Interrelationships between the extracellular matrix and the immune microenvironment that govern epithelial tumour progression.

Solid tumours are composed of cancer cells characterised by genetic mutations that underpin the disease, but also contain a suite of genetically normal cells and the extracellular matrix (ECM). These two latter components are constituents of the tumour microenvironment (TME), and are key determinants of tumour biology and thereby the outcomes for patients. The tumour ECM has been the subject of intense research over the past two decades, revealing key biochemical and mechanobiological principles that underpin its role in tumour cell proliferation and survival. However, the ECM also strongly influences the genetically normal immune cells within the microenvironment, regulating not only their proliferation and survival, but also their differentiation and access to tumour cells. Here we review recent advances in our knowledge of how the ECM regulates the tumour immune microenvironment and vice versa, comparing normal skin wound healing to the pathological condition of tumour progression.

Mechanical Signaling in the Mammary Microenvironment: From Homeostasis to Cancer.

It is becoming increasingly appreciated that biophysical influences on tissues are at least as important as biochemical influences in regulating normal development and homeostasis. Furthermore, diseases of aberrant tissue homeostasis such as cancers are driven by the abnormal biophysics of cancerous tissues. The mammary gland, a mechanoresponsive tissue, is exquisitely sensitive to changes in its mechanical microenvironment. Forces play an important role in normal mammary development, lactation, and involution, as well as in mammary neoplasia. As such the mechanical influences on normal tissue homeostasis and neoplasia are easily studied in this tissue. Here, we discuss the role of mechanical forces in these developmental and homeostatic processes and highlight insights gained from new findings in the field of mammary mechanobiology. We also discuss the potential for harnessing these insights into novel anticancer therapy approaches that halt tumor progression, with opportunities to revolutionize cancer care and outcomes for patients.

Differentiation of the tumor microenvironment: are CAFs the Organizer?

Cancers contain a suite of genetically stable cells within an extracellular matrix, collectively termed the tumor microenvironment (TME). The TME strongly influences disease outcome for patients. Gleaning clues from the literature, we propose that the TME should be viewed not as disparate populations of cells constituting a pathological lesion, but as a cohesive tissue constituting a novel pathological organ, arising from the coordinated differentiation of its constituent cell types - a process we have termed tumor-associated neodifferentiation (TAND). We also discuss why cancer-associated fibroblasts (CAFs) may assume the role of Organizer of this organ, directing the recruitment and differentiation of cells within the TME. Viewing the microenvironment in this way will reveal new cancer vulnerabilities that may be exploited for therapy.

Publisher Correction: ROCK-mediated selective activation of PERK signalling causes fibroblast reprogramming and tumour progression through a CRELD2-dependent mechanism.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

ROCK-mediated selective activation of PERK signalling causes fibroblast reprogramming and tumour progression through a CRELD2-dependent mechanism.

It is well accepted that cancers co-opt the microenvironment for their growth. However, the molecular mechanisms that underlie cancer-microenvironment interactions are still poorly defined. Here, we show that Rho-associated kinase (ROCK) in the mammary tumour epithelium selectively actuates protein-kinase-R-like endoplasmic reticulum kinase (PERK), causing the recruitment and persistent education of tumour-promoting cancer-associated fibroblasts (CAFs), which are part of the cancer microenvironment. An analysis of tumours from patients and mice reveals that cysteine-rich with EGF-like domains 2 (CRELD2) is the paracrine factor that underlies PERK-mediated CAF education downstream of ROCK. We find that CRELD2 is regulated by PERK-regulated ATF4, and depleting CRELD2 suppressed tumour progression, demonstrating that the paracrine ROCK-PERK-ATF4-CRELD2 axis promotes the progression of breast cancer, with implications for cancer therapy.