PIK3Cδ expression by fibroblasts promotes triple-negative breast cancer progression

Gagliano, Teresa; Shah, Kalpit; Gargani, Sofia; Lao, Liyan; Alsaleem, Mansour; Chen, Jianing; Ntafis, Vasileios; Huang, Penghan; Ditsiou, Angeliki; Vella, Viviana; Yadav, Kritika; Bienkowska, Kamila; Bresciani, Giulia; Kang, Kai; Li, Leping; Carter, Philip; Benstead-Hume, Graeme; O’Hanlon, Timothy; Dean, Michael; Pearl, Frances M. G.; Lee, Soo‐Chin; Rakha, Emad A.; Green, Andrew; Kontoyiannis, Dimitris L.; Song, Erwei; Stebbing, Justin; Giamas, Georgios

doi:10.1172/jci128313

Cited by 33 publications

(24 citation statements)

References 72 publications

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“…Then, fibroblasts were cocultured with MDA-MB-231 cells, and the formed spheroids were plated in Matrigel in order to promote invasion. The authors found that this PIK3Cδ kinase modulated MDA-MB-231 invasion in a paracrine way and that its inhibition could represent an alternative therapeutic option for TNBC treatment [ 82 ].…”

Section: Sirna Therapeutics Targeting the Tmementioning

confidence: 99%

Modulating the Crosstalk between the Tumor and the Microenvironment Using SiRNA: A Flexible Strategy for Breast Cancer Treatment

Roscigno

Scognamiglio

Ingenito

et al. 2020

Cancers

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Tumorigenesis is a complex and multistep process in which sequential mutations in oncogenes and tumor-suppressor genes result in enhanced proliferation and apoptosis escape. Over the past decades, several studies have provided evidence that tumors are more than merely a mass of malignant cancer cells, with the tumor microenvironment (TME) also contributing to cancer progression. For this reason, the focus of cancer research in recent years has shifted from the malignant cancer cell itself to the TME and its interactions. Since the TME actively participates in tumor progression, therapeutic strategies targeting it have created great interest. In this context, much attention has been paid to the potential application of small interfering RNA (siRNA), a class of non-coding RNA that has the ability to downregulate the expression of target genes in a sequence-specific way. This is paving the way for a novel therapeutic approach for the treatment of several diseases, including cancer. In this review, we describe recent efforts in developing siRNA therapeutics for the treatment of breast cancer, with particular emphasis on TME regulation. We focus on studies that adapt siRNA design to reprogram/re-educate the TME and eradicate the interplay between cancer cells and TME.

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Section: Sirna Therapeutics Targeting the Tmementioning

confidence: 99%

Modulating the Crosstalk between the Tumor and the Microenvironment Using SiRNA: A Flexible Strategy for Breast Cancer Treatment

Roscigno

Scognamiglio

Ingenito

et al. 2020

Cancers

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“…The tumour stroma is histologically an integral part of cancer tissue and represents a complex composition of different cell types, including fibroblasts, immune cells and cells of the vasculature, and extracellular matrix [2] . There is strong evidence that tumorigenesis is controlled by the complex interaction between cancer cells and stroma elements and numerous experimental studies suggest that the tumour stroma exerts tumour-promoting effects [3] , [4] , [5] , [6] , [7] , [8] . In line with this, many stroma features were identified that were related to tumour aggressiveness and ultimately impact patient outcome [ 3 , [9] , [10] , [11] ].…”

Section: Introductionmentioning

confidence: 99%

The prognostic impact of the tumour stroma fraction: A machine learning-based analysis in 16 human solid tumour types

et al. 2021

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Background The development of a reactive tumour stroma is a hallmark of tumour progression and pronounced tumour stroma is generally considered to be associated with clinical aggressiveness. The variability between tumour types regarding stroma fraction, and its prognosis associations, have not been systematically analysed. Methods Using an objective machine-learning method we quantified the tumour stroma in 16 solid cancer types from 2732 patients, representing retrospective tissue collections of surgically resected primary tumours. Image analysis performed tissue segmentation into stromal and epithelial compartment based on pan-cytokeratin staining and autofluorescence patterns. Findings The stroma fraction was highly variable within and across the tumour types, with kidney cancer showing the lowest and pancreato-biliary type periampullary cancer showing the highest stroma proportion (median 19% and 73% respectively). Adjusted Cox regression models revealed both positive (pancreato-biliary type periampullary cancer and oestrogen negative breast cancer, HR(95%CI)=0.56(0.34-0.92) and HR(95%CI)=0.41(0.17-0.98) respectively) and negative (intestinal type periampullary cancer, HR(95%CI)=3.59(1.49-8.62)) associations of the tumour stroma fraction with survival. Interpretation Our study provides an objective quantification of the tumour stroma fraction across major types of solid cancer. Findings strongly argue against the commonly promoted view of a general associations between high stroma abundance and poor prognosis. The results also suggest that full exploitation of the prognostic potential of tumour stroma requires analyses that go beyond determination of stroma abundance. Funding The Swedish Cancer Society, The Lions Cancer Foundation Uppsala, The Swedish Government Grant for Clinical Research, The Mrs Berta Kamprad Foundation, Sweden, Sellanders foundation, P.O.Zetterling Foundation, and The Sjöberg Foundation, Sweden.

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“…A recent finding revealed the PERK signaling was selectively activated by Rho-associated kinase which caused fibroblast reprogramming and contributed to BC progression ( Boyle et al, 2020 ). Furthermore, fibroblast-expressed PIK3Cδ was found promoting TNBC progression with the help of a high-throughput siRNA kinome screening technology and recognized as a potential target ( Gagliano et al, 2020 ). The tumor microenvironment forms the core site in which neoplastic cells, stromal fibroblasts and cancer-associated fibroblasts interact with each other, and exosomes play a complex role in that interplay ( Figure 2 ).…”

Section: The Effects Of Exosomes In the Breast Cancer Tumor Microenvironmentmentioning

confidence: 99%

The Advancing Roles of Exosomes in Breast Cancer

Wang

Sun

Huang

et al. 2021

Front. Cell Dev. Biol.

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Breast cancer (BC) develops from breast tissue and is the most common aggressive malignant tumor in women worldwide. Although advanced treatment strategies have been applied and reduced current mortality rates, BC control remains unsatisfactory. It is essential to elucidate the underlying molecular mechanisms to assist clinical options. Exosomes are a type of extracellular vesicles and mediate cellular communications by delivering various biomolecules (oncogenes, oncomiRs, proteins, and even pharmacological compounds). These bioactive molecules can be transferred to change the transcriptome of target cells and influence tumor-related signaling pathways. Extensive studies have implicated exosomes in BC biology, including therapeutic resistance and the surrounding microenvironment. This review focuses on discussing the functions of exosomes in tumor treatment resistance, invasion and metastasis of BC. Moreover, we will also summarize multiple interactions between exosomes and the BC tumor microenvironment. Finally, we propose promising clinical applications of exosomes in BC.

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PIK3Cδ expression by fibroblasts promotes triple-negative breast cancer progression

Cited by 33 publications

References 72 publications

Modulating the Crosstalk between the Tumor and the Microenvironment Using SiRNA: A Flexible Strategy for Breast Cancer Treatment

Modulating the Crosstalk between the Tumor and the Microenvironment Using SiRNA: A Flexible Strategy for Breast Cancer Treatment

The prognostic impact of the tumour stroma fraction: A machine learning-based analysis in 16 human solid tumour types

The Advancing Roles of Exosomes in Breast Cancer

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