Reprogramming normal cells into tumour precursors requires ECM stiffness and oncogene-mediated changes of cell mechanical properties

Abstract

Defining the interplay between genetic events and microenvironmental contexts necessary to initiate tumorigenesis in normal cells is a central endeavor in cancer biology. We found that RTK/Ras oncogenes reprogram normal, freshly explanted primary mouse and human cells into tumor precursors, in a process requiring increased force transmission between oncogene-expressing cells and their surrounding extracellular matrix (ECM). Microenvironments approximating the normal softness of healthy tissues, or blunting cellular mechanotransduction, prevent oncogene-mediated cell reprogramming and tumor emergence. However, RTK/Ras oncogenes empower a disproportional cellular response to the mechanical properties of the cell's environment, such that when cells experience even subtle supraphysiological ECM rigidity they are converted into tumor-initiating cells. These regulations rely on YAP/TAZ mechanotransduction, and YAP/TAZ target genes account for a large fraction of the transcriptional responses downstream of oncogenic signaling. This work lays the groundwork for exploiting oncogenic mechanosignaling as vulnerability at the onset of tumorigenesis, including tumor prevention strategies.

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

“…YAP and TAZ are the principal triggers of numerous cell-autonomous responses but also implicated in mechanosensing and mechanotransduction, thus orchestrating interactions between tumor cells and the tumor microenvironment [15,27]. They capture information from the physical environment experienced by the cell and convert it into a transcriptional response.…”

“…Recently, it has been shown that microenvironments approximating the normal softness of healthy tissues prevent oncogene-mediated cell reprogramming and tumor emergence, events relying on YAP/TAZ mechanotransduction. Conversely, even subtle supra-physiological extracellular-matrix rigidity is transforming cells into tumor-initiating cells [15]. All these regulations rely on YAP/TAZ mechanotransduction, and YAP/TAZ target genes account for a large fraction of the transcriptional responses downstream of oncogenic signaling.…”

“…YAP and TAZ act as the ultimate nuclear effectors of signals transmitted from intrinsic biochemical and extrinsic biomechanical cues resulting from changes in the microenvironment and the architecture of tissues, including extracellular matrix rigidity, cell-cell and cell-matrix adhesion, cell density, shape and polarity, all of which play a role in metastatic dissemination and the homing of tumor cells to distant sites. Most recently, it was demonstrated that mechanosignal-transduction from stiffening surrounding extracellular matrix through YAP/TAZ is required to allow for oncogene-induced neoplastic reprograming of cells [15]. During the metastatic process, the highly plastic tumor cell shape is repeatedly changing between more round and compact and a more spread-out geometry.…”

Cytotoxic lymphocytes use mechanosurveillance to target biophysical vulnerabilities in cancer

“…ECM remodeling is generally thought to promote malignancy by stimulating cancer cell migration, epithelial to mesenchymal transition (EMT), and transcriptional programs important for tumorigenesis (Kai et al, 2019). ECM stiffness, in particular, has been shown to drive cancer cell proliferation via the transcription factor YAP (Yes-associated protein) (Albrengues et al, 2018; Panciera et al, 2020). These same changes in the ECM, however, could also promote anti-tumor immunity in certain contexts.…”

Targeting Mechanotransduction in Osteosarcoma: A Comparative Oncology Perspective

“…There are a considerable number of unknowns that will need to be addressed in order to fully understand the mechanical landscape of OSA, some of which are briefly discussed below: How does the mechanical bone and lung microenvironment change during osteosarcoma progression? Panciera and colleagues (2020) recently found that constitutive oncogenic signalling, specifically by Kirsten rat sarcoma viral oncogene homolog (K-RAS) or HER2, alone, is not enough to reprogram mammary cells into tumour-initiating cells but might additionally require a stiffer-than-normal mechanical microenvironment [ 191 ]. Given that calcified collagenous bone is already a stiff microenvironment, it is unclear how, and if, the osteoid production by tumour cells contributes to the stiffness of the microenvironment and what are the implications of such contribution to tumour development and progression.…”