c-Abl and Arg are activated in human primary melanomas, promote melanoma cell invasion via distinct pathways, and drive metastatic progression

Ganguly, Sourik S.; Fiore, Leann S.; Sims, Jonathan T.; Friend, J Woodrow; Srinivasan, Divyamani; Thacker, Matthew; Cibull, Michael L.; Wang, C; Novak, Marián; Kaetzel, David M.; Plattner, Rina

doi:10.1038/onc.2011.361

Cited by 59 publications

(135 citation statements)

References 51 publications

Supporting

Mentioning

129

Contrasting

Order By: Relevance

“…We observed that c-Abl/Arg expression was increased in breast cancer cell lines relative to human mammary epithelial cells and in melanoma cell lines relative to primary melanocytes. 83,84 In breast cancer cells, c-Abl and/or Arg were only highly active in some lines, and activation did not correlate with expression, whereas in melanoma cells, lines with higher expression had higher activities. 83 , and active c-Abl was localized in the cytoplasm, similar to BCRAbl and v-Abl.…”

Section: Mechanisms Of C-abl and Arg Activation In Solid Tumorsmentioning

confidence: 99%

“…83,84 In breast cancer cells, c-Abl and/or Arg were only highly active in some lines, and activation did not correlate with expression, whereas in melanoma cells, lines with higher expression had higher activities. 83 , and active c-Abl was localized in the cytoplasm, similar to BCRAbl and v-Abl. 84,85 Significantly, c-Abl/ Arg activities (assessed by phosphorylation of substrates, Crk/CrkL) were dramatically elevated in primary melanomas relative to benign nevi or normal skin.…”

Section: Mechanisms Of C-abl and Arg Activation In Solid Tumorsmentioning

confidence: 99%

“…83 Furthermore, IVIS metastatic fluorescence correlated with c-Abl/Arg activity (pCrk/ CrkL staining) in lung lesions from treated animals, indicating that nilotinib's anti-metastatic capability is linked to c-Abl/Arg inhibition. 83 Consistent with our data, c-Abl/Arg were shown to be activated in metastatic murine melanoma cells (B16F10) relative to its nonmetastatic counterpart (B16F0), and silencing c-Abl/Arg inhibited invasion and matrix degradation.…”

Section: Monographsmentioning

confidence: 99%

“…84,85 Significantly, c-Abl/ Arg activities (assessed by phosphorylation of substrates, Crk/CrkL) were dramatically elevated in primary melanomas relative to benign nevi or normal skin. 83,79 We showed that constitutively active IGF-1R, Her-2, EGFR, and/or SFKs contributed to c-Abl/Arg activation in melanoma and breast cancer lines, ruling out mutation as the method of activation and uncovering a novel activation mechanism in solid tumors (Fig. 1).…”

Section: Mechanisms Of C-abl and Arg Activation In Solid Tumorsmentioning

confidence: 99%

“…[107][108][109][110] Using imatinib, nilotinib, and 2 independent siRNAs, we showed that active c-Abl and/or Arg were required for proliferation, survival during nutrient deprivation, and Matrigel invasion of human melanoma cell lines. 83 Significantly, although both c-Abl and Arg were required for invasion, they promoted invasion via different mechanisms. Whereas c-Abl promoted invasion by increasing MMP-1 transcription via STAT3, Arg promoted invasion by increasing MMP-1, -3, and MT1-MMP transcription independent of STAT3 ( Fig.…”

Section: Melanomamentioning

confidence: 99%

See 4 more Smart Citations

Activation of Abl Family Kinases in Solid Tumors

Ganguly

Plattner

2012

Genes & Cancer

View full text Add to dashboard Cite

Although c-Abl and Arg non-receptor tyrosine kinases are well known for driving leukemia development, their role in solid tumors has not been appreciated until recently. Accumulating evidence now indicates that c-Abl and/or Arg are activated in some solid tumor cell lines via unique mechanisms that do not involve gene mutation/translocation, and c-Abl/Arg activation promotes matrix degradation, invasion, proliferation, tumorigenesis, and/ or metastasis, depending on the tumor type. However, some data suggest that c-Abl also may suppress invasion, proliferation, and tumorigenesis in certain cell contexts. Thus, c-Abl/Arg may serve as molecular switches that suppress proliferation and invasion in response to some stimuli (e.g., ephrins) or when inactive/regulated, or as promote invasion and proliferation in response to other signals (e.g., activated growth factor receptors, loss of inhibitor expression), which induce sustained activation. Clearly, more data are required to determine the extent and prevalence of c-Abl/Arg activation in primary tumors and during progression, and additional animal studies are needed to substantiate in vitro findings. Furthermore, c-Abl/ Arg inhibitors have been used in numerous solid tumor clinical trials; however, none of these trials were restricted to patients whose tumors expressed highly activated c-Abl/Arg (targeted trial). Targeted trials are critical for determining whether c-Abl/Arg inhibitors can be effective treatment options for patients whose tumors are driven by c-Abl/Arg.

show abstract

Section: Mechanisms Of C-abl and Arg Activation In Solid Tumorsmentioning

confidence: 99%

Section: Mechanisms Of C-abl and Arg Activation In Solid Tumorsmentioning

confidence: 99%

Section: Monographsmentioning

confidence: 99%

Section: Mechanisms Of C-abl and Arg Activation In Solid Tumorsmentioning

confidence: 99%

Section: Melanomamentioning

confidence: 99%

See 3 more Smart Citations

Activation of Abl Family Kinases in Solid Tumors

Ganguly

Plattner

2012

Genes & Cancer

View full text Add to dashboard Cite

show abstract

GAB1‐ABL1 fusions in tumors that have histologic overlap with NTRK‐rearranged spindle cell tumors

Choo

Rakheja

Davis

et al. 2021

Genes Chromosomes & Cancer

View full text Add to dashboard Cite

Fibroblastic spindle cell tumors are a heterogeneous group of rare soft tissue tumors that are increasingly recognized as associated with a variety of kinase gene fusions. We report two cases of GAB1‐ABL1 fusions in spindle cell tumors that histologically overlap with neurotrophic tyrosine receptor kinase (NTRK)‐rearranged spindle cell tumors. The first case occurred in a 76‐year‐old female who had a large deep‐seated spindle cell tumor composed of monotonous ovoid to spindle cells in a background of thick stromal collagen bands with prominent hyalinized vessels and inconspicuous mitoses (<1/10 HPF). Immunohistochemical stains showed co‐expression of S100 and CD34. A GAB1‐ABL1 fusion was detected by whole transcriptome RNA sequencing. The patient had a partial response to imatinib. The second case was previously described as a solitary fibrous tumor, occurring in a 9‐year‐old female with a cellular spindle cell tumor with patchy CD34 immunoexpression but no expression of S100. Upon clinicopathologic re‐review, including anchored multiplex next‐generation sequencing, a GAB1‐ABL1 fusion was identified. In summary, we report the first two cases of spindle cell tumors with variable expression of CD34 and/or S100, driven by GAB1‐ABL1 gene fusions with histologic overlap with NTRK‐rearranged spindle cell tumors, suggesting that ABL‐fusions may also be oncogenic drivers within this spectrum of tumors. These cases highlight the evolving understanding of fibroblastic spindle cell tumor biology and the utility of sequencing in identifying a targetable alteration.

show abstract

Potential protein markers for breast cancer recurrence: a retrospective cohort study

Plattner

Zhou

et al. 2018

Cancer Causes Control

View full text Add to dashboard Cite

Background We evaluated five key proteins involved in various cancer-related pathways and assessed their relation to breast cancer recurrence. Methods We used the Kentucky Cancer Registry to retrospectively identify primary invasive breast cancer cases (n=475) that were diagnosed and treated at University of Kentucky Medical Center between 2000 and 2007. Breast cancer recurrence was observed in 62 cases during the five-year followup after diagnosis. Protein expression or activity level was analyzed from surgery tissue using immunohistochemical assays. Results Compared to ER+/PR+/HER2- patients without recurrence, those with recurrence had higher TWIST expression (p=0.049) but lower ABL1/ABL2 activity (p=0.003) in primary tumors. We also found that triple-negative breast cancer patients with recurrence had higher SNAI1 expression compared to those without recurrence (p=0.03). After adjusting for potential confounders, the higher ABL1/ABL2 activity in primary tumors was associated with a decreased risk of recurrence (OR=0.72, 95%CI = 0.85-0.90) among ER+/PR+/HER2- patients. In addition, among patients with recurrence we observed that the activity level of ABL1/ABL2 was significantly increased in recurrent tumors compared to the matched primary tumors regardless of the subtype (p=0.013). Conclusions These findings provide evidence that the expression/activity level of various proteins may be differentially associated with risk of recurrence of breast tumor subtypes.

show abstract

c-Abl and Arg are activated in human primary melanomas, promote melanoma cell invasion via distinct pathways, and drive metastatic progression

Cited by 59 publications

References 51 publications

Activation of Abl Family Kinases in Solid Tumors

Activation of Abl Family Kinases in Solid Tumors

GAB1‐ABL1 fusions in tumors that have histologic overlap with NTRK‐rearranged spindle cell tumors

Potential protein markers for breast cancer recurrence: a retrospective cohort study

Contact Info

Product

Resources

About