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Loss of Kindlin-1 drives a more aggressive phenotype in cutaneous squamous cell carcinoma

ABSTRACT: Kindler syndrome (KS) is a rare genodermatosis resulting from loss-of-function mutations in FERMT1, the gene that encodes Kindlin-1. KS patients have a high propensity to develop aggressive and metastatic cutaneous squamous cell carcinoma (SCC). In this study, we show that loss of Kindlin-1 in a mouse model of cutaneous SCC leads to increased migration, invasion and degradation of collagen. Loss of Kindlin-1 increased tumor growth in vivo and in 3D spheroids, which was associated with the development of a hypoxic tumor environment and increased glycolysis. One of the most highly upregulated genes in Kindlin-1-depleted tumors was Mmp13, and the increased expression of MMP13 was responsible for driving the increased migration and invasion of the Kindlin-1-depleted SCC cells. These results provide evidence that Kindlin-1 loss in SCC can promote migration and invasion through the upregulation of MMP13, and offer novel insights into how Kindlin-1 loss leads to the development of a hypoxic environment that is permissive for tumor growth.

ORGANISM(S): Mus musculus

PROVIDER: GSE236883 | GEO | 2023/07/14

REPOSITORIES: GEO

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Defining an invasion signature at the leading edge of cutaneous squamous cell carcinoma (SCC): IL-24 driven MMP-7 and MMP-13 expression.

Project description:Purpose: Primary cutaneous squamous cell carcinoma (SCC) can be an invasive cancer in skin and has the potential to metastasize. We aimed to define the cancer related molecular changes that distinguish non-invasive from invasive SCC. Experimental design: We used laser capture microdissection technique in combination with cDNA microarray analysis in order to determine molecular changes that associate with SCC progression. Results: We defined invasion-associated genes as those udifferentially regulated only in SCC invasive nests, but not in actinic keratosis-like dysplasia or SCC in situ regions, compared to normal epidermis. We designated these genes as “invasion signature gene set of cutaneous SCC”. Overall we found 383 up- and 354 down-regulated probe-sets that constitute the invasion signature gene set. As part of this profile, SCC invasion is associated with aberrant gene expression changes of numerous MMPs including MMP7 (FCH=5.43, FDR<0.01) and MMP13 (FCH=12.53, FDR<0.01). IL-24 is also up-regulated in the leading invasive edge of SCC (FCH=6.74, FDR<0.01). IL-24 enhanced mRNA expression of both MMP7 and MMP13 in a human SCC cell line. Laminin332, which is one of the target molecules of MMP7, had altered expression at the leading edge of SCC invasion nests at both the genomic and protein level. Conclusions: We defined the distribution of MMPs within human cutaneous SCC tissue showing distinct expression with progression from normal skin to actinic keratosis to SCC in situ to invasive carcinoma. We further suggest a potential role for IL-24 in progression to invasion via MMP7 and MMP13. Laser capture microdissection was performed on 5 cases of actinic keratosis, 5 cases of in situ SCC, and 5 cases of invasive SCC.

2013-04-30 | E-GEOD-42677 | biostudies-arrayexpress

Defining an invasion signature at the leading edge of cutaneous squamous cell carcinoma (SCC): IL-24 driven MMP-7 and MMP-13 expression.

2013-04-30 | GSE42677 | GEO

Mechanism of Kindlin-2 regulating invasion and metastasis of human Hepatocellular carcinoma

Project description:To explore the mechanism of Kindlin-2 regulating invasion and metastasis of human Hepatocellular carcinoma, we performed gene expression microarray analysis on Kindlin-2 knockdown LM3 cells and the control cells to compare the gene expression levels between the two groups.

2017-04-19 | GSE97951 | GEO

Gene expression in SAS cell lines upon SNAI1 silencing

Project description:Collective cell migration is one of the principal modes for cancer cell movements. However, the triggering event for collective migration and its clinical significance is unclear. Here, we found that Snail, a major inducer of epithelial-mesenchymal transition (EMT), is critical for orchestrating collective migration in squamous cell carcinoma (SCC). To invstigate how Snail contribute to collective migration and invasion, we used microarrays to identify the global gene alterations regulated by Snail in SCC cells.

2018-08-25 | GSE87841 | GEO

Loss of Laminin α3 induces cell invasion and macrophage infiltration in cutaneous squamous cell carcinoma

Project description:Cutaneous squamous cell carcinoma (cSCC) is a common cancer which invades into dermis through the basement membrane. Laminins are basement membrane proteins which are copiously secreted by SCC keratinocytes. Here we provide evidence using in vitro and in vivo 3D models as well as human tumors that the loss of the laminin a3 chain observed in poorly differentiated cSCC increases tumor invasion with an amoeboid phenotype. There is an increase in recruitment and differentiation of TAMs around invading tumor with a shift towards M2 TAMs. These data provide evidence that loss of the laminin a3 chain in cSCC has an effect on both the epithelial and immune components of cSCC resulting in an aggressive tumor microenvironment.

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Kindlin-2 modulates PTH1R to regulate bone mass and PTH actions in bone

Project description:To investigation the role of PTH and Kindlin-2 in bone development, we performed single-cell RNA-sequencing. From Con-veh, Con-PTH, cKO-veh, cKO-PTH, we profiled more than 20k single cells, including multi-potent mesenchymal stromal cells (MSC), osteoprogenitors, osteoblasts, chondrocytes, fibroblasts, endothelial cells, smooth muscle cells, skeletal muscle cells, pericytes, and schwann cells. We found proportion of part of these cells were significant altered by PTH or Kindlin-2 loss, especially for MSC, osteoblast, chondrocyte, and fibroblast. Transcriptomic analysis revealed gene expression was dramatically regulated by PTH or Kindlin-2 loss.

2020-10-01 | GSE150291 | GEO

Expression data of cDNA from the ACHN control and Kindlin-2-depleting cells

Project description:Kindlin-2, an integrin-interacting FERM-domain-containing protein, has been known to play critical roles for tumor progression. However, the role of Kindlin-2 in renal cell carcinoma (RCC) progression has not been reported. We aim to investigate the role of Kindlin-2 in the progression of RCC and the underlying mechanisms. To uncover the related pathway in which Kindlin-2 is involved to promote clear cell renal cell carcinoma progression, ACHN control and Kindlin-2-depleting cells were analyzed by Affymetrix GeneChip human Gene 1.0 ST Arrays. ACHN cells were transfected with control short hairpin RNA (shRNA) or Kindlin-2 shRNA. ACHN control and Kindlin-2-depleting cells cDNAs were hybridized to Affymetrix GeneChip Human Gene 1.0 ST arrays. Data were analyzed by Expression Console 1.4.1.

2015-12-16 | E-GEOD-76020 | biostudies-arrayexpress

Gene expression profile at single cell level of mammary gland from Kindlin-2 genetically modified mouse model

Project description:During gestation, alveolar cells are derived from luminal progenitors in the mammary gland. However, the mechanism underlying luminal progenitor commitment to alveolar cells remains largely unknown. By using five genetically modified mouse lines and single cell RNA sequencing, we identified a Kindlin-2 - Stat3 - Dll1 signaling cascade in myoepithelial cells which controls the inactivation of Notch signaling in luminal cells that consequently drives luminal progenitor commitment to alveolar cells. We found that loss of Kindlin-2 in myoepithelial cells impairs mammary morphogenesis and alveologenesis, and lactation. Single-cell profiling reveals that Kindlin-2 loss significantly decreases the proportion of alveolar cells.

2023-03-07 | GSE222028 | GEO

CST interacts with the cohesin complex and promotes chromosome cohesion

Project description:Sister chromatid cohesion (SCC), the pairing of sister chromatids following DNA replication until mitosis, is established by loading of the cohesin complex on newly replicated chromatids. Cohesin must then be maintained until mitosis to prevent segregation defects and aneuploidy. However, how SCC is established and maintained until mitosis remains incompletely understood and emerging evidence suggests that replication stress may lead to premature SCC loss. Here, we report that the single-stranded DNA-binding protein CTC1-STN1-TEN1 (CST) aids in SCC. CST primarily functions in telomere length regulation but also has known roles in replication restart and DNA repair. Following depletion of CST subunits, we observed an increase in the complete loss of SCC. Additionally, we determined that CST associates with the cohesin complex. Unexpectedly, we did not find evidence of altered cohesion or mitotic progression in the absence of CST; however, we did find that treatment with various replication inhibitors increased the association between CST and cohesin. Since replication stress was recently shown to induce SCC loss, we hypothesized that CST may be required to maintain or remodel SCC following DNA replication fork stalling. In agreement with this idea, SCC loss was greatly increased in CST-depleted cells following exogenous replication stress. Based on our findings, we propose that CST aids in the maintenance of SCC at stalled replication forks to prevent premature cohesion loss.

2021-07-28 | PXD026264 | Pride

Regulation of 5-hydroxymethylcytosine by TET2 contributes to Squamous Cell Carcinoma tumorigenesis

Project description:DNA methylation is a key regulatory event controlling a variety of physiological processes and can have dramatic effects on gene transcription. Methylated Cytosine (5mC) can be oxidized by the TET family of enzymes to 5-hydroxymethylcytosine (5-hmC), a key intermediate in the de-methylation cycle, and 5-hmC levels are reduced in malignancies such as AML and melanoma. We constructed a tissue microarray of human cutaneous Squamous Cell Carcinoma (SCC) tumors and found a global reduction in 5-hmC levels compared to adjacent skin. Using a murine K14-CreER system, we have found that loss of Tet2 promotes carcinogen-induced SCC, and cooperates with loss of Tp53 in to drive spontaneous SCC tumors in epithelial tissues. Loss of Tet2 in the normal epidermis leads to site-specific changes in 5-hmC levels, with many genes showing both increased and decreased levels of 5-hmC. Importantly, many of these changes were in genes regulating keratinocyte differentiation and self-renewal, consistent with reported roles for Tet enzymes in controlling lineage commitment in hematopoietic stem cells and ES cells. These results establish a functional role for Tet2 in the regulation of 5-hmC in the epidermis and demonstrate that Tet2 is a bone fide tumor suppressor in SCC.

2021-09-23 | GSE167949 | GEO

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