migration (Wenes et al, 2016, Uribesalgo et al, 2019, Primac et al, 2019. Additionally, each metastatic pathway was associated with unique biological processes such as "chromosome segregation" and "T helper cell differentiation" in path 1, and "extracellular matrix organization", "toll-like receptor signaling"…”

Section: Gene Enrichment Demonstrates Distinct Metastatic and Immune mentioning

confidence: 89%

Genome profiles of lymphovascular breast cancer cells reveal multiple clonally differentiated outcomes with multi-regional LCM and G&T-seq

Zhu

Wang

Lin

et al. 2019

Preprint

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The authors declare that there is no conflict of interest regarding the publication of this article.Character count: 52,408 (60,000 characters MAX including spaces and main figure legends but excluding STAR Methods text, supplemental item legends, and References section): Summary (Currently 120 words): 120 words MAXWe comprehensively analyzed the genomic and transcriptional profiles of 97 laser capture microdissection (LCM) isolated cell clusters from a single patient with triple negative breast cancer (TNBC). By performing simultaneous genome and transcriptome amplification and sequencing (G&T-seq) on these clusters, we identified four RNA cancer cell clones that were directly linked to DNA clone counterparts. We also detected the presence of a lymphovascular invasive (LVI) clone characterized by chromosome instability (CIN), and a specific genomic and transcriptional pattern shared with several primary cancer cell clusters. Furthermore, combination phylogeny analysis pointed to three evolutionarily distinct metastatic pathways in this patient, and hub gene evaluation found the down regulation of ribosomal protein mRNA to be a potential prognostic marker for breast cancer.Keywords: Triple negative breast cancer (TNBC), lymphovascular invasion (LVI), metastasis, lymphatics, laser capture microdissection (LCM), G&T-seq (genome and transcriptome sequencing) Significance (Currently 120 words): 120 words MAXThe lymphatic system is a unidirectional vascular network responsible for trafficking immune cells and lymphatic fluid. However, many cancer cell types use this system as a primary means of metastatic spread to regional lymph nodes. We describe the use of laser capture microdissection in the isolation of lymphovascular invasive (LVI) cancer cell clusters from within lymphatic vessels of a single breast cancer patient. Genomic and transcriptional profiling of LVI associated cancer cells, and cancer cell clusters derived from the primary tumor and lymph nodes of this patient, was performed using G&T-seq. Our findings improve our understanding of LVI metastatic mechanisms, and reveal that poor breast cancer survival outcomes may be related to the extensive down-regulation of transcripts encoding ribosomal proteins. Highlights:1. LVI clone shares a specific genome and transcriptome pattern with a small proportion of primary cancer cell clusters.2. G&T sequencing revealed RNA cancer cell clones to be highly correlative to DNA clones.3. Three evolutionarily and transcriptionally distinct pathways of tumor clone development and metastasis were found in one TNBC patient using combination phylogeny analysis. 4.Extensive ribosomal protein down-regulation may be a potential marker of poor prognosis in breast cancer patients.

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Stromal integrin α11 regulates PDGFRβ signaling and promotes breast cancer progression

Abstract: Conflict of interest: DG is named as an inventor on a patent application relating to the Mab203E1H5 (EP18155716) antibody filed by the University of Bergen.

Cited by 117 publications

References 76 publications

Deciphering the temporal heterogeneity of cancer-associated fibroblast subpopulations in breast cancer

Deciphering the temporal heterogeneity of cancer-associated fibroblast subpopulations in breast cancer

Reciprocal Interplay Between Fibrillar Collagens and Collagen-Binding Integrins: Implications in Cancer Progression and Metastasis

Genome profiles of lymphovascular breast cancer cells reveal multiple clonally differentiated outcomes with multi-regional LCM and G&T-seq

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