Weakly migratory metastatic breast cancer cells activate fibroblasts via microvesicle-Tg2 to facilitate dissemination and metastasis

Abstract

Cancer cell migration is highly heterogeneous, and the migratory capability of cancer cells is thought to be an indicator of metastatic potential. It is becoming clear that a cancer cell does not have to be inherently migratory to metastasize, with weakly migratory cancer cells often found to be highly metastatic. However, the mechanism through which weakly migratory cells escape from the primary tumor remains unclear. Here, utilizing phenotypically sorted highly and weakly migratory human breast cancer cells, we demonstrate that weakly migratory metastatic cells disseminate from the primary tumor via communication with stromal cells. While highly migratory cells are capable of single cell migration, weakly migratory cells rely on cell-cell signaling with fibroblasts to escape the primary tumor. Weakly migratory cells release microvesicles rich in tissue transglutaminase 2 (Tg2) which activate murine fibroblasts and lead weakly migratory cancer cell migration in vitro. These microvesicles also induce tumor stiffening and fibroblast activation in vivo and enhance the metastasis of weakly migratory cells. Our results identify microvesicles and Tg2 as potential therapeutic targets for metastasis and reveal a novel aspect of the metastatic cascade in which weakly migratory cells release microvesicles which activate fibroblasts to enhance cancer cell dissemination.

Identification and experimental verification of an anoikis and immune related signature in prognosis for lung adenocarcinoma

“…However, the ECM also plays a particularly important role in the metastasis of tumors (33). Both fibroblasts and vascular endothelial cells in the tumor microenvironment produce a variety of cytokines that promote tumor migration and invasion (34)(35)(36). Meanwhile, various matrix proteins, collagen and other soluble molecules in the tumor microenvironment can also promote tumor metastasis.…”

The Role of Transglutaminase 2 in Cancer: An Update

“…Despite significant efforts in recent decades, the mechanism driving tumorigenesis and progression remains elusive [ 64 ]. Since 1996, it has been postulated that TG2 plays a role in breast cancer [ 26 ], demonstrating its involvement in fostering the EMT [ 48 ], advancing metastatic progression [ 65 , 66 , 67 ], and contributing to drug resistance [ 36 , 37 , 38 ]; see Figure 6 .…”

“…Even in breast cancer, TG2 expression promotes the metastatic process: weakly migratory metastatic cells can release TG2-containing microvesicles, causing fibroblast activation and inducing tumor stiffening and spreading [ 65 ]. The role of TG2 in promoting the establishment of a pulmonary metastatic niche is further supported by another study which highlights the induction of fibronectin fibrillogenesis on the surface of TG2 micro-vesicles and a consequent reprogramming of lung fibroblasts [ 66 ].…”

“…Despite significant efforts in recent decades, the mechanism driving tumorigenesis and progression remains elusive [64]. Since 1996, it has been postulated that TG2 plays a role in breast cancer [26], demonstrating its involvement in fostering the EMT [48], advancing metastatic progression [65][66][67], and contributing to drug resistance [36][37][38]; see Figure 6. TG2 has been also evaluated as a promising breast cancer prognostic biomarker that sustains cell proliferation and glycolytic metabolism through the mitogen-activated protein kinase/extracellular signal-related protein kinase/lactate dehydrogenase TG2 has been also evaluated as a promising breast cancer prognostic biomarker that sustains cell proliferation and glycolytic metabolism through the mitogen-activated protein kinase/extracellular signal-related protein kinase/lactate dehydrogenase (MEK/ERK/LDH) pathway or by inducing hypoxia-inducible factor 1-alpha (HIF-1α) via NF-κB [64].…”

The covert symphony: cellular and molecular accomplices in breast cancer metastasis

“…For instance, a specific subset of CAFs was found to have the unique ability to convert poorly metastatic MCF-7 cells into a metastatic state, implicating an SDF-1/CXCR4 axis as a crucial facilitator of this transformation ( Sharma et al, 2021 ). Other studies demonstrate transglutaminase 2 (Tsg2)-rich microvesicles in facilitating cancer cell-CAF interactions for dissemination ( Schwager et al, 2022 ). The presence of fibroblasts marked by low PDGFRα and high PDGFRβ associated with a higher risk of local recurrence in another study, where Notch signaling, linked to the disruption of the basement membrane, drives these fibroblasts to adopt a phenotype associated with increased expression of matrix-remodeling enzymes and TGF-β ligands ( Strell et al, 2019 ).…”