TGFβ-induced expression of long noncoding lincRNA Platr18 controls breast cancer axonogenesis

Metastasis is the leading driver of cancer-related death. Tumor cell plasticity associated with the epithelial-mesenchymal transition (EMT), an embryonic program also observed in carcinomas, has been proposed to explain the colonization of distant organs by the primary tumor cells. Many studies have...

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Bibliographic Details
Published in:Life science alliance 2022-02, Vol.5 (2), p.e202101261
Main Authors: Grelet, Simon, Fréreux, Cécile, Obellianne, Clémence, Noguchi, Ken, Howley, Breege V, Dalton, Annamarie C, Howe, Philip H
Format: Article
Language:English
Subjects:
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Epithelial-Mesenchymal Transition
Female
Gene Expression Regulation, Neoplastic
Humans
RNA, Long Noncoding - genetics
Transforming Growth Factor beta - metabolism
Tumor Microenvironment - genetics
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Summary:Metastasis is the leading driver of cancer-related death. Tumor cell plasticity associated with the epithelial-mesenchymal transition (EMT), an embryonic program also observed in carcinomas, has been proposed to explain the colonization of distant organs by the primary tumor cells. Many studies have established correlations between EMT marker expression in the primary tumor and metastasis in vivo. However, the longstanding model of EMT-transitioned cells disseminating to secondary sites is still actively debated and hybrid states are presently considered as more relevant during tumor progression and metastasis. Here, we describe an unexplored role of EMT on the tumor microenvironment by controlling tumor innervation. Using in vitro and in vivo breast tumor progression models, we demonstrate that TGFβ-mediated tumor cell EMT triggers the expression of the embryonic LincRNA Platr18 those elevated expression controls the expression of the axon guidance protein semaphorin-4F and other neuron-related molecules such as IGSF11/VSIG-3. Platr18/Sema4F axis silencing abrogates axonogenesis and attenuates metastasis. Our observations suggest that EMT-transitioned cells are also locally required in the primary tumor to support distant dissemination by promoting axonogenesis, a biological process known for its role in metastatic progression of breast cancer.
ISSN:2575-1077
2575-1077
DOI:10.26508/LSA.202101261