As one of the most common forms of cancer, lung cancers present as a collection of different histological subtypes. These subtypes are characterized by distinct sets of driver mutations and phenotypic appearance, and they often show varying degrees of heterogenicity, aggressiveness, and response/resistance to therapy. Intriguingly, lung cancers are also capable of showing features of multiple subtypes or converting from one subtype to another. The intertumoral and intratumoral heterogeneity of lung cancers as well as incidences of subtype transdifferentiation raise the question of to what extent the tumor characteristics are dictated by the cell of origin rather than the acquired driver lesions. We provide here an overview of the studies in experimental mouse models that try to address this question. These studies convincingly show that both the cell of origin and the genetic driver lesions play a critical role in shaping the phenotypes of lung tumors. However, they also illustrate that there is far from a direct one-to-one relationship between the cell of origin and the cancer subtype, as most epithelial cells can be reprogrammed toward diverse lung cancer fates when exposed to the appropriate set of driver mutations.

Highlights d PKA inhibition or PP2A activation inhibits SCLC growth d The GNAS/PKA axis promotes SCLC growth d Proteomics studies uncover widespread PKA targets and downstream signaling networks d PKA activation promotes a cancer stem cell state

Recently, energy- and intensity-modulated electron radiotherapy (MERT) has garnered a growing interest for the treatment of superficial targets. In this work. we carried out a comparative dosimetry study to evaluate MERT, photon beam intensity-modulated radiation therapy (IMRT) and conventional tangential photon beams for the treatment of breast cancer. A Monte Carlo based treatment planning system has been investigated, which consists of a set of software tools to perform accurate dose calculation, treatment optimization, leaf sequencing and plan analysis. We have compared breast treatment plans generated using this home-grown treatment optimization and dose calculation software forthese treatment techniques. The MERT plans were planned with up to two gantry angles and four nominal energies (6, 9, 12 and 16 MeV). The tangential photon treatment plans were planned with 6 MV wedged photon beams. The IMRT plans were planned using both multiple-gantry 6 MV photon beams or two 6 MV tangential beams. Our results show that tangential IMRT can reduce the dose to the lung, heart and contralateral breast compared to conventional tangential wedged beams (up to 50% reduction in high dose volume or 5 Gy in the maximum dose). MERT can reduce the maximum dose to the lung by up to 20 Gy and to the heart by up to 35 Gy compared to conventional tangential wedged beams. Multiple beam angle IMRT can significantly reduce the maximum dose to the lung and heart (up to 20 Gy) but it induces low and medium doses to a large volume of normal tissues including lung, heart and contralateral breast. It is concluded that MERT has superior capabilities to achieve dose conformity both laterally and in the depth direction, which will be well suited for treating superficial targets such as breast cancer.

Levels of cyclin D increase upon AMBRA1 lossAMBRA1-knockout cells showed increased phosphorylation of RB and cell-cycle gene expression with palbociclib treatment compared to control cells (Fig. 1e, Extended Data Fig. 1p, q), which suggested an increased activity of cyclin-dependent kinases. Accordingly, we observed a notable increase of proteins in the cyclin-D family and

High-grade gliomas (HGGs) include the most common and the most aggressive primary brain tumor of adults and children. Despite multimodality treatment, most high-grade gliomas eventually recur and are ultimately incurable. Several studies suggest that the initiation, progression, and recurrence of gliomas are driven, at least partly, by cancer stem-like cells. A defining characteristic of these cancer stem-like cells is their capacity to self-renew. We have identified a hypoxia-induced pathway that utilizes the Hypoxia Inducible Factor 1α (HIF-1α) transcription factor and the JAK1/2-STAT3 (Janus Kinase 1/2 - Signal Transducer and Activator of Transcription 3) axis to enhance the self-renewal of glioma stem-like cells. Hypoxia is a commonly found pathologic feature of HGGs. Under hypoxic conditions, HIF-1α levels are greatly increased in glioma stem-like cells. Increased HIF-1α activates the JAK1/2-STAT3 axis and enhances tumor stem-like cell self-renewal. Our data further demonstrate the importance of Vascular Endothelial Growth Factor (VEGF) secretion for this pathway of hypoxia-mediated self-renewal. Brefeldin A and EHT-1864, agents that significantly inhibit VEGF secretion, decreased stem cell self-renewal, inhibited tumor growth, and increased the survival of mice allografted with S100β-v-erbB/p53−/− glioma stem-like cells. These agents also inhibit the expression of a hypoxia gene expression signature that is associated with decreased survival of HGG patients. These findings suggest that targeting the secretion of extracellular, autocrine/paracrine mediators of glioma stem-like cell self-renewal could potentially contribute to the treatment of HGGs.