Critical requirement of SOS1 for tumor development and microenvironment modulation in KRASG12D-driven lung adenocarcinoma

被引：17

作者：

Baltanas, Fernando C. ^{[1
,2
,3
,4
]}

Garcia-Navas, Rosula ^{[1
,2
]}

Rodriguez-Ramos, Pablo ^{[1
,2
]}

Calzada, Nuria ^{[1
,2
]}

Cuesta, Cristina ^{[5
]}

Borrajo, Javier ^{[6
]}

Fuentes-Mateos, Rocio ^{[1
,2
]}

Olarte-San Juan, Andrea ^{[1
,2
]}

Vidana, Nerea ^{[1
,2
]}

Castellano, Esther ^{[5
]}

Santos, Eugenio ^{[1
,2
]}

机构：

[1] Univ Salamanca, Inst Canc Mol & Cellular Biol, Canc Res Ctr, Lab 1,CSIC, Salamanca 37007, Spain

[2] CIBERONC, Salamanca 37007, Spain

[3] Univ Seville, CSIC, Virgen del Rocio Univ Hosp, Inst Biomed Seville IBiS, Seville, Spain

[4] Univ Seville, Dept Med Physiol & Biophys, Seville, Spain

[5] Univ Salamanca, Inst Canc Mol & Cellular Biol, Canc Res Ctr, Lab 5,CSIC, Salamanca 37007, Spain

[6] Univ Salamanca, Dept Biomed Sci & Diagnost, Salamanca 37007, Spain

来源：

NATURE COMMUNICATIONS | 2023年 / 14卷 / 01期

关键词：

K-RAS; CANCER; PROMOTES; KRAS; ACTIVATION;

D O I：

10.1038/s41467-023-41583-1

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The impact of genetic ablation of SOS1 or SOS2 is evaluated in a murine model of KRAS(G12D)-driven lung adenocarcinoma (LUAD). SOS2 ablation shows some protection during early stages but only SOS1 ablation causes significant, specific long term increase of survival/lifespan of the KRAS(G12D) mice associated to markedly reduced tumor burden and reduced populations of cancer-associated fibroblasts, macrophages and T-lymphocytes in the lung tumor microenvironment (TME). SOS1 ablation also causes specific shrinkage and regression of LUAD tumoral masses and components of the TME in pre-established KRAS(G12D) LUAD tumors. The critical requirement of SOS1 for KRAS(G12D)-driven LUAD is further confirmed by means of intravenous tail injection of KRAS(G12D) tumor cells into SOS1KO/KRASWT mice, or of SOS1-less, KRAS(G12D) tumor cells into wildtype mice. In silico analyses of human lung cancer databases support also the dominant role of SOS1 regarding tumor development and survival in LUAD patients. Our data indicate that SOS1 is critically required for development of KRAS(G12D)-driven LUAD and confirm the validity of this RAS-GEF activator as an actionable therapeutic target in KRAS mutant LUAD.

引用

页数：16

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