Antibody targeting of CD24 efficiently retards growth and influences cytokine milieu in experimental carcinomas

Melanoma is often characterized by a constitutively active RAS-RAF-MEK-ERK pathway. For targeted therapy, BRAF inhibitors are available that are powerful in the beginning but resistance occurs rather fast. A better understanding of the mechanisms of resistance is urgently needed to increase the success of the treatment. Here, we observed that SOX2 and CD24 are upregulated upon BRAF inhibitor treatment. A similar upregulation was seen in targeted therapy-resistant, melanoma-derived induced pluripotent cancer cells (iPCCs). SOX2 and CD24 are known to promote an undifferentiated and cancer stem cell-like phenotype associated with resistance. We, therefore, elucidated the role of SOX2 and CD24 in targeted therapy resistance in more detail. We found that the upregulation of SOX2 and CD24 required activation of STAT3 and that SOX2 induced the expression of CD24 by binding to its promoter. We find that the overexpression of SOX2 or CD24 significantly increases the resistance toward BRAF inhibitors, while SOX2 knock-down rendered cells more sensitivity toward treatment. The overexpression of CD24 or SOX2 induced Src and STAT3 activity. Importantly, by either CD24 knock-down or Src/STAT3 inhibition in resistant SOX2-overexpressing cells, the sensitivity toward BRAF inhibitors was re-established. Hence, we suggest a novel mechanism of adaptive resistance whereby BRAF inhibition is circumvented via the activation of STAT3, SOX2 and CD24. Thus, to prevent adaptive resistance, it might be beneficial to combine Src/STAT3 inhibitors together with MAPK pathway inhibitors.

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“…50 We suggest that BRAFi treatment leads to an increase in STAT3 activation shortly after treatment which promotes SOX2 expression.…”

Section: Discussionmentioning

confidence: 82%

SOX2‐mediated upregulation of CD24 promotes adaptive resistance toward targeted therapy in melanoma

Hüser

Sachindra

Granados

et al. 2018

Intl Journal of Cancer

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“…The biological and human pathological relevance of GON4L, YY1 and CD24 in bladder cancer encouraged us to examine GON4L in other cancer types, particularly types where CD24 and AR are known to be biologically and clinically relevant, such as prostate (9,39), breast (6,39) and lung (13,39). GON4L is also mostly either gained or amplified in these cancer types in multiple cohorts (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Knockdown of CD24 also retards the growth, progression and metastasis of prostate cancer (9), gastric cancer (10), and breast cancer (11). Targeting CD24 by anti-CD24 antibody inhibits growth and/or metastasis in models of osteosarcoma (12), lung (13), pancreatic, colorectal (14) and bladder (15) cancer. Thus, identifying genes whose depletion reduces CD24 expression are likely to be clinically relevant and provide additional and targetable regulators of tumor growth.…”

Section: Introductionmentioning

confidence: 99%

GON4L Drives Cancer Growth through a YY1–Androgen Receptor–CD24 Axis

et al. 2016

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In principle, the inhibition of candidate gain-of-function genes defined through genomic analyses of large patient cohorts offers an attractive therapeutic strategy. In this study, we focused on changes in expression of CD24, a well validated clinical biomarker of poor prognosis and a driver of tumor growth and metastasis, as a benchmark to assess functional relevance. Through this approach, we identified GON4L as a regulator of CD24 from screening a pooled shRNA library of 176 candidate gain-of-function genes. GON4L depletion reduced CD24 expression in human bladder cancer cells, blocked cell proliferation in vitro and tumor xenograft growth in vivo. Mechanistically, GON4L interacted with transcription factor YY1, promoting its association with the androgen receptor to drive CD24 expression and cell growth. In clinical bladder cancer specimens, expression of GON4L, YY1 and CD24 was elevated compared to normal bladder urothelium. This pathway is biologically relevant in other cancer types as well, where CD24 and the androgen receptor are clinically prognostic, given that silencing of GON4L and YY1 suppressed CD24 expression and growth of human lung, prostate and breast cancer cells. Overall, our results define GON4L as a novel driver of cancer growth, offering new biomarker and therapeutic opportunities.

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“…Thus, anti-CD24 therapy may promote down-regulation of Breg cells and promote increased T cell activity on tumors. One study supported this notion by showing that anti-CD24 mAb treatment was able to lead to changes in tumor cytokine levels in mice (45). In conclusion, one could imagine combining anti-CD24 mAb with agents targeting transcription factors which regulate CD24 expression such as androgen receptor (10), HIF1 (12), and GON4L (10,12).…”

Section: Discussionmentioning

confidence: 96%

Nuclear CD24 Drives Tumor Growth and Is Predictive of Poor Patient Prognosis

Duex¹,

Owens²,

Chauca-Diaz³

et al. 2017

Cancer Research

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Elevated tumor expression of the cell surface GPI-linked CD24 protein signals poor patient prognosis in many tumor types. However, some cancer cells selected to be negative for surface CD24 (surCD24-) still retain aggressive phenotypes in vitro and in vivo. Here we resolve this apparent paradox with the discovery of biologically active, nuclear CD24 (nucCD24) and finding that its levels are unchanged in surCD24- cells. Using the complementary techniques of biochemical cellular fractionation and immunofluorescence, we demonstrate a signal for CD24 in the nucleus in cells from various histological types of cancer. Nuclear-specific expression of CD24 (NLS-CD24) increased anchorage independent growth in vitro and tumor formation in vivo. Immunohistochemistry of patient tumor samples revealed the presence of nucCD24, whose signal intensity correlated positively with the presence of metastatic disease. Analysis of gene expression between cells expressing CD24 and NLS-CD24 revealed a unique nucCD24 transcriptional signature. The median score derived from this signature was able to stratify overall survival in 4 patient datasets from bladder cancer and 5 patient datasets from colorectal cancer. Patients with high scores (more nucCD24-like) had reduced survival. These findings define a novel and functionally important intracellular location of CD24, they explain why surCD24- cells can remain aggressive, and they highlight the need to consider nucCD24 in both fundamental research and therapeutic development.

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Antibody targeting of CD24 efficiently retards growth and influences cytokine milieu in experimental carcinomas

Cited by 66 publications

References 33 publications

SOX2‐mediated upregulation of CD24 promotes adaptive resistance toward targeted therapy in melanoma

SOX2‐mediated upregulation of CD24 promotes adaptive resistance toward targeted therapy in melanoma

GON4L Drives Cancer Growth through a YY1–Androgen Receptor–CD24 Axis

Nuclear CD24 Drives Tumor Growth and Is Predictive of Poor Patient Prognosis

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