MACC1 promotes pancreatic cancer metastasis by interacting with the EMT regulator SNAI1

Zhang, Xianglian; Luo, Ya; Cen, Yu; Qiu, Xin; Li, Jing; Jie, Meng-Meng; Yang, Shi‐Ming; Qin, Shanyu

doi:10.1038/s41419-022-05285-8

Cited by 20 publications

(7 citation statements)

References 52 publications

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“…Figure b shows similar gene expression profiles for (i) cells cultured in stiff 3D conditions (“stiff to stiff”) and cells moved from stiff to soft 3D culture (“stiff to soft”) and (ii) cells cultured in soft 3D conditions (“soft to soft”) and cells moved from soft to stiff 3D culture (“soft to stiff”). Remarkably, the top three downregulated genes in conditions where cells experienced a stiff 3D microenvironment for any length of time were tumor suppressor genes LATS1 , BCAR3 , and CDKN2C . − Of the top upregulated genes in stiff-primed conditions (log 2 fold-change >2, p -value < 0.05), several of these genes have been identified as prognostic markers in cancer, including SLC6A4 , MACC1 , SLC14A2 , CRB3 , NFKBIL1 , RAC3 , CLIC3 , CYBA , FRMD6-AS1 , LAIR1 , L1TD1 , SEMA3E , PCDH11Y , MIRLET7BHG , and TERC (Figure b). − We performed GO Term analysis comparing cells primed in soft culture vs cells primed in stiff culture and note changes in terms including transcriptional misregulation in cancer, chromatin organization, nucleus organization, and metabolism of RNA, which may suggest epigenetic mechanisms act as a component responsible for some of these transcriptional changes (Figure S9). For the genes that may be correlated with mechanical memory, we examined TCGA for pancreatic cancer patient prognosis data .…”

Section: Resultsmentioning

confidence: 99%

Survival-Associated Cellular Response Maintained in Pancreatic Ductal Adenocarcinoma (PDAC) Switched Between Soft and Stiff 3D Microgel Culture

Atkins,

Rosas,

Månsson

et al. 2024

ACS Biomater. Sci. Eng.

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Pancreatic ductal adenocarcinoma (PDAC) accounts for about 90% of all pancreatic cancer cases. Five-year survival rates have remained below 12% since the 1970s, in part due to the difficulty in detection prior to metastasis (migration and invasion into neighboring organs and glands). Mechanical memory is a concept that has emerged over the past decade that may provide a path toward understanding how invading PDAC cells "remember" the mechanical properties of their diseased ("stiff", elastic modulus, E ≈ 10 kPa) microenvironment even while invading a healthy ("soft", E ≈ 1 kPa) microenvironment. Here, we investigated the role of mechanical priming by culturing a dilute suspension of PDAC (FG) cells within a 3D, rheologically tunable microgel platform from hydrogels with tunable mechanical properties. We conducted a suite of acute (short-term) priming studies where we cultured PDAC cells in either a soft (E ≈ 1 kPa) or stiff (E ≈ 10 kPa) environment for 6 h, then removed and placed them into a new soft or stiff 3D environment for another 18 h. Following these steps, we conducted RNA-seq analyses to quantify gene expression. Initial priming in the 3D culture showed persistent gene expression for the duration of the study, regardless of the subsequent environments (stiff or soft). Stiff 3D culture was associated with the downregulation of tumor suppressors (LATS1, BCAR3, CDKN2C), as well as the upregulation of cancer-associated genes (RAC3). Immunofluorescence staining (BCAR3, RAC3) further supported the persistence of this cellular response, with BCAR3 upregulated in soft culture and RAC3 upregulated in stiffprimed culture. Stiff-primed genes were stratified against patient data found in The Cancer Genome Atlas (TCGA). Upregulated genes in stiff-primed 3D culture were associated with decreased survival in patient data, suggesting a link between patient survival and mechanical priming.

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Section: Resultsmentioning

confidence: 99%

Survival-Associated Cellular Response Maintained in Pancreatic Ductal Adenocarcinoma (PDAC) Switched Between Soft and Stiff 3D Microgel Culture

Atkins,

Rosas,

Månsson

et al. 2024

ACS Biomater. Sci. Eng.

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“…MACC1 is directly phosphorylated by MEK1, a component of the Erk mitogen-activated protein kinase (MAPK) pathway, resulting in enhanced Erk activation as well as migration and metastasis in colon cancer cells [56]. MACC1-enhanced transcriptional events contribute to epithelial-mesenchymal transition (EMT) in pancreatic cancer cells [57]. Previous work showed that CCN1 and MACC1 cooperate to promote human colorectal cancer cell metastasis, adhesion, migration, differentiation, angiogenesis, and survival [33].…”

Section: Discussionmentioning

confidence: 99%

Global Proteomics Analysis of Lysophosphatidic Acid Signaling in PC-3 Human Prostate Cancer Cells: Role of CCN1

Balijepalli,

Yue,

Prasad

et al. 2024

IJMS

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Cysteine-rich angiogenic factor 61 (CCN1/Cyr61) is a matricellular protein that is induced and secreted in response to growth factors. Our previous work showed that 18:1-lysophosphatidic acid (LPA), which activates the G protein-coupled receptor LPAR1, induces CCN1 between 2–4 h in PC-3 human prostate cancer cells in a manner than enhances cell-substrate adhesion. While the time course of induction suggests that CCN1 contributes to intermediate events in LPA action, the roles of CCN1 in LPA-mediated signal transduction have not been fully elucidated. This study utilized a comprehensive global proteomics approach to identify proteins up- or down-regulated in response to treatment of PC-3 cells with LPA for three hours, during the time of peak CCN1 levels. In addition, the effects of siRNA-mediated CCN1 knockdown on LPA responses were analyzed. The results show that, in addition to CCN1, LPA increased the levels of multiple proteins. Proteins up-regulated by LPA included metastasis-associated in colon cancer protein 1 (MACC1) and thrombospondin-1 (TSP1/THBS1); both MACC1 and TSP1 regulated cancer cell adhesion and motility. LPA down-regulated thioredoxin interacting protein (TXNIP). CCN1 knockdown suppressed the LPA-induced up-regulation of 30 proteins; these included MACC1 and TSP1, as confirmed by immunoblotting. Gene ontology and STRING analyses revealed multiple pathways impacted by LPA and CCN1. These results indicate that CCN1 contributes to LPA signaling cascades that occur during the intermediate phase after the initial stimulus. The study provides a rationale for the development of interventions to disrupt the LPA-CCN1 axis.

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“…The recurrence of colon cancer post-radical surgery is intricately linked to factors such as the excised tumor lesion's completeness, the biological activity of tumor cells, and the self-proliferation traits of residual tumor cells[ 9 , 10 ]. For patients with poorly differentiated tumor cells or in advanced clinical stages, the risk of recurrence may progressively rise post-surgery, correspondingly increasing the mortality rate[ 11 , 12 ].…”

Section: Discussionmentioning

confidence: 99%

Correlation between the expressions of metastasis-associated factor-1 in colon cancer and vacuolar ATP synthase

He,

Cao,

Huang

et al. 2023

World J Gastrointest Surg

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BACKGROUND Clinical prognosis often worsens due to high recurrence rates following radical surgery for colon cancer. The examination of high-risk recurrence factors post-surgery provides critical insights for disease evaluation and treatment planning. AIM To explore the relationship between metastasis-associated factor-1 in colon cancer (MACC1) and vacuolar ATP synthase (V-ATPase) expression in colon cancer tissues, and recurrence rate in patients undergoing radical colon cancer surgery. METHODS We selected 104 patients treated with radical colon cancer surgery at our hospital from January 2018 to June 2021. Immunohistochemical staining was utilized to assess the expression levels of MACC1 and V-ATPase in these patients. RESULTS The rates of MACC1 and V-ATPase positivity were 64.42% and 67.31%, respectively, in colon cancer tissues, which were significantly higher than in paracancerous tissues (P < 0.05). Among patients with TNM stage III, medium to low differentiation, and lymph node metastasis, the positive rates of MACC1 and V-ATPase were significantly elevated in comparison to patients with TNM stage I-II, high differentiation, and no lymph node metastasis (P < 0.05). The rate of MACC1 positivity was 76.67% in patients with tumor diameters > 5 cm, notably higher than in patients with tumor diameters ≤ 5 cm (P < 0.05). We observed a positive correlation between MACC1 and V-ATPase expression (rs = 0.797, P < 0.05). The positive rates of MACC1 and V-ATPase were significantly higher in patients with recurrence compared to those without (P < 0.05). Logistic regression analysis revealed TNM stage, lymph node metastasis, MACC1 expression, and V-ATPase expression as risk factors for postoperative colon cancer recurrence (OR = 6.322, 3.435, 2.683, and 2.421; P < 0.05). CONCLUSION The upregulated expression of MACC1 and V-ATPase in colon cancer patients appears to correlate with clinicopathological features and post-radical surgery recurrence.

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MACC1 promotes pancreatic cancer metastasis by interacting with the EMT regulator SNAI1

Cited by 20 publications

References 52 publications

Survival-Associated Cellular Response Maintained in Pancreatic Ductal Adenocarcinoma (PDAC) Switched Between Soft and Stiff 3D Microgel Culture

Survival-Associated Cellular Response Maintained in Pancreatic Ductal Adenocarcinoma (PDAC) Switched Between Soft and Stiff 3D Microgel Culture

Global Proteomics Analysis of Lysophosphatidic Acid Signaling in PC-3 Human Prostate Cancer Cells: Role of CCN1

Correlation between the expressions of metastasis-associated factor-1 in colon cancer and vacuolar ATP synthase

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