**9. Conclusions**

This chapter highlights the original involvement of *SRCIN1*/p140Cap in NB, providing evidence that *SRCIN1* gene expression may be exploited as a marker of good outcomes in NB (**Figure 7**). *SRCIN1* mRNA levels are clinically relevant in NB

#### **Figure 7.**

*Overview of* SRCIN1 *involvement in NB. The data reported here indicate a key causal role of* SRCIN1*/ p140Cap in dampening cell signaling, tumor growth, metastasis and drug sensitivity in NB cells, leading to a good outcome in NB patients.*

patients, with high levels of expression positively correlating with good prognosis and high survival rate. Of note, *SRCIN1* mRNA behaves as an independent risk factor, thus providing evidence that *SRCIN1* is a useful, additional marker for better stratifying NB patient cohorts.

Overall, the protein p140Cap acts as a tumor suppressor gene in NB tumors, dampening tumor volume and decreasing progression towards distant metastasis. This might occur because of an increased ability to undergo apoptosis and a decreased capability of p140Cap NB cells to proliferate *in vivo*. Tumor microenvironment could also play a role, as shown by decreased permeability of p140Cap tumor vessels, likely due to the increased presence of pericytes, as shown by their specific marker NG2 [93].

An urgent need in NB is to increase the five-year OS rate of high-risk NB patients, which is still less than 40% [94]. Despite emerging new therapies, the impact of treatments is very heavy for affected children, which can have serious consequences for years to come [95]. The data showing that p140Cap expressing NB have significantly increased sensitivity to low doses (10 nM concentration) of doxorubicin and etoposide, two drugs used in first line NB treatment, open new perspectives. Further, the fact that a combo treatment with Src inhibitors and low doses doxorubicin or etoposide, sensitize mock cells, reducing cell viability to that of p140Cap cells treated with chemotherapy alone, is an encouraging result. Therefore, it would be interesting to set combinatorial approaches with low doses of both chemotherapy drugs and specific inhibitors, including also the Jak2 pathway, to quantify the additional/synergistic effects. Further, to increase the understanding of the mechanism of action of p140Cap on the sensitization to specific drugs, it would be very useful to identify the vital molecular signaling mechanisms involved. To achieve these results, both automated platforms for cell viability and genome-wide CRISPR-CAS9 technology are largely available. In conclusion, we believe that these data demonstrate the potential clinical impact of SRCIN1/p140Cap expression and of p140Cap-regulated pathways in NB tumors. These results pave the way to include *SRCIN1* mRNA in the NB patients' prognostic status, as a key marker for patient outcome.

#### **Acknowledgements**

The figures and Tables have been adapted from ref. [43] Grasso et al., 2020. We give here appropriate acknowledgment to the original authors of this publication (Silvia Grasso, Melissa Alzona, Alessia Lamolinara, Andrea Saglietto, Federico Tommaso Bianchi, Sara Cabodi, Iris Chiara Salaroglio, Federica Fusella, Marzia Ognibene, Manuela Iezzi, Annalisa Pezzolo, Valeria Poli, Ferdinando Di Cunto, Alessandra Eva, Chiara Riganti, Luigi Varesio). This work was supported by AIRC (Associazione Italiana Ricerca Cancro) to PD (IG- 20107), Compagnia San Paolo, Torino, Progetto DEFLECT to PD; Fondazione CRT 2020.1798 to PD.

### **Conflict of interest**

There is no competing of interest to declare.

#### **Rights and permissions**

The article Grasso et al., [43] is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution

**91**

*The Scaffold Protein p140Cap as a Molecular Hub for Limiting Cancer Progression…*

and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article is included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/, as indicated in https://www.nature.com/articles/

*DOI: http://dx.doi.org/10.5772/intechopen.96383*

Abl Abelson Tyrosine-Protein Kinase

BDNF Brain-Derived Neurotrophic Factor BRCA1 BRCA1 DNA repair associated CAP Cas-associated protein

CDK4/6 cyclin D-cyclin-dependent kinase 4/6

cn-LOH copy-neutral Loss Of Heterozygosity

ERBB2 erb-b2 receptor tyrosine kinase 2 ERK extracellular signal-regulated kinase ERK5 Extracellular signal-regulated kinase 5

H2AX H2A histone family member X

IDP Intrinsic Disorder Protein IDR Intrinsically Disordered Regions

IHC Immunohistochemistry

MAX myc-associated factor X

*MYCN* MYCN proto-oncogene

Ki67 marker of proliferation Ki-67

MAPK mitogen-activated protein kinase

IL-6 Interleukin 6

JAK Janus kinase

LIN28B lin-28 homolog B

NB Neuroblastoma

FYN FYN oncogene related to SRC, FGR, YES

IC50 the half maximal inhibitory concentration

INSS International Neuroblastoma Staging System

MGMT O(6)-Methylguanine-DNA methyltransferase

AKT AKT serine/threonine kinase 1 ALK Anaplastic Lymphoma Kinase AML Acute myeloid leukemia Bcl-2 B-cell lymphoma 2 *Bcl-2* B-cell lymphoma gene 2

a-CGH array - Comparative Genomic Hybridization

CD31 platelet and endothelial cell adhesion molecule 1

EB3 microtubule associated protein RP/EB family member 3

s41418-019-0386-6

**Abbreviations**

CD105 endoglin

CI Combination Index

EFS event free survival

FAK focal adhesion kinase

Csk C-terminal Src kinase DS Dendritic spines

*The Scaffold Protein p140Cap as a Molecular Hub for Limiting Cancer Progression… DOI: http://dx.doi.org/10.5772/intechopen.96383*

and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article is included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/, as indicated in https://www.nature.com/articles/ s41418-019-0386-6
