Malignant transformation entails important changes in the control of cell proliferation through the rewiring of selected signaling pathways. Cancer cells then become very dependent on the proper function of those pathways, and their inhibition offers therapeutic opportunities. Here we identify the stress kinase p38α as a nononcogenic signaling molecule that enables the progression of Kras^G12V-driven lung cancer. We demonstrate in vivo that, despite acting as a tumor suppressor in healthy alveolar progenitor cells, p38α contributes to the proliferation and malignization of lung cancer epithelial cells. We show that high expression levels of p38α correlate with poor survival in lung adenocarcinoma patients, and that genetic or chemical inhibition of p38α halts tumor growth in lung cancer mouse models. Moreover, we reveal a lung cancer epithelial cell-autonomous function for p38α promoting the expression of TIMP-1, which in turn stimulates cell proliferation in an autocrine manner. Altogether, our results suggest that epithelial p38α promotes Kras^G12V-driven lung cancer progression via maintenance of cellular self-growth stimulatory signals. Significance Nearly half of the cases of lung cancer bear mutations in the RAS pathway. Unfortunately, no specific drugs are available to successfully target many RAS-driven tumors that are not surgically resectable. Despite the sound rationale for targeting oncogene products for cancer therapeutics, this often leads to development of resistance. As an alternative, nononcogenic proteins can sometimes facilitate tumor progression, and, even though they are neither mutated nor overexpressed in the malignant cells, they may represent potential targets for anticancer therapies. We have found that nononcogenic signaling through p38α plays a tumor-promoting function in lung adenocarcinoma epithelial cells by inducing the expression of TIMP-1, a growth factor-like protein. We propose that p38α inhibition could be therapeutically useful.

Breast cancer is a complex and heterogeneous disease that displays diverse molecular subtypes and clinical outcomes. Although it is known that the location of tumors can affect their biological behavior, the underlying mechanisms are not fully understood. In our previous study, we found a differential methylation profile and membrane potential between left (L)- and right (R)-sided breast tumors. In this current study, we aimed to identify the ion channels responsible for this phenomenon and determine any associated phenotypic features. To achieve this, experiments were conducted in mammary tumors in mice, human patient samples, and with data from public datasets. The results revealed that L-sided tumors have a more depolarized state than R-sided. We identified a 6-ion channel-gene signature (CACNA1C, CACNA2D2, CACNB2, KCNJ11, SCN3A, and SCN3B) associated with the side: L-tumors exhibit lower expression levels than R-tumors. Additionally, in silico analyses show that the signature correlates inversely with DNA methylation writers and with key biological processes involved in cancer progression, such as proliferation and stemness. The signature also correlates inversely with patient survival rates. In an in vivo mouse model, we confirmed that KI67 and CD44 markers were increased in L-sided tumors and a similar tendency for KI67 was found in patient L-tumors. Overall, this study provides new insights into the potential impact of anatomical location on breast cancer biology and highlights the need for further investigation into possible differential treatment options.

Melanoma is one of the deathliest cancers worldwide and its incidence is reaching epidemic proportions. It is characterized by intrinsic chemo-resistance, low response rates to treatment and high metastatic potential. Because of this, new therapeutic options are permanently required. Tessaria absinthioides (Hook. & Arn.) DC. is a traditional medicinal plant, with antioxidant, selective cytotoxicity and anti-colorectal cancer evidence-based properties. This study aims to demonstrate the antitumoral and antimetastatic effects of T. absinthioides decoction (DETa), correlating in vitro and in vivo activities in a murine melanoma model. DETa was assayed on B16F0 murine non-metastatic cells to determine cytotoxicity and clonogenicity; while, in the B16F10 metastatic siblings, adhesion, wound healing migration and Boyden chamber invasion were studied. The ex vivo intestinal-sac model was used to quantify DETa bioavailability. Meanwhile, in C57BL6/wt mice, DETa was orally administered to evaluate its antitumoral and antimetastatic activities. DETa induced cytotoxicity in a dose- and time-dependent manner, affecting the long-term clonogenic survival, as well as the processes of adhesion and migration. Then, the intestinal absorption of DETa phenolics was proven, while the systemic anti-tumoral and anti-metastatic activities of DETa were confirmed. Results demonstrated that DETa has antimelanoma activity promoting this botanical compound as a relevant agent for cancer research and treatment.

Breast cancer is a complex and heterogeneous disease that displays diverse molecular subtypes and clinical outcomes. Although it is known that the location of tumors can affect their biological behavior, the underlying mechanisms are not fully understood. In our previous study, we found a differential methylation profile and membrane potential between left (L) and right (R)-sided breast tumors. In this current study, we aimed to identify the ion channels responsible for this phenomenon and determine any associated phenotypic features. To achieve this, experiments were conducted in mammary tumors in mice, human patient samples, and with data from public datasets. The results revealed that L-sided tumors have a more depolarized state than R-ones. We identified a 6-ion channel-gene signature (CACNA1C, CACNA2D2, CACNB2, KCNJ11, SCN3A, and SCN3B) associated with side: L-tumors exhibit lower expression levels than R-ones. Additionally, in silico analyses show that the signature correlates inversely with DNA methylation writers and with key biological processes involved in cancer progression, such as proliferation and stemness. The signature also correlates inversely with patients’ survival rates. In an in vivo mouse model, we confirmed that KI67 and CD44 markers were increased in L-sided tumors and similar tendency for KI67 was found in patient L-tumors. Overall, this study provides new insights into the potential impact of anatomical location on breast cancer biology and highlights the need for further investigation into possible differential treatment options.

Mitochondrial diseases, caused by mutations in nuclear or mitochondrial DNA (mtDNA), have limited treatment options. For mtDNA mutations, reducing the mutant-to-wild-type mtDNA ratio (heteroplasmy shift) is a promising strategy, though it currently faces challenges. Previous research showed that severe mitochondrial dysfunction triggers an adaptive nuclear epigenetic response, through changes in DNA methylation, absent or less important for subtle mitochondrial impairment. Therefore, we hypothesized that targeting nuclear DNA methylation could impair cells with high-mutant mtDNA load while sparing those with lower levels, reducing overall heteroplasmy. Using cybrid models harboring two disease-causing mtDNA mutations—m.13513 G > A and m.8344 A > G—at varying heteroplasmies, we discovered that both the mutation type and load distinctly shape the nuclear DNA methylome. We found this methylation pattern critical for the survival of high-heteroplasmy cells but not for low-heteroplasmy ones. Treatment with FDA-approved DNA methylation inhibitors selectively impacted high-heteroplasmy cybrids and reduced heteroplasmy. These findings were validated in cultured cells and xenografts. Our findings highlight nuclear DNA methylation as a key regulator of heteroplasmic cell survival and a potential therapeutic target for mitochondrial diseases.