CREB3L1 promotes tumor growth and metastasis of anaplastic thyroid carcinoma by remodeling the tumor microenvironment

Abstract

Anaplastic thyroid carcinoma (ATC) is an extremely malignant type of endocrine cancer frequently accompanied by extrathyroidal extension or metastasis through mechanisms that remain elusive. We screened for the CREB3 transcription-factor family in a large cohort, consisting of four microarray datasets. This revealed that CREB3L1 was specifically up regulated in ATC tissues and negatively associated with overall survival of patients with thyroid cancer. Consistently, high expression of CREB3L1 was negatively correlated with progression-free survival in an independent cohort. CREB3L1 knockdown dramatically attenuated invasion of ATC cells, whereas overexpression of CREB3L1 facilitated the invasion of papillary thyroid carcinoma (PTC) cells. Loss of CREB3L1 inhibited metastasis and tumor growth of ATC xenografts in zebrafish and nude mouse model. Single-cell RNA-sequencing analysis revealed that CREB3L1 expression gradually increased during the neoplastic progression of a thyroid follicular epithelial cell to an ATC cell, accompanied by the activation of the extracellular matrix (ECM) signaling. CREB3L1 knockdown significantly decreased the expression of collagen subtypes in ATC cells and the fibrillar collagen in xenografts. Due to the loss of CREB3L1, ATC cells were unable to activate alpha-smooth muscle actin (α-SMA)-positive cancer-associated fibroblasts (CAFs). After CREB3L1 knockdown, the presence of CAFs inhibited the growth of ATC spheroids and the metastasis of ATC cells. Further cytokine array screening showed that ATC cells activated α-SMA-positive CAFs through CREB3L1-mediated IL-1α production. Moreover, KPNA2 mediated the nuclear translocation of CREB3L1, thus allowing it to activate downstream ECM signaling. These results demonstrate that CREB3L1 maintains the CAF-like property of ATC cells by activating the ECM signaling, which remodels the tumor stromal microenvironment and drives the malignancy of ATC. Graphical Abstract

The molecular classification of cancer‐associated fibroblasts on a pan‐cancer single‐cell transcriptional atlas

“…In contrast, IRF9 , a TF involved in immune response regulation, was primarily found in iCAF, 50 while MEF2C , influencing myogenesis and angiogenesis, was mostly present in myCAF 51 . Lastly, CREB3L1 , a TF that regulates collagen formation, 52 was uniquely expressed in matCAF (Figure 3F). Interestingly, similar patterns were noted in other cancer types such as BRCA and LUAD, where the active TF regulatory networks of diverse CAF subtypes likewise demonstrated significant functional distinctions (Figure S7B,C).…”

Potential miRNA-gene interactions determining progression of various ATLL cancer subtypes after infection by HTLV-1 oncovirus

“…The dataset details are explained in Table 1. The possible batch effect among datasets was removed using the function of removeBatchEffect in the Limma package version 3.54 in the R 4.2.2 environment [10,[17][18][19][20][21]. The data was also quantile normalized.…”

The molecular classification of cancer-associated fibroblasts on a pan-cancer single-cell transcriptional profiling

“…In COAD, we observed that NFIX [54], a TF regulating cell proliferation, was mainly expressed in proCAF. Meanwhile, as a member of TFs regulating immune response, IRF9 was predominantly expressed in iCAF [55]; while MEF2C, a TF regulating myogenesis and angiogenesis [56], was overwhelmingly expressed in myCAF; and CREB3L1, a TF regulating collagen formation [57], was exclusively expressed in matCAF (Fig. 3F).…”