RESUMO
Chromosomal instability (CIN) is a hallmark of cancer aggressiveness, providing genetic plasticity and tumor heterogeneity that allows the tumor to evolve and adapt to stress conditions. CIN is considered a cancer therapeutic biomarker because healthy cells do not exhibit CIN. Despite recent efforts to identify therapeutic strategies related to CIN, the results obtained have been very limited. CIN is characterized by a genetic signature where a collection of genes, mostly mitotic regulators, are overexpressed in CIN-positive tumors, providing aggressiveness and poor prognosis. We attempted to identify new therapeutic strategies related to CIN genes by performing a drug screen, using cells that individually express CIN-associated genes in an inducible manner. We find that the overexpression of targeting protein for Xklp2 (TPX2) enhances sensitivity to the proto-oncogene c-Src (SRC) inhibitor dasatinib due to activation of the Yes-associated protein 1 (YAP) pathway. Furthermore, using breast cancer data from The Cancer Genome Atlas (TCGA) and a cohort of cancer-derived patient samples, we find that both TPX2 overexpression and YAP activation are present in a significant percentage of cancer tumor samples and are associated with poor prognosis; therefore, they are putative biomarkers for selection for dasatinib therapy.
RESUMO
Gasdermins (GSDM) genes play complex roles in inflammatory diseases and cancer. Gasdermin-B (GSDMB) is frequently upregulated in human cancers, especially in HER2-amplified breast carcinomas, and can promote diverse pro-tumor functions (invasion, metastasis, therapy-resistance). In particular, the GSDMB shortest translated variant (isoform 2; GSDMB2) increases aggressive behavior in breast cancer cells. Paradoxically, GSDMB can also have tumor suppressor (cell death induction) effects in specific biological contexts. However, whether GSDMB has inherent oncogenic, or tumor suppressor function in vivo has not been demonstrated yet in preclinical mouse models, since mice lack GSDMB orthologue. Therefore, to decipher GSDMB cancer functions in vivo we first generated a novel knock-in mouse model (R26-GB2) ubiquitously expressing human GSDMB2. The comprehensive histopathological analysis of multiple tissues from 75 animals showed that nucleus-cytoplasmic GSDMB2 expression did not clearly affect the overall frequency nor the histology of spontaneous neoplasias (mostly lung carcinomas), but associated with reduced incidence of gastric tumors, compared to wildtype animals. Next, to assess specifically the GSDMB2 roles in breast cancer, we generated two additional double transgenic mouse models, that co-express GSDMB2 with either the HER2/NEU oncogene (R26-GB2/MMTV-NEU mice) or the Polyoma middle-T antigen (R26-GB2/MMTV-PyMT) in breast tumors. Consistent with the pro-tumor effect of GSDMB in HER2+ human breast carcinomas, R26-GB2/MMTV-NEU GSDMB2-positive mice have double breast cancer incidence than wildtype animals. By contrast, in the R26-GB2/MMTV-PyMT model of fast growing and highly metastatic mammary tumors, GSDMB2 expression did not significantly influence cancer development nor metastatic potential. In conclusion, our data prove that GSDMB2 in vivo pro-tumor effect is evidenced only in specific biological contexts (in concert with the HER2 oncogene), while GSDMB2 alone does not have overall intrinsic oncogenic potential in genetically modified mice. Our novel models are useful to identify the precise stimuli and molecular mechanisms governing GSDMB functions in neoplasias and can be the basis for the future development of additional tissue-specific and context-dependent cancer models.
Assuntos
Neoplasias do Sistema Nervoso Central/patologia , Evolução Clonal , Linfonodos/patologia , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/patologia , Sequência de Bases , Neoplasias do Sistema Nervoso Central/complicações , Neoplasias do Sistema Nervoso Central/genética , Feminino , Rearranjo Gênico , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Linfoma Folicular/complicações , Linfoma Folicular/genética , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/genética , Pessoa de Meia-Idade , Prognóstico , Homologia de SequênciaRESUMO
Paciente varón de 30 años que consultó por una lesión en el 5.° dedo del pie derecho con afectación cutánea del pulpejo y de todo el borde externo. Macroscópicamente se trataba de una lesión violácea con superficie queratósica de 1cm. En la radiografía simple se objetivó un aumento de partes blandas, de posible origen vascular. La resonancia mostró una lesión que erosionaba la cortical de la falange distal, de señal muy hiperintensa compatible con malformación vascular de bajo flujo. Se realizó extirpación de la lesión mediante amputación de la falange distal y a nivel histológico se observó una lesión formada por vasos de tipo venoso y tipo linfático que eran D2-40 positivos. En las malformaciones vasculares la participación cutánea, aunque sea mínima, puede esconder una importante afectación profunda. Cuando asientan sobre planos óseos hay que descartar la erosión de la cortical del hueso subyacente (AU)
A 30 year old male presented with a cutaneous lesion on the distal area of the 5th toe with involvement of the outer edges. Macroscopically, it was a 1cm violaceous and keratotic lesion. Radiography showed an increase in soft tissue, possibly due to a vascular lesion. MRI showed a hyper-intense signal with erosion of the distal phalanx compatible with a low-flow vascular malformation. The distal phalanx was amputated. Histopathology revealed a lesion formed by venous and D2-40 positive lymphatic vessels. This case highlights the fact that even minimal skin involvement in vascular malformations may conceal an important deeper lesion, such as erosion of the cortical bone (AU)
Assuntos
Humanos , Masculino , Adulto , Malformações Vasculares/patologia , Dedos do Pé/anormalidades , Vasos Linfáticos/anormalidades , Malformações Vasculares/cirurgia , Anticorpos Monoclonais/análise , Osso e Ossos/patologiaRESUMO
A 30 year old male presented with a cutaneous lesion on the distal area of the 5th toe with involvement of the outer edges. Macroscopically, it was a 1cm violaceous and keratotic lesion. Radiography showed an increase in soft tissue, possibly due to a vascular lesion. MRI showed a hyper-intense signal with erosion of the distal phalanx compatible with a low-flow vascular malformation. The distal phalanx was amputated. Histopathology revealed a lesion formed by venous and D2-40 positive lymphatic vessels. This case highlights the fact that even minimal skin involvement in vascular malformations may conceal an important deeper lesion, such as erosion of the cortical bone.
