ERBB3-induced furin promotes the progression and metastasis of ovarian cancer via the IGF1R/STAT3 signaling axis

Chen, Changliang; Gupta, Prachi; Parashar, Deepak; Nair, Gopakumar G.; George, Jasmine; Geethadevi, Anjali; Wang, Wei; Tsaih, Shirng‐Wern; Bradley, William H.; Ramchandran, Ramani; Rader, Janet S.; Chaluvally‐Raghavan, Pradeep; Pradeep, Sunila

doi:10.1038/s41388-020-1194-7

Cited by 36 publications

(37 citation statements)

References 38 publications

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“…Briefly, 2 × 10 4 cells were seeded into 12-well culture plates with the complete culture media and scanned for 4 days. Cell migration was determined by wound-healing assay as previously described 34 , 40 , 41 . Wound closure was quantified by measuring wound areas from ≥3 different fields using ImageJ 1.8.0 (NIH).…”

Section: Methodsmentioning

confidence: 99%

WAVE3 phosphorylation regulates the interplay between PI3K, TGF-β, and EGF signaling pathways in breast cancer

Wang¹,

Kansakar²,

Markovic³

et al. 2020

Oncogenesis

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Both TGF-β and the PI3K-AKT signaling pathways are known activators of various intracellular pathways that regulate critical cellular functions, including cancer cell survival and proliferation. The interplay between these two oncogenic pathways plays a major role in promoting the initiation, growth, and progression of tumors, including breast cancers. The molecular underpinning of the inter-relationship between these pathways is, however, not fully understood, as is the role of WAVE3 phosphorylation in the regulation of tumor growth and progression. WAVE3 has been established as a major driver of the invasion–metastasis cascade in breast cancer and other tumors of epithelial origin. WAVE3 phosphorylation downstream of PI3K was also shown to regulate cell migration. Here we show that, in addition to PI3K, WAVE3 tyrosine phosphorylation can also be achieved downstream of TGF-β and EGF and that WAVE3 tyrosine phosphorylation is required for its oncogenic activity. Our in vitro analyses found loss of WAVE3 phosphorylation to significantly inhibit cell migration, as well as tumorsphere growth and invasion. In mouse models for breast cancer, loss of WAVE3 phosphorylation inhibited tumor growth of two aggressive breast cancer cell lines of triple-negative subtype. More importantly, we found that WAVE3 phosphorylation is also required for the activation of PI3K, TGF-β, and EGF signaling and their respective downstream effectors. Therefore, our study identified a novel function for WAVE3 in the regulation of breast cancer development and progression through the modulation of a positive feedback loop between WAVE3 and PI3K-TGF-β-EGF signaling pathways.

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Section: Methodsmentioning

confidence: 99%

WAVE3 phosphorylation regulates the interplay between PI3K, TGF-β, and EGF signaling pathways in breast cancer

Wang¹,

Kansakar²,

Markovic³

et al. 2020

Oncogenesis

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“…In addition, IGF1R activation determines phosphorylation and nuclear translocation of STAT3, which modulates transcriptional activation of cancer-associated genes. In ovarian cancer, the activation of the IGF1R/STAT3 axis promotes cell migration, invasion and in vitro spheroid formation and induces in vivo tumor growth [ 62 ]. Additional cancer genes modulated by a dysregulated IGF1R-STAT3 axis are ALDH1 [ 63 ] and Nanog [ 64 ], which enhance the epithelial-to-mesenchymal transition (EMT)-associated cancer stem cells (CSC)-like properties in non-small cell lung cancer and colorectal cancer, respectively.…”

Section: The Igf System In Cancermentioning

confidence: 99%

Novel Regulators of the IGF System in Cancer

2021

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The insulin-like growth factor (IGF) system is a dynamic network of proteins, which includes cognate ligands, membrane receptors, ligand binding proteins and functional downstream effectors. It plays a critical role in regulating several important physiological processes including cell growth, metabolism and differentiation. Importantly, alterations in expression levels or activation of components of the IGF network are implicated in many pathological conditions including diabetes, obesity and cancer initiation and progression. In this review we will initially cover some general aspects of IGF action and regulation in cancer and then focus in particular on the role of transcriptional regulators and novel interacting proteins, which functionally contribute in fine tuning IGF1R signaling in several cancer models. A deeper understanding of the biological relevance of this network of IGF1R modulators might provide novel therapeutic opportunities to block this system in neoplasia.

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“…IHC staining for CLPTM1L (Human: Polyclonal anti-CLPTM1L (HPA014791, Sigma Aldrich, St. Louis, MO, Mouse: Novus anti-CLPTM1L, NBP1-62477) was performed on the Dako Autostainer Plus using the Dako EnVision™ FLEX High pH Detection Kit (K8010) (Dako, Carpinteria, CA). Immunohistochemical staining performed as described earlier 33 , 34 . Briefly, slides were deparaffinized to Xylene.…”

Section: Methodsmentioning

confidence: 99%

Targeted biologic inhibition of both tumor cell-intrinsic and intercellular CLPTM1L/CRR9-mediated chemotherapeutic drug resistance

et al. 2021

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Recurrence of therapy-resistant tumors is a principal problem in solid tumor oncology, particularly in ovarian cancer. Despite common complete responses to first line, platinum-based therapies, most women with ovarian cancer recur, and eventually, nearly all with recurrent disease develop platinum resistance. Likewise, both intrinsic and acquired resistance contribute to the dismal prognosis of pancreatic cancer. Our previous work and that of others has established CLPTM1L (cleft lip and palate transmembrane protein 1-like)/CRR9 (cisplatin resistance related protein 9) as a cytoprotective oncofetal protein that is present on the tumor cell surface. We show that CLPTM1L is broadly overexpressed and accumulated on the plasma membrane of ovarian tumor cells, while weakly or not expressed in normal tissues. High expression of CLPTM1L is associated with poor outcome in ovarian serous adenocarcinoma. Robust re-sensitization of resistant ovarian cancer cells to platinum-based therapy was achieved using human monoclonal biologics inhibiting CLPTM1L in both orthotopic isografts and patient-derived cisplatin resistant xenograft models. Furthermore, we demonstrate that in addition to cell-autonomous cytoprotection by CLPTM1L, extracellular CLPTM1L confers resistance to chemotherapeutic killing in an ectodomain-dependent fashion, and that this intercellular resistance mechanism is inhibited by anti-CLPTM1L biologics. Specifically, exosomal CLPTM1L from cisplatin-resistant ovarian carcinoma cell lines conferred resistance to cisplatin in drug-sensitive parental cell lines. CLPTM1L is present in extracellular vesicle fractions of tumor culture supernatants and in patients’ serum with increasing abundance upon chemotherapy treatment. These findings have encouraging implications for the use of anti-CLPTM1L targeted biologics in the treatment of therapy-resistant tumors.

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ERBB3-induced furin promotes the progression and metastasis of ovarian cancer via the IGF1R/STAT3 signaling axis

Cited by 36 publications

References 38 publications

WAVE3 phosphorylation regulates the interplay between PI3K, TGF-β, and EGF signaling pathways in breast cancer

WAVE3 phosphorylation regulates the interplay between PI3K, TGF-β, and EGF signaling pathways in breast cancer

Novel Regulators of the IGF System in Cancer

Targeted biologic inhibition of both tumor cell-intrinsic and intercellular CLPTM1L/CRR9-mediated chemotherapeutic drug resistance

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